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Terça-feira, 21.07.15

Genetics May Determine Success of HIV Vaccines

 

Genetics May Determine Success of HIV Vaccines

 
Genetics May Determine Success of HIV Vaccines
Genetics May Determine Success of HIV Vaccines

HealthDay News — Genetics may help determine whether an HIV vaccine will work, a new study published in Science Translational Medicinesuggests. 

Daniel Geraghty, PhD, a scientist with the Fred Hutchinson Cancer Research Center in Seattle, and colleagues analyzed results of a vaccine trial in Thailand that concluded in 2009. Over 42 months, the vaccine protected against HIV infection 31% of the time.

The new analysis revealed that the vaccine was effective only in people with a specific gene variant. In others, the vaccine appeared to raise the risk of infection. To better understand this discrepancy, the researchers analyzed the HLA genotypes of 760 study participants. Those with an HLA gene variant called DPB1*13 were protected 71% of the time, they found.

"The gene identified in this study is one of those that has long been known to be directly involved in the immune response to infection," Geraghty, president and CEO of Scisco Genetics, told HealthDay. It's essential to a process that helps cells tell the immune system if they're healthy or infected, he explained. The genetic variation is common, he added. 

Meanwhile, another genetic variation (DQB1*06)  — one the researchers say is more common in the general population than in Thailand — made infection more likely.

Reference

  1. Prentice HA et al. Sci Transl Med. 2015; doi:10.1126/scitranslmed.aab4005. 

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por cyto às 18:54

Terça-feira, 21.07.15

Postoperative Radiation Therapy for Endometrial Cancer

 

Postoperative Radiation Therapy for Endometrial Cancer: American Society of Clinical Oncology Clinical Practice Guideline Endorsement of the American Society for Radiation Oncology Evidence-Based Guideline

  1. Larissa A. Meyer,
  2. Kari Bohlke,
  3. Matthew A. Powell,
  4. Amanda N. Fader,
  5. Gregg E. Franklin,
  6. Larissa J. Lee,
  7. Daniela Matei,
  8. Lourie Coallier and
  9. Alexi A. Wright

+Author Affiliations

  1. Larissa A. Meyer, University of Texas MD Anderson Cancer Center, Houston, TX; Kari Bohlke, American Society of Clinical Oncology, Alexandria, VA; Matthew A. Powell, Washington University School of Medicine, St Louis, MO; Amanda N. Fader, Kelly Gynecologic Oncology Service, Johns Hopkins Hospital, Baltimore, MD; Gregg E. Franklin, New Mexico Cancer Center, Albuquerque, NM; Larissa J. Lee, Brigham and Women's Hospital, Dana-Farber Cancer Institute; Alexi A. Wright, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA; Daniela Matei, Indiana University School of Medicine, Indianapolis, IN; and Lourie Coallier, patient representative, Stanford, CA.
  1. Corresponding author: American Society of Clinical Oncology, 2318 Mill Rd, Suite 800, Alexandria, VA 22314; e-mail: guidelines@asco.org

Abstract

Purpose To provide guidance on the role of adjuvant radiation therapy in the treatment of endometrial cancer.

Methods “The Role of Postoperative Radiation Therapy for Endometrial Cancer: An ASTRO Evidence-Based Guideline” by Klopp et al, published in 2014 in Practical Radiation Oncology, was reviewed for developmental rigor by methodologists. The American Society for Radiation Oncology (ASTRO) guideline content and recommendations were further reviewed by the American Society of Clinical Oncology (ASCO) Endorsement Panel.

Results The ASCO Endorsement Panel determined that the recommendations from the ASTRO guideline are clear, thorough, and based on the most relevant scientific evidence. ASCO endorsed the ASTRO guideline with several qualifying statements.

Recommendations Surveillance without adjuvant radiation therapy is a reasonable option for women without residual disease in the hysterectomy specimen and for women with grade 1 or 2 cancer and < 50% myometrial invasion, especially when no other high-risk features are present. For women with grade 1 or 2 cancer and ≥ 50% myometrial invasion or grade 3 cancer and < 50% myometrial invasion, vaginal brachytherapy is as effective as pelvic radiation therapy at preventing vaginal recurrence and is preferred. Patients with grade 3 cancer and ≥ 50% myometrial invasion or cervical stroma invasion may benefit from pelvic radiation to prevent pelvic recurrence. For women with high-risk early-stage disease and advanced disease, the ASCO Endorsement Panel added qualifying statements to the ASTRO recommendations to provide stronger statements in favor of chemotherapy (with or without radiation therapy).

INTRODUCTION

Endometrial cancer is the most common gynecologic cancer among women in the United States, with roughly 54,000 new cases expected in 2015.1 Worldwide, endometrial cancer is the second most common gynecologic cancer (after cervical cancer) and the sixth most common cancer overall among women.2

Surgery is the primary treatment for endometrial cancer, and many women with early-stage endometrial cancer and a low risk of cancer recurrence require no additional treatment.3,4 Adjuvant treatment for women with an intermediate or high risk of recurrence continues to evolve, and options include radiation therapy, chemotherapy, or a combination of these modalities. To provide guidance on the use of postoperative radiation therapy for endometrial cancer, the American Society for Radiation Oncology (ASTRO) published evidence-based recommendations inPractical Radiation Oncology in 2014.5

The purpose of this American Society of Clinical Oncology (ASCO) guideline is to critically appraise and endorse the ASTRO guideline on postoperative radiation therapy for endometrial cancer. This endorsement reinforces the recommendations provided in the ASTRO guideline and acknowledges the effort put forth by ASTRO to produce an evidence-based guideline informing practitioners who care for women with endometrial cancer. The ASTRO recommendations are listed in the Bottom Line Box, with qualifying statements from the ASCO Endorsement Panel. The full ASTRO guideline is available at www.practicalradonc.org/article/S1879-8500(14)00005-8/fulltext, with supplemental material available at www.practicalradonc.org/cms/attachment/2014676400/2036188629/mmc1.pdf.

THE BOTTOM LINE

The American Society of Clinical Oncology (ASCO) endorses “The Role of Postoperative Radiation Therapy for Endometrial Cancer: An ASTRO Evidence-Based Guideline,” With Qualifying Statements

Guideline Questions

After surgery for endometrioid endometrial cancer, which women require no additional therapy? Which women should receive vaginal cuff brachytherapy, external-beam radiation therapy, or multimodality treatment?

Target Population
  • Women who have had surgery for endometrial cancer

Target Audience
  • Medical oncologists, gynecologic oncologists, radiation oncologists, and surgical oncologists

Methods

An ASCO Endorsement Panel was convened to consider endorsing “The Role of Postoperative Radiation Therapy for Endometrial Cancer: An ASTRO Evidence-Based Guideline.” The American Society for Radiation Oncology (ASTRO) guideline was based on a systematic review of the medical literature. The ASCO Endorsement Panel considered the methodology employed in the ASTRO guideline and carefully reviewed the ASTRO guideline content to determine appropriateness for ASCO endorsement.

Recommendations

ASTRO recommendations are listed here, with qualifying statements added by the ASCO panel listed in bold italics.*

Which patients with endometrioid endometrial cancer require no additional therapy after hysterectomy?

  • Following total abdominal hysterectomy with or without node dissection, no radiation therapy is a reasonable option for patients without residual disease in the hysterectomy specimen, despite positive biopsy (despite a positive prehysterectomy biopsy of any grade).

  • Following total abdominal hysterectomy with or without node dissection, no radiation therapy is a reasonable option for patients with grade 1 or 2 cancers with either no invasion or < 50% myometrial invasion.

  • Vaginal cuff brachytherapy may be considered in patients with negative node dissection with grade 3 tumor without myometrial invasion.

  • Vaginal cuff brachytherapy may be considered in patients with negative node dissection with grade 1 or 2 tumors with < 50% myometrial invasion and higher-risk features, such as age > 60 and/or LVSI [lymphovascular space invasion].

Which patients with endometrioid endometrial cancer should receive vaginal cuff irradiation?

  • Vaginal cuff brachytherapy is as effective as pelvic radiation at preventing vaginal recurrence for patients with: (1) grade 1 or 2 tumors with 50% myometrial invasion or (2) grade 3 tumors with < 50% myometrial invasion.

  • Vaginal cuff brachytherapy is preferred to pelvic radiation in patients with the above risk factors, particularly in patients who have had comprehensive nodal assessment.

Which women should receive postoperative external beam radiation?

  • Patients with grade 3 cancer with ≥ 50% myometrial invasion or cervical stroma invasion (of any grade; personal communication, A. Klopp, February 2015) may benefit from pelvic radiation to reduce the risk of pelvic recurrence.

  • Patients with grade 1 or 2 tumors with ≥ 50% myometrial invasion may also benefit from pelvic radiation to reduce pelvic recurrence if other risk factors are present, such as age > 60 years and/or LVSI.Vaginal brachytherapy may be a better option for patients with these features, especially if surgical staging was adequate, and nodes were negative.

  • The best available evidence at this time suggests that reasonable options for adjuvant treatment of patients with positive nodes or involved uterine serosa, ovaries/fallopian tubes, vagina, bladder, or rectum include external beam radiation therapy, as well as adjuvant chemotherapy. The best evidence for this population supports the use of chemotherapy, but consideration of external beam radiation therapy is reasonable.

  • Chemotherapy without external beam radiation may be considered for some patients with positive nodes or involved uterine serosa, ovaries/fallopian tubes, vagina, bladder, or rectum based on pathologic risk factors for pelvic recurrence.

  • Radiation therapy without chemotherapy may be considered for some patients with positive nodes or involved uterine serosa, ovaries/fallopian tubes, vagina, bladder, or rectum based on pathologic risk factors for pelvic recurrence. Patients receiving chemotherapy seem to have improved survival compared with radiation therapy alone.

When should brachytherapy be used in addition to external beam radiation?

  • Prospective data are lacking to validate the use of vaginal brachytherapy after pelvic radiation, and most retrospective studies show no evidence of a benefit, albeit with small patient numbers. Use of vaginal brachytherapy in patients also undergoing pelvic external beam radiation is not generally warranted, unless risk factors for vaginal recurrence are present.

How should radiation therapy and chemotherapy be integrated in the management of stage I to III endometrioid endometrial cancer?

  • The best available evidence suggests that concurrent chemoradiation followed by adjuvant chemotherapy is indicated for patients with positive nodes or involved uterine serosa, ovaries/fallopian tubes, vagina, bladder, or rectum. Evidence regarding concurrent chemoradiation is limited at this time, and this recommendation is based on expert opinion; we anticipate level-one evidence from upcoming prospective randomized clinical trials (GOG 0258 and PORTEC-3). Chemotherapy may also be considered in certain patients with high-risk early-stage endometrial cancer, and clinical trials addressing this question are under way.

  • Alternative sequencing strategies with external beam radiation and chemotherapy are also acceptable. Prospective trials have examined sequential radiation therapy and chemotherapy. Evidence supporting sandwich-type therapy is currentlylimited.

Additional Resources

More information, including a Methodology Supplement, is available atwww.asco.org/endorsements/endometrial. Patient information is available atwww.cancer.net. Full text of “The Role of Postoperative Radiation Therapy for Endometrial Cancer: Executive Summary of an American Society for Radiation Oncology Evidence-Based Guideline” is available atwww.practicalradonc.org/article/S1879-8500(14)00005-8/fulltext, with supplemental material available atwww.practicalradonc.org/cms/attachment/2014676400/2036188629/mmc1.pdf. These publications include information about the strength of each recommendation and the quality of the evidence.

ASCO believes that cancer clinical trials are vital to inform medical decisions and improve cancer care and that all patients should have the opportunity to participate.

* Recommendations reprinted from Klopp A et al, Practical Radiation Oncology, 4:137-144, 2014, with permission from Elsevier.

OVERVIEW OF THE ASCO GUIDELINE ENDORSEMENT PROCESS

ASCO has policies and procedures for endorsing practice guidelines that have been developed by other professional organizations. The goal of guideline endorsement is to increase the number of high-quality, ASCO-vetted guidelines available to the ASCO membership. The ASCO endorsement process involves an assessment by ASCO staff of candidate guidelines for methodologic quality using the Rigour of Development subscale of the Appraisal of Guidelines for Research and Evaluation II (AGREE II) instrument. (Methodology Supplement provides more detail.)

Disclaimer

The clinical practice guideline and other guidance published herein are provided by ASCO to assist providers in clinical decision making. The information herein should not be relied on as being complete or accurate, nor should it be considered as inclusive of all proper treatments or methods of care or as a statement of the standard of care. With the rapid development of scientific knowledge, new evidence may emerge between the time information is developed and when it is published or read. The information is not continually updated and may not reflect the most recent evidence. The information addresses only the topics specifically identified herein and is not applicable to other interventions, diseases, or stages of diseases. This information does not mandate any particular course of medical care. Furthermore, the information is not intended to substitute for the independent professional judgment of the treating provider, because the information does not account for individual variation among patients. Recommendations reflect high, moderate, or low confidence that the recommendation reflects the net effect of a given course of action. The use of words like “must,” “must not,” “should,” and “should not” indicates that a course of action is recommended or not recommended for either most or many patients, but there is latitude for the treating physician to select other courses of action in individual cases. In all cases, the selected course of action should be considered by the treating provider in the context of treating the individual patient. Use of the information is voluntary. ASCO provides this information on an as-is basis and makes no warranty, express or implied, regarding the information. ASCO specifically disclaims any warranties of merchantability or fitness for a particular use or purpose. ASCO assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of this information or for any errors or omissions.

Guideline and Conflicts of Interest

The ASCO Endorsement Panel (Appendix Table A1, online only) was assembled in accordance with the ASCO Conflicts of Interest Management Procedures for Clinical Practice Guidelines (summarized at http://www.asco.org/rwc). Members of the panel completed the ASCO disclosure form, which requires disclosure of financial and other interests that are relevant to the subject matter of the guideline, including relationships with commercial entities that are reasonably likely to experience direct regulatory or commercial impact as a result of promulgation of the guideline. Categories for disclosure include Employment; Leadership; Stock or Other Ownership; Honoraria, Consulting or Advisory Role; Speaker's Bureau; Research Funding; Patents, Royalties, Other Intellectual Property; Expert Testimony; Travel, Accommodations, Expenses; and Other Relationships. In accordance with these procedures, the majority of the members of the panel did not disclose any such relationships.

CLINICAL QUESTIONS AND TARGET POPULATION

The ASTRO guideline addressed five key questions: (1) Which patients with endometrioid endometrial cancer require no additional therapy after hysterectomy? (2) Which patients with endometrioid endometrial cancer should receive vaginal cuff radiation? (3) Which women with early-stage endometrial cancer should receive postoperative external beam radiation therapy (EBRT), and which women with stage III to IVA endometrial cancer should receive postoperative EBRT? (4) When should brachytherapy be used in addition to EBRT? (5) How should radiation therapy and chemotherapy be integrated in the management of endometrial cancer? The clinical questions and corresponding recommendations are provided in the Bottom Line Box.

The target population for the ASTRO guideline is women with stage I to IV endometrial cancer of any histologic grade.

SUMMARY OF THE ASTRO GUIDELINE DEVELOPMENT METHODOLOGY

The ASTRO guideline was developed by an expert panel that included radiation oncologists, gynecologic oncologists, and radiation physicists in both academic and private practice settings. The literature search of MEDLINE PubMed, EMBASE, and the Specialized Register of the Cochrane Gynaecological Cancer Review Group spanned the period from 1980 through 2011. Details of the search strategies and the study inclusion criteria and outcomes of interest are available atwww.practicalradonc.org/cms/attachment/2014676400/2036188629/mmc1.pdf. The search identified 330 studies that were fully extracted to provide supportive evidence for the guideline recommendations.

Guideline statements were developed based on the body of evidence categorized by the American College of Physicians strength-of-evidence rating. The level of consensus among the panelists was evaluated using a modified Delphi approach. An initial draft of the guideline was reviewed by three expert reviewers, and a revised draft was made available for public comment.

RESULTS OF THE ASCO METHODOLOGY REVIEW

The methodology review of the ASTRO guideline was completed independently by two ASCO guideline staff members using the Rigour of Development subscale from the AGREE II instrument. Detailed results of the scoring for this guideline are available in the Methodology Supplement. Overall, the ASTRO guideline scored 68%. Scores were generally high, with the exception of those for procedures for updating. The preliminary ASCO content reviewers of the ASTRO guideline, as well as the ASCO Endorsement Panel, found the recommendations well supported in the original guideline. Each section was clear and well referenced from the systematic review.

This is the most recent information as of the publication date. For updates, the most recent information, and to submit new evidence, please visitwww.asco.org/endorsements/endometrial and the ASCO Guidelines Wiki (http://www.asco.org/guidelineswiki).

METHODS AND RESULTS OF THE ASCO UPDATED LITERATURE REVIEW

ASCO guidelines staff conducted an updated literature search. MEDLINE was searched for entries dating from September 1, 2011, to September 10, 2014 (inclusive). The search was restricted to articles published in English and to systematic reviews, meta-analyses, and randomized controlled trials.

The updated search yielded 68 records. A review of these results by the ASCO Endorsement Panel revealed no new evidence that would warrant substantive modification of the ASTRO recommendations. To help inform the discussion and qualifying statements, eight publications from the ASTRO systematic review,613 four publications from the updated literature search,1417 and two additional publications identified by the ASCO Endorsement Panel and reviewers18,19 are discussed.

RESULTS OF THE ASCO CONTENT REVIEW

The ASCO Endorsement Panel reviewed the ASTRO guideline and concurs that the recommendations are clear, thorough, based on the most relevant scientific evidence in this content area, and present options that will be acceptable to patients. Overall, the ASCO Endorsement Panel agrees with the recommendations as stated in the guideline, with several qualifications discussed in the next section.

DISCUSSION

The ASCO Endorsement Panel emphasized a few points regarding postoperative therapy for endometrial cancer:

Lack of a survival benefit with EBRT in early-stage disease.

In a 2012 Cochrane review of adjuvant radiotherapy for stage I endometrial cancer, EBRT reduced the risk of locoregional recurrence (hazard ratio [HR], 0.36; 95% CI, 0.25 to 0.52) but did not have a statistically significant effect on overall survival (HR, 0.99; 95% CI, 0.82 to 1.20) or endometrial cancer–specific survival (HR, 0.96; 95% CI, 0.72 to 1.28).16 The lack of a survival benefit was observed among women in each risk group (low, intermediate, or high). Although the possibility of a benefit among high-risk women could not be excluded, EBRT increased morbidity and reduced quality of life.

Choosing vaginal brachytherapy over EBRT in high-intermediate-risk disease for locoregional control.

The preference of the ASCO Endorsement Panel for vaginal brachytherapy over EBRT for patients with endometrioid histology, grade 1 or 2 tumors, and ≥ 50% myometrial invasion was based primarily on results from the GOG-99 (Gynecologic Oncology Group), PORTEC-1 (Post Operative Radiation Therapy in Endometrial Carcinoma), and PORTEC-2 trials. In GOG-99, EBRT reduced the risk of locoregional recurrence, particularly among women with high-intermediate-risk disease.8 In women randomly assigned to no additional therapy, a majority of the locoregional recurrences occurred in the vagina. EBRT also reduced the risk of locoregional recurrence in the PORTEC-1 trial, but it increased the risk of treatment-related toxicities, including bowel and bladder complications.6,18 The PORTEC-2 trial built on these findings by comparing EBRT with vaginal brachytherapy among women with high-intermediate-risk disease. The two approaches resulted in similar rates of disease-free and overall survival, but vaginal brachytherapy was associated with lower rates of acute GI toxicity.11 The risk of second malignancy after adjuvant radiation therapy was not significantly increased in the PORTEC patient population,14,19although higher rates of secondary cancers have been reported in younger women with longer follow-up.17

Chemotherapy in women with high-risk early-stage or advanced disease.

The ASCO Endorsement Panel emphasized the potential benefits of chemotherapy for women with high-risk early-stage or advanced disease. The GOG-122 trial compared whole-abdominal radiation therapy with doxorubicin and cisplatin chemotherapy in women with stage III or IV endometrial cancer and ≤ 2 cm of postoperative residual disease. Stage-adjusted results suggested that chemotherapy was associated with higher progression-free and overall survival, but also higher rates of acute toxicity.12 In the JGOG 2033 (Japanese Gynecologic Oncology Group) trial, women with stage IC to IIIC endometrial cancer were randomly assigned to pelvic radiotherapy or cyclophosphamide, doxorubicin, and cisplatin chemotherapy. The overall results demonstrated no statistically significant difference between study arms in progression-free or overall survival, suggesting that either treatment approach is reasonable.13 However, in a higher-risk subgroup, defined as either patients age > 70 years with stage IC or grade 3 endometrioid cancer or patients with stage II to IIIA (positive cytology) disease with > 50% myometrial invasion, there was an improvement in overall survival associated with chemotherapy (89.7% v 73.6%; P = .006). In another trial of women with high-risk endometrial cancer by Maggi et al,10no statistically significant differences in outcome among women treated with external radiotherapy or cisplatin, doxorubicin, and cyclophosphamide chemotherapy were reported. However, in a pooled analysis of GOG-122 and the Maggi et al trial, chemotherapy resulted in better overall and progression-free survival than radiotherapy among women with stage III or IV disease (overall survival: HR, 0.75; 95% CI, 0.57 to 0.99; progression-free survival: HR, 0.74; 95% CI, 0.59 to 0.92).15

The effect of adding chemotherapy to radiotherapy was evaluated in a pooled analysis of two randomized trials. Among women with stage I to III endometrial cancer and high-risk features, sequential adjuvant chemotherapy and radiotherapy resulted in better progression-free survival than radiotherapy alone (HR, 0.63; 95% CI, 0.44 to 0.89).7 However, the addition of chemotherapy did not improve progression-free or overall survival in another trial of sequential therapy versus radiotherapy.9

Women with early-stage high-risk disease, including those with deep myometrial invasion and grade 3 tumors, were excluded from the PORTEC trials and under-represented in GOG-99 and the other studies discussed. Given the high rate of distant metastasis in this setting, the role of chemotherapy is being evaluated for patients with early-stage high-risk disease in the GOG-0249 and PORTEC-3 trials. Combinations of chemotherapy and radiation therapy are also being evaluated for patients with advanced-stage disease in the GOG-0258 trial, as well as in the PORTEC-3 study.

The importance of clinical trials.

Given the questions that remain about the optimal postoperative treatment of endometrial cancer, particularly for women with high-risk disease, participation in clinical trials must be encouraged.

Consideration of fertility and quality of life.

When considering the postoperative treatment options available to women with endometrial cancer, discussions with patients must include the impact of treatment options on both short- and longer-term quality of life. Furthermore, management of premenopausal women with endometrial cancer should include a discussion of the effect of treatment on fertility and options available for preservation of ovarian function. ASCO recommendations regarding fertility preservation in patients with cancer are available at www.asco.org/guidelines/fertility.

ENDORSEMENT RECOMMENDATION

ASCO endorses “The Role of Postoperative Radiation Therapy for Endometrial Cancer: An ASTRO Evidence-Based Guideline” by Klopp et al, published in 2014 inPractical Radiation Oncology, with qualifying statements.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Disclosures provided by the authors are available with this article at www.jco.org.

AUTHOR CONTRIBUTIONS

Manuscript writing: All authors

Final approval of manuscript: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Postoperative Radiation Therapy for Endometrial Cancer: American Society of Clinical Oncology Clinical Practice Guideline Endorsement of the American Society for Radiation Oncology Evidence-Based Guideline

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc orjco.ascopubs.org/site/ifc.

Larissa A. Meyer

Travel, Accommodations, Expenses: AstraZeneca

Kari Bohlke

No relationship to disclose

Matthew A. Powell

Honoraria: Roche/Genetech

Consulting or Advisory Role: Roche/Genentech, Arno Therapeutics, Eisai

Speakers' Bureau: Genentech/Roche

Amanda N. Fader

Speakers' Bureau: Ethicon Endosurgery

Travel, Accommodations, Expenses: Intuitive Surgical

Gregg E. Franklin

Employment: New Mexico Cancer Center

Stock or Other Ownership: New Mexico Cancer Center, RainTree

Consulting or Advisory Role: Varian Medical Systems

Speakers' Bureau: Bayer Healthcare

Larissa J. Lee

Travel, Accommodations, Expenses: Intuitive Surgical (I)

Daniela Matei

Honoraria: AstraZenecca

Consulting or Advisory Role: AstraZeneca

Travel, Accommodations, Expenses: AstraZeneca

Lourie Coallier

No relationship to disclose

Alexi A. Wright

No relationship to disclose

Acknowledgment

We thank Gunter von Minckwitz, Jeffrey M. Clarke, and the Clinical Practice Guidelines Committee for their thoughtful reviews and insightful comments on this guideline endorsement.

Appendix

Table A1.

Endorsement Panel Members

 

Footnotes

  • Clinical Practice Guideline Committee approval: January 30, 2015.

  • Editor's note: This American Society of Clinical Oncology (ASCO) clinical practice guideline endorsement provides recommendations based on the review and analyses of the relevant literature in “The Role of Postoperative Radiation Therapy for Endometrial Cancer: An ASTRO Evidence-Based Guideline” by Klopp et al, published in 2014 in Practical Radiation Oncology. Additional information, which may include a Methodology Supplement, Data Supplements, slide sets, patient versions, frequently asked questions, and other clinical tools and resources, is available at www.asco.org/endorsements/endometrial.

  • Authors' disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article.

 

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por cyto às 18:51

Terça-feira, 21.07.15

TSRI study reveals alternative approach to current anti-HIV strategies

 

TSRI study reveals alternative approach to current anti-HIV strategies

Published on July 9, 2015 at 8:49 AM 

AIDS Study Points to ‘Functional Cure’

HIV-infected patients remain on antiretroviral therapy for life because the virus survives over the long-term in infected dormant cells. Interruption of current types of antiretroviral therapy results in a rebound of the virus and clinical progression to AIDS.

But now, scientists from the Florida campus of The Scripps Research Institute (TSRI) have shown that, unlike other antiretroviral therapies, a natural compound called Cortistatin A reduces residual levels of virus from these infected dormant cells, establishing a near-permanent state of latency and greatly diminishing the virus' capacity for reactivation.

"Our results highlight an alternative approach to current anti-HIV strategies," said Susana Valente, a TSRI associate professor who led the study. "Prior treatment with Cortistatin A significantly inhibits and delays viral rebound in the absence of any drug. Our results suggest current antiretroviral regimens could be supplemented with a Tat inhibitor such as Cortistatin A to achieve a functional HIV-1 cure, reducing levels of the virus and preventing reactivation from latent reservoirs."

The study was published this week in the journal mBio.

Cortistatin A was isolated from a marine sponge, Corticium simplex, in 2006, and in 2008, TSRI chemist Phil Baran won the global race to synthesize the compound. A configuration of the compound, didehydro-Cortistatin A, was shown in earlier studies to target the protein Tat, which exponentially increases viral production.

The new study shows that didehydro-Cortistatin A inhibits replication in HIV-infected cells by significantly reducing levels of viral messenger RNA - the blueprints for producing proteins and more infection.

"In latently infected primary T cells isolated from nine HIV-infected subjects being treated with antiretroviral drugs, didehydro-Cortistatin A reduced viral reactivation by an average of 92.3 percent," said Guillaume Mousseau, the first author of the study and a member of the Valente lab.

The results suggest an alternative to a widely studied strategy for latent HIV eradication known as "kick and kill," which tries to purge viral reservoirs by "kicking" them out of their latency with reversing agents and stopping new rounds of infection with an immunotherapy agent to boost the body's own immune system response while on antiretroviral treatment.

"In our proposed model, didehydro-Cortistatin A inhibits the viral transcriptional activator, Tat, far more completely, delaying or even halting viral replication, reactivation and replenishment of the latent viral reservoir," said Valente.

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por cyto às 18:25

Terça-feira, 21.07.15

Scientists elucidate which mechanisms block natural killer cells and how this could be lifted

 

Scientists elucidate which mechanisms block natural killer cells and how this could be lifted

Published on July 8, 2015 at 12:00 PM 

Natural killer cells of the immune system can fend off malignant lymphoma cells and thus are considered a promising therapeutic approach. However, in the direct vicinity of the tumor they lose their effect. Scientists of Helmholtz Zentrum München have now elucidated which mechanisms block the natural killer cells and how this blockade could be lifted. The results were recently published in the European Journal of Immunology.

Natural killer cells (NK cells) are part of the immune system and provide an innate immunity against exogenous and altered endogenous structures. This also appears to apply to tumor cells, against which the body could develop immunity as it does against pathogens, e.g. against viruses. Tumors of the lymph nodes, called lymphomas, are malignant neoplasms that originate from the B cells or T cells of the lymphatic system. B cell lymphomas are very difficult to treat - which is why innovative approaches to therapy are needed. Earlier studies have shown that NK cells have the potential to attack B lymphoma cells and are therefore considered a possible approach to new treatment strategies. In the living organism, however, tumor control by NK cells has been found to be clearly limited.

NK cells become functionally impaired in the tumor microenvironment

In their experiments, the team led by Prof. Dr. Ralph Mocikat of the Institute of Molecular Immunology (IMI) at Helmholtz Zentrum München, found that the NK cells in the immediate vicinity of the tumor showed reduced function. If the cells were placed in a normal environment, their function could be restored within a few hours. This suggests that the factors responsible for the inactivation of the NK cells derive from the tumor itself.

An inflammatory cytokine inactivates NK cells - altered surface molecules block immune activation

The scientists engaged in the research project identified two important tumor-specific factors that are associated with impaired NK cell function. First, a specific inflammatory cytokine (IL-10) is indirectly involved in the inactivation of NK cells. Second, the tumor cells develop protective mechanisms against the NK cells. Thus, the research group showed that specific surface molecules of the tumor cells (NKG2D ligands) which NK cells could bind are down-regulated. Consequently, the NK cells lack an important activation mechanism and are no longer able to carry out cytotoxic activity. Despite the inhibitory strategies of the tumor cells, at an early stage the NK cells produce the cytokine interferon-gamma (IFN-γ), the scientists reported. IFN-γ is essential to activate further immune responses that support the fight against the tumor.

Immunotherapy possible using NK cells - with optimization potential

"Our results show that the transfer of NK cells is a possible strategic option to treat B cell lymphoma. According to our findings, this therapeutic approach can be optimized when transferred NK cells are already activated in vitro prior to their injection, thus bypassing the missing activation potential in the tumor microenvironment. An additional injection of IFN-γ or of antibodies against IL-10 could further support the immune activity," said study leader Mocikat.

Source:

Helmholtz Zentrum München - German Research Center for Environmental Health

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por cyto às 18:20

Terça-feira, 21.07.15

Study stresses importance of investigating telomeres to improve diagnoses, develop treatments for many diseases

 

Study stresses importance of investigating telomeres to improve diagnoses, develop treatments for many diseases

Published on July 16, 2015 at 3:04 AM 

Studying telomeres, the structures that protect the ends of chromosomes, has become a key issue in biology. In recent years, not only has their relation to ageing been confirmed; defective telomeres seem to be linked to more and more illnesses, including many types of cancer. The review published by Paula Martínez and María Blasco from the CNIO in Trends in Biochemical Sciences, stresses the importance of investigating these structures to improve diagnoses and develop possible treatments for many diseases. Telomeres, in the opinion of these researchers, will become increasingly important in clinical studies.

The chromosomes in every single cell are made up of DNA and shaped like strands, with a kind of protective cap at the end of each strand of DNA. Without this end protective cap, the DNA strands would chemically bond to other strands, i.e. the chromosomes would merge and that would be lethal for the cell. The structures that prevent this catastrophe are the telomeres. They were discovered in the 1930s but decades elapsed before someone decided to study them in any depth and since the late 1990s they have always been on the cutting edge of biology research. Biologists are often surprised by their amazing and unexpected complexity, and their health-related significance.

"The biology of telomeres is extremely complex and the more we discover the more we realise what remains to be discovered", says Paula Martínez from CNIO's Telomere and Telomerase Group. "What surprises me most is the high number of factors we are finding that are essential to the preservation of telomeres and, above all, the precise coordination that is required between them all".

The fact that telomeres have been tightly preserved throughout the evolutionary tree -in most eukaryotes: vertebrates, plants and even unicellular organisms such as yeast- indicates their importance. In addition to preventing the merger of chromosomes, telomeres are needed to prevent the loss of genetic information each time a cell divides.

PREVENTING INFORMATION LOSS

When a cell replicates, the molecular machinery in charge of duplicating the chromosomes - so that each daughter cell has a copy -cannot reach the tip. This is inherently impossible due to the way the DNA replication machinery works, and it implies that any genetic material at the end of a chromosome with significant information for the cell would be lost. Telomeres prevent this from happening: they consist of a DNA sequence that does not contain genes and that is repeated numerous times- in humans and other species the sequence is TTAGGG; the letters correspond to three of the building blocks that make up the DNA: thymine, adenine and guanine.

Consequently, the shortening of the DNA with every division is not significant. At least not until a certain limit is reached. When the telomeres become too short, we see the problems associated with ageing: cells reach a point where they interpret critically short telomeres as irreparable damage and react by no longer dividing, which prevents tissue from regenerating.

This happens in healthy cells but not in cancer cells. There is an enzyme, telomerase, which is capable of lengthening the telomeres de novo. This enzyme is not present in most cells of an adult organism but it is active in tumour cells. By repairing the telomeres, the telomerase enables cancer cells to proliferate and become virtually immortal.

This link to ageing and cancer, has led to the intense study of telomere-based strategies to combat cancer and diseases associated with ageing. Blasco's group has recently shown that it is possible to make cancer cells mortal by acting on the telomeres.

ZOOMING IN TO THE TIP OF THE BUFFER

The above-mentioned description of telomeres however is a simplified version of the story. We now know that there is a protective structure enveloping telomeric DNA consisting of six proteins known as shelterins, which are crucial. Another more recent discovery is that there are proteins that, although not in the telomeres themselves, interact with them at specific times to enable them to perform their functions.

These proteins enable the telomeres to unwind, for example; because, the sequence repeated in telomeres, TTAGGG, ends in a single strand of DNA that curves forming a loop and connects to the original strand of the double chain forming a triple chain. "Yes, it is very complicated", admits Martínez. "Structures of up to four chains of DNA can form".

When a cell divides, the telomeres are also replicated. This implies that the end loop must unwind first and then form again. This process also contributes to the shortening of telomeres and we now know that some of the shelterins as well as other associated proteins that interact with telomeres are key elements in this process.

TELOMERE SYNDROMES

According to Martínez, "there is now more evidence about relationship between telomere maintenance and several illnesses".

Telomere syndromes, or telomeropathies, have been identified in patients with mutations of the telomerase enzyme. This group includes, for example, pulmonary fibrosis and problems related to the malfunction of the bone marrow. A direct relationship between telomere dysfunctions and many types of cancer has also been found. More recently, we have also discovered that mutations of the proteins that protect telomeric DNA, the shelterins, and those that interact with the telomeres, are linked to various diseases, such as dyskeratosis congenita, Hoyeraal-Hreidarsson syndrome or Revesz syndrome.

"These discoveries underline the plethora of components and pathways that control telomere functions", write the authors in the paper. "In the future, research will bring to light more unknown factors that will improve our understanding of the mechanisms governing cancer and syndromes linked to the shortening of telomeres. We hope that this knowledge will be transferred to the clinic in order to improve the diagnosis and treatment of diseases".

Source:

Centro Nacional de Investigaciones Oncologicas (CNIO)

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por cyto às 18:18

Terça-feira, 21.07.15

Novel cancer drug candidate developed in Singapore advances into clinical trials

 

Novel cancer drug candidate developed in Singapore advances into clinical trials

Published on July 17, 2015 at 2:01 AM

A made-in-Singapore cancer drug has advanced into clinical trials, charting a milestone in Singapore's biomedical sciences initiative that will go towards improving the lives of cancer patients in Singapore, and worldwide. The Agency for Science, Technology and Research (A*STAR) and Duke-National University of Singapore Graduate Medical School (Duke-NUS) today announced the start of a Phase I clinical trial of novel cancer drug candidate, ETC-159. This is the first publicly-funded drug candidate discovered and developed in Singapore to advance into first-in-human trials, and will target a range of cancers. Overall, cancer is the leading cause of death in Singapore, accounting for 30 percent of deaths in 2013. Cancer has also resulted in 8.2 million deaths world-wide .

ETC-159 targets a number of cancers including colorectal, ovarian and pancreatic cancers which contribute to a significant proportion of Singapore's cancer burden. These cancers are linked to a group of cell signalling pathways known as Wnt signalling, that have been identified to promote cancer growth and spread when elevated or dysregulated. As ETC-159 is an inhibitor of these pathways, it could suppress cancer proliferation and prevent cancer progression.

This drug candidate therefore offers a promising novel and targeted cancer therapy that could shape future cancer therapeutic strategies.

ETC-159 was discovered and developed through a collaboration between A*STAR's Experimental Therapeutics Centre (ETC), Drug Discovery and Development (D3) unit and Duke-NUS since 2009. This was based on the discovery work of Prof David Virshup from Duke-NUS, who has continued to contribute to the development of the drug candidate.

The Phase I clinical trial will evaluate the safety and tolerability of ETC-159 in advanced solid tumours of up to 58 patients. The first patient was dosed on 18 June 2015.

Dr Benjamin Seet, Executive Director of A*STAR's Biomedical Research Council, said, "This breakthrough, which closely follows local company MerLion Pharmaceuticals' recent success in obtaining FDA approval for one of its drugs, marks an inflection point in Singapore's biomedical sciences initiative. Despite the protracted process of drug discovery and development, I am confident that we will see more locally developed drugs in the pipeline being tested and implemented."

Prof Ranga Rama Krishnan, Chairman of the National Medical Research Council (NMRC), Singapore, said, "The first dosing of a drug developed by A*STAR based on a scientific discovery by Duke-NUS researchers, is an example of the terrific and exciting progress that has been made when different entities come together to work on a common problem. This will lead to developing new treatments that can benefit patients in Singapore and beyond."

Prof Alex Matter, Chief Executive Officer of ETC and D3 said, "The discovery and subsequent development of this drug candidate marks a major breakthrough in cancer therapeutics. It also demonstrates the world-class drug discovery and development capabilities we have built up at ETC and D3, complemented by valued partners like Duke-NUS. We will continue to strengthen these capabilities and partnerships to continue developing a pipeline of promising drug candidates and advancing them into the clinic."

Prof David Virshup, inaugural Director of the Programme in Cancer and Stem Cell Biology at Duke-NUS, said, "As the drug candidate provides a targeted cancer therapy, it could potentially minimise side effects and make cancer treatments more bearable for cancer patients. This is a major milestone that was made possible by Singapore's ongoing investment in basic and translational biomedical research to address unmet medical needs. It is fitting that Singaporeans might be the first to benefit from this Singapore-developed drug."

A*STAR's ETC and Duke-NUS are the primary drivers of the discovery and development of the drug candidate. D3 joined the collaboration in 2013 to bring the project forward to achieve proof of concept in humans.

D3 has obtained ethics and regulatory approval for this trial from the SingHealth Centralised Institutional Review Board (CIRB) and the Singapore Health Sciences Authority (HSA) respectively. The first two sites for the trial are the National Cancer Centre Singapore (NCCS) and the National University Hospital (NUH), Singapore. Trial sites in the United States will be opened as the trial progresses.

Source:

Biomedical Sciences Institutes (BMSI)

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por cyto às 18:15

Terça-feira, 21.07.15

Ludwig, CRI launch clinical trials to evaluate immunotherapies for treatment of GBM and solid tumors

 

Ludwig, CRI launch clinical trials to evaluate immunotherapies for treatment of GBM and solid tumors

Published on July 8, 2015 at 11:50 PM 

Ludwig Cancer Research (Ludwig) and the Cancer Research Institute (CRI) have launched clinical trials evaluating an immunotherapy for the treatment of the brain cancer glioblastoma multiforme (GBM), and a combination of immunotherapies for a variety of solid tumors.

The trials are being conducted through the CVC Clinical Trials Network in collaboration with MedImmune, the global biologics research and development arm of AstraZeneca. The CVC Clinical Trials Network -- jointly managed by Ludwig and CRI -- is a coordinated global network of basic and clinical immunologists with expertise in devising and developing immunotherapies for the treatment of cancer. The CVC Clinical Trials Network is led by Jedd Wolchok, Ludwig member and director of the Ludwig Collaborative Laboratory at Memorial Sloan Kettering Cancer Center, as well as associate director of the CRI Scientific Advisory Council.

The GBM trial is a nonrandomized, multicenter Phase 2 trial testing the effects of MedImmune's checkpoint blockade antibody durvalumab (MEDI4736) in patients with GBM, which is the most aggressive and deadly type of adult brain cancer. The study will be conducted using three cohorts of patients - newly diagnosed, recurrent patients and those with tumors which have become unresponsive to standard treatment of care.

"GBM is an inevitably lethal cancer that has so far eluded every therapy in the pharmaceutical arsenal," said Jonathan Skipper, Ludwig's executive director of technology development. "We are hopeful that adding a promising immunotherapy to the treatment regimen for this brain cancer will yield significant benefits for patients who today have a median life expectancy of roughly 15 months, even with the best treatment available."

Durvalumab is an investigational human monoclonal antibody directed against programmed cell death ligand 1 (PD-L1). Signals from PD-L1 help tumors avoid detection by the immune system. Durvalumab blocks these signals, countering the tumor's immune-evading tactics. The antibody belongs to an emerging class of immunotherapies commonly referred to as checkpoint inhibitors because they remove checks the body places on immune activation.

"Checkpoint inhibitors have deservedly stirred considerable excitement in the oncology community as their application yields notable results against a growing variety of cancers," said Adam Kolom, managing director of CRI's venture fund and Clinical Accelerator, which organizes and provides philanthropic funding and clinical resources for this and other promising immunotherapy trials. "This will be the first time the immunotherapeutic agent will be tested against this difficult-to-treat cancer, and its outcomes are eagerly anticipated by the GBM patient community."

The other trial, which Ludwig and CRI launched in 2013, is a Phase 1 nonrandomized multicenter trial evaluating the combination of durvalumab with another checkpoint blockade therapy (tremelimumab, anti-CTLA-4) for the treatment of a variety of advanced solid tumors including ovarian cancer, non-small cell lung cancer, colorectal cancer, head and neck cancer, cervical cancer and kidney cancer.

Both clinical trials, which are now under way, are part of a larger clinical research program supported by Ludwig and CRI to speed the evaluation of novel cancer immunotherapies, alone or in combination with other cancer drugs. All of the studies will include collection of genetic and immunologic data derived from clinical samples obtained from patients. Such information will provide clues to the impact of the evaluated therapies and suggest refined or new strategies for treating cancer.

Source:

Ludwig Institute for Cancer Research

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por cyto às 18:12

Terça-feira, 21.07.15

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

 

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

Published on July 21, 2015 at 2:37 AM 

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

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

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

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

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

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

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

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

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

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

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

Source:

University of Maryland Medical Center

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por cyto às 18:10

Terça-feira, 21.07.15

clinical study data on ImmunTraCkeR assay in the Journal for ImmunoTherapy of Cancer

 

ImmunID announces publication of clinical study data on ImmunTraCkeR assay in the Journal for ImmunoTherapy of Cancer

Published on July 8, 2015 at 10:02 AM 

ImmunID today announced the publication of a short report in the Journal for ImmunoTherapy of Cancer (JITC) showing that the analysis of peripheral T cell receptor diversity using the company's ImmunTraCkeR® assay is associated with clinical outcomes following Ipilimumab treatment in metastatic melanoma. Results from the study, conducted at Memorial Sloan Kettering Cancer Center, were first presented at the SITC 2014 Annual Meeting.

Study results suggest that ImmunTraCkeR® may ultimately be used as a companion diagnostic for immune checkpoint agents, to determine eligibility to the treatment.

"We are delighted to have been selected by the JITC editorial board for publication. ImmunID's mission is to add precision to the immuno-oncology revolution by personalizing immunotherapy. A large multicenter study is currently underway (Predict-ID Melanoma, France) with the aim to validate prediction capabilities of ImmunTraCkeR® for response to immune checkpoint inhibitors. This is an area of high unmet medical need and could be game-changing for patients," said Bernhard Sixt, ImmunID's Chairman and Chief Executive Officer.

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por cyto às 18:06

Terça-feira, 21.07.15

Single molecule appears to be central regulator driving cancer metastasis

 

Single molecule appears to be central regulator driving cancer metastasis

Published on July 14, 2015 at 6:21 AM · 

Cancer is a disease of cell growth, but most tumors only become lethal once they metastasize or spread from their first location to sites throughout the body. For the first time, researchers at Thomas Jefferson University in Philadelphia report a single molecule that appears to be the central regulator driving metastasis in prostate cancer. The study, published online July 13th in Cancer Cell, offers a target for the development of a drug that could prevent metastasis in prostate cancer, and possibly other cancers as well.

"Finding a way to halt or prevent cancer metastasis has proven elusive. We discovered that a molecule called DNA-PKcs could give us a means of knocking out major pathways that control metastasis before it begins," says Karen Knudsen, Ph.D., Director of the Sidney Kimmel Cancer Center at Thomas Jefferson University, the Hilary Koprowski Professor and Chair of Cancer Biology, Professor of Urology, Radiation Oncology, and Medical Oncology at Jefferson.

Metastasis is thought of as the last stage of cancer. The tumor undergoes a number of changes to its DNA - mutations - that make the cells more mobile, able to enter the bloodstream, and then also sticky enough to anchor down in a new location, such as the bone, the lungs, the liver or other organs, where new tumors start to grow. Although these processes are fairly well characterized, there appeared to be many non-overlapping pathways that ultimately lead to these traits.

Now, Dr. Knudsen and colleagues have shown that one molecule appears to be central to many of the processes required for a cancer to spread. That molecule is a DNA repair kinase called DNA-PKcs. The kinase rejoins broken or mutated DNA strands in a cancer cell, acting as a glue to the many broken pieces of DNA and keeping alive a cell that should normally self-destruct. In fact, previous studies had shown that DNA-PKcs was linked to treatment resistance in prostate cancer, in part because it would repair the usually lethal damage to tumors caused by radiation therapy and other treatments. Importantly, Dr. Knudsen's work showed that DNA-PKcs has other, far-reaching roles in cancer.

The researchers showed that DNA-PKcs also appears act as a master regulator of signaling networks that turn on the entire program of metastatic processes. Specifically, the DNA-PKcs modulates the Rho/Rac enzyme, which allows many cancer cell types to become mobile, as well as a number of other gene networks involved in other steps in the metastatic cascade, such as cell migration and invasion.

In addition to experiments in prostate cancer cell lines, Dr. Knudsen and colleagues also showed that in mice carrying human models of prostate cancer, they could block the development of metastases by using agents that suppress DNA-PKcs production or function. And in mice with aggressive human tumors, an inhibitor of DNA-PKcs reduced overall tumor burden in metastatic sites.

In a final analysis that demonstrated the importance of DNA-PKcs in human disease, the researchers analyzed 232 samples from prostate cancer patients for the amount of DNA-PKcs those cells contained and compared those levels to the patients' medical records. They saw that a spike in the kinase levels was a strong predictor of developing metastases and poor outcomes in prostate cancer. They also showed that DNA-PKcs was much more active in human samples of castrate-resistant prostate cancer, an aggressive and treatment-resistant form of the disease.

"These results strongly suggest that DNA-PKcs is a master regulator of the pathways and signals that lead to the development of metastases in prostate cancer, and that high levels of DNA-PKcs could predict which early stage tumors may go on to metastasize," says Dr. Knudsen.

"The finding that DNA-PKcs is a likely driver of lethal disease states was unexpected, and the discovery was made possible by key collaborations across academia and industry," explains Dr. Knudsen. Key collaborators on the study, in addition to leaders of the Sidney Kimmel Cancer Center's Prostate Program, included the laboratories of Felix Feng (University of Michigan), Scott Tomlins (University of Michigan), Owen Witte (UCLA), Cory Abate-Shen (Columbia University), Nima Sharifi (Cleveland Clinic) and Jeffrey Karnes (Mayo Clinic), and contributions from GenomeDx.

Although not all molecules are easily turned into drugs, at least one pharma company has already developed a drug that inhibits DNA-PKcs, and is currently testing it in a phase 1 study (NCT01353625). "We are enthusiastic about the next step of clinical assessment for testing DNA-PKcs inhibitors in the clinic. A new trial will commence shortly using the Celgene CC-115 DNA-PKcs inhibitor. This new trial will be for patients advancing on standard of care therapies, and will be available at multiple centers connected through the Prostate Cancer Clinical Trials Consortium, of which we are a member," explained Dr. Knudsen.

"Although the pathway to drug approval can take many years, this new trial will provide some insight into the effect of DNAP-PKcs inhibitors as anti-tumor agents. In parallel, using this kinase as a marker of severe disease may also help identify patients whose tumors will develop into aggressive metastatic disease, so that we can treat them with more aggressive therapy earlier," says Dr. Knudsen. "Given the role of DNA-PKcs in DNA repair as well as control of tumor metastasis, there will be challenges in clinical implementation, but this discovery unveils new opportunities for preventing or treating advanced disease."

Source:

Thomas Jefferson University

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por cyto às 18:05

Terça-feira, 21.07.15

Isis Innovation, Ludwig Cancer Research announce launch of new cancer immunotherapy spinout

 

Isis Innovation, Ludwig Cancer Research announce launch of new cancer immunotherapy spinout

Published on July 9, 2015 at 7:30 AM 

Isis Innovation, the University of Oxford's technology commercialisation company, and Ludwig Cancer Research are proud to announce the launch of a new spinout company, iOx Therapeutics. iOx Therapeutics will develop a novel cancer immunotherapy discovered through a collaboration between Ludwig Cancer Research and Professor Vincenzo Cerundolo, the director of the MRC Human Immunology Unit within the University of Oxford's Weatherall Institute of Molecular Medicine.

Since 2003, Professor Cerundolo, supported by funding from Ludwig Cancer Research, has led a research team working in collaboration with Professor Gurdyal Besra and Dr. Liam Cox of the University of Birmingham and Professor Richard Schmidt of the University of Konstanz. This team discovered multiple synthetic lipid compounds, now under development by iOx, which activate iNKT cells. A large body of evidence suggests that iNKT cells play an important role in anti-tumour immune responses and could prove highly effective in combination with other immunotherapies.

"Preclinical studies of our iNKT-activating compounds have been extremely promising," said Professor Cerundolo. "We've been able to show that these molecules can halt the progression of tumours in animal models. I am very excited to see them moving toward the clinic, and gratified that our research could prove to be of benefit to cancer patients."

"The new immune checkpoint inhibitors recently approved by regulatory agencies, such as anti-PD-1 antibodies, sabotage the strategies used by tumour cells to suppress the immune system and so induce potent anti-tumour immune responses in many patients," said Dr. Jonathan Skipper, Ludwig's executive director of technology development. "There is good reason to expect that iOX's iNKT agonists could significantly improve these responses, and we look forward to seeing the results of their clinical evaluation."

The company has discussed plans for a first human trial with the UK Medicines and Healthcare products Regulatory Agency. The trial will be run by Professor Mark Middleton, director of the Oxford Experimental Cancer Medicine Centre at Oxford University Hospitals NHS Trust.

Jim Mellon, an Oxford alumnus, has invested in the company through SalvaRx, an oncology-focused investment vehicle that provides capital and drug development expertise to support emerging technologies and companies.

Isis Innovation Head of Technology Transfer, Life Sciences Dr. Adam Stoten said, "The field of cancer immunotherapy is moving forward with unprecedented momentum and we're delighted to support Professor Cerundolo and his team in their goal of finding new and better cancer treatments."

Source:

Ludwig Institute for Cancer Research

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por cyto às 18:00

Terça-feira, 21.07.15

In vivo analysis of Nef’s role in HIV-1 replication, systemic T cell activation and CD4 + T cell loss

 

In vivo analysis of Nef’s role in HIV-1 replication, systemic T cell activation and CD4 + T cell loss

Richard L Watkins, John L Foster* and J Victor Garcia*

*Corresponding authors: John L Foster john_foster@med.unc.edu - J V Garciavictor_garcia@med.unc.edu

Author Affiliations

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Retrovirology 2015, 12:61  doi:10.1186/s12977-015-0187-z

Published: 14 July 2015

Abstract

Nef is a multifunctional HIV-1 protein critical for progression to AIDS. Humans infected with nef(−) HIV-1 have greatly delayed or no disease consequences. We have contrasted nef(−) and nef(+) infection of BLT humanized mice to better characterize Nef’s pathogenic effects.

Mice were inoculated with CCR5-tropic HIV-1 JRCSF (JRCSF) or JRCSF with an irreversibly inactivated nef (JRCSFNefdd). In peripheral blood (PB), JRCSF exhibited high levels of viral RNA (peak viral loads of 4.71 × 10 6  ± 1.23 × 10 6 copies/ml) and a progressive, 75% loss of CD4 + T cells over 17 weeks. Similar losses were observed in CD4 + T cells from bone marrow, spleen, lymph node, lung and liver but thymocytes were not significantly decreased. JRCSFNefdd also had high peak viral loads (2.31 × 10 6  ± 1.67 × 10 6 ) but induced no loss of PB CD4 + T cells. In organs, JRCSFNefdd produced small, but significant, reductions in CD4 + T cell levels and did not affect the level of thymocytes. Uninfected mice have low levels of HLA-DR + CD38 +CD8 + T cells in blood (1–2%). Six weeks post inoculation, JRCSF infection resulted in significantly elevated levels of activated CD8 + T cells (6.37 ± 1.07%). T cell activation coincided with PB CD4 + T cell loss which suggests a common Nef-dependent mechanism. At 12 weeks, in JRCSF infected animals PB T cell activation sharply increased to 19.7 ± 2.9% then subsided to 5.4 ± 1.4% at 14 weeks. HLA-DR + CD38 + CD8 + T cell levels in JRCSFNefdd infected mice did not rise above 1–2% despite sustained high levels of viremia. Interestingly, we also noted that in mice engrafted with human tissue expressing a putative protective HLA-B allele (B42:01), JRCSFNefdd exhibited a substantial (200-fold) reduced viral load compared to JRCSF.

Nef expression was necessary for both systemic T cell activation and substantial CD4 + T cell loss from blood and tissues. JRCSFNefdd infection did not activate CD8 + T cells or reduce the level of CD4 + T cells in blood but did result in a small Nef-independent decrease in CD4 + T cells in organs. These observations strongly support the conclusion that viral pathogenicity is mostly driven by Nef. We also observed for the first time substantial host-specific suppression of HIV-1 replication in a small animal infection model.

Keywords:

HIV-1; Nef; Replication; Pathogenesis

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por cyto às 17:53

Terça-feira, 21.07.15

Cancer Clusters (Fact Sheet)

 

Cancer Clusters (Fact Sheet)

What is a cancer cluster?

A cancer cluster is the occurrence of a greater than expected number of cancer cases among a group of people in a defined geographic area over a specific time period. A cancer cluster may be suspected when people report that several family members, friends, neighbors, or coworkers have been diagnosed with the same or related types of cancer.

Cancer clusters can help scientists identify cancer-causing substances in the environment. For example, in the early 1970s, a cluster of cases of angiosarcoma of the liver, a rare cancer, was detected among workers in a chemical plant. Further investigation showed that the workers were all exposed to vinyl chloride and that workers in other plants that used vinyl chloride also had an increased rate of angiosarcoma of the liver. Exposure to vinyl chloride is now known to be a major risk factor for angiosarcoma of the liver.

However, most suspected cancer clusters turn out, on detailed investigation, not to be true cancer clusters. That is, no cause can be identified, and the clustering of cases turns out to be a random occurrence.

Where can someone report a suspected cancer cluster or find out if one is being investigated?

Concerned individuals can contact their local or state health department to report a suspected cancer cluster or to find out if one is being investigated. Health departments provide the first response to questions about cancer clusters because they, together with state cancer registries, will have the most up-to-date data on cancer incidence in the area. If additional resources are needed to investigate a suspected cancer cluster, the state health department may request assistance from federal agencies, including the Centers for Disease Control and Prevention (CDC) and the Agency for Toxic Substances and Disease Registry (ATSDR), which is part of the CDC.

The CDC website provides links to state and local health departments. These agencies may also be listed in the blue pages of government listings in telephone books.

Although NCI does not lead investigations of individual cancer clusters, NCI researchers and staff may provide assistance to other investigative agencies as needed. In addition, scientists at NCI and researchers who are funded by NCI analyze variations in cancer trends, including the frequency, distribution, and patterns of cancer in groups of people. These analyses can detect patterns of cancer in specific populations. For example, NCI's Cancer Mortality Maps website uses data on deaths from the National Center for Health Statistics, which is part of the CDC, and population estimates from the U.S. Census Bureau to provide dynamically generated maps that show geographic patterns of cancer death rates throughout the United States.

How are suspected cancer clusters investigated?

Health departments use established criteria to investigate reports of cancer clusters. The Centers for Disease Control and the Council of State and Territorial Epidemiologists have released updated guidelines for investigating suspected cancer clusters and responding to community concerns (1).

As a first step, the investigating agency gathers information from the person who reported the suspected cancer cluster. The investigators ask for details about the suspected cluster, such as the types of cancer and number of cases of each type, the age of the people with cancer, and the area and time period over which the cancers were diagnosed. They also ask about specific environmental hazards or concerns in the affected area.

If the review of the findings from this initial investigation suggests the need for further evaluation, investigators then compare information about cases in the suspected cluster with records in the state cancer registry and census data.

If the second step reveals a statistically significant excess of cancer cases, the third step is to determine whether an epidemiologic study can be carried out to investigate whether the cluster is associated with risk factors in the local environment. Sometimes, even if there is a clear excess of cancer cases, it is not feasible to carry out further study—for example, if the total number of cases is very small.

Finally, if an epidemiologic study is feasible, the fourth step is to determine whether the cluster of cancer cases is associated with a suspect contaminant in the environment. Even if a possible association with an environmental contaminant is found, however, further studies would be needed to confirm that the environmental contaminant did cause the cluster.

What are the challenges in investigating suspected cancer clusters?

Investigators face several challenges when determining whether a greater than expected number of cancer cases represents a cancer cluster.

Understanding the kind of cancers involved

To assess a suspected cancer cluster accurately, investigators must determine whether the type of cancer involved is a primary cancer (a cancer that is located in the original organ or tissue where the cancer started) or a cancer that has metastasized (spread) to another site in the body from the original tissue or organ where the cancer began (also called a secondary cancer). Investigators consider only the primary cancer when they investigate a suspected cancer cluster. A confirmed cancer cluster is more likely if it involves one type of cancer than if it involves multiple different cancer types. This is because most carcinogens in the environment cause only a specific cancer type rather than causing cancer in general.

Ascertaining the number of cancer cases in the suspected cluster

Many reported clusters include too few cancer cases for investigators to determine whether the number of cancer cases is statistically significantly greater than the expected number.  

Determining statistical significance

To confirm the existence of a cluster, investigators must show that the number of cancer cases in the cluster is statistically significantly greater than the number of cancer cases expected given the age, sex, and racial distribution of the group of people who developed the disease. If the difference between the actual and expected number of cancer cases is statistically significant, the finding is unlikely to be the result of chance alone. However, it is important to keep in mind that even a statistically significant difference between actual and expected numbers of cases can arise by chance.

Determining the relevant population and geographic area

An important challenge in confirming a cancer cluster is accurately defining the group of people who should be considered potentially at risk of developing the specific cancer (typically the total number of people who live in a specific geographic area). When defining a cancer cluster, there can be a tendency to expand the geographic borders as additional cases of the suspected disease are discovered. However, if investigators define the borders of a cluster based on where they find cancer cases, they may alarm people about cancers that are not related to the suspected cluster. Instead, investigators first define the population and geographic area that is "at risk" and then identify cancer cases within those parameters.

Identifying a cause for a cluster

A confirmed cancer cluster—that is, a finding of a statistically significant excess of cancers—may not be the result of any single external cause or hazard (also called an exposure). A cancer cluster could be the result of chance, an error in the calculation of the expected number of cancer cases, differences in how cancer cases were classified, or a known cause of cancer, such as smoking. Even if a cluster is confirmed, it can be very difficult to identify the cause. People move in and out of a geographic area over time, which can make it difficult for investigators to identify hazards or potential carcinogens to which they may have been exposed and to obtain medical records to confirm the diagnosis of cancer. Also, it typically takes a long time for cancer to develop, and any relevant exposure may have occurred in the past or in a different geographic area from where the cancer was diagnosed.

Where can people get more information about cancer clusters?

In addition to state and local health departments and cancer registries, the following agencies may have more information about cancer clusters.

Agency for Toxic Substances and Disease Registry (ATSDR)
Centers for Disease Control and Prevention

1–800–232–4636 (1–800–CDC–INFO)
http://www.atsdr.cdc.gov

The CDC's ATSDR conducts public health assessments of potentially hazardous waste sites, performs health consultations on specific hazardous substances, designs and conducts health surveillance programs, and provides education and training about hazardous substances. Information about public health assessments conducted by ATSDR can be found on its Public Health Assessments and Health Consultations page. Reports can be searched by state or U.S. territory. Contact information for ATSDR regional offices is available online.

National Center for Environmental Health (NCEH)
Centers for Disease Control and Prevention

1–800–232–4636 (1–800–CDC–INFO)
cdcinfo@cdc.gov
http://www.cdc.gov/nceh/clusters

The CDC's NCEH works to promote healthy and safe environments and prevent harmful exposures. The NCEH website includes general information about cancer clusters, links to resources, and answers to frequently asked questions.

National Institute for Occupational Safety and Health (NIOSH)
Hazard Evaluation and Technical Assistance Branch
Health Hazard Evaluation (HHE) Program
Centers for Disease Control and Prevention

513–841–4382
HHERequestHelp@cdc.gov
http://www.cdc.gov/niosh/hhe

The HHE Program of CDC's NIOSH investigates potentially hazardous working conditions, including suspected cancer clusters. Employees, authorized employee representatives, and employers can request these evaluations. HHE reports are available on the NIOSH website.

Office of Occupational Medicine
Occupational Safety and Health Administration (OSHA)
U.S. Department of Labor

202–693–2323
http://www.osha.gov/dts/oom/index.html

OSHA's Office of Occupational Medicine performs workplace-related case evaluations and cluster investigations, including medical record reviews, employee interviews, and medical screening activities.



Selected References

1. Centers for Disease Control and Prevention. Investigating Suspected Cancer Clusters and Responding to Community Concerns: Guidelines from CDC and the Council of State and Territorial Epidemiologists. Morbidity and Mortality Weekly Report 2013;62(RR08):1-14. [PubMed Abstract]

Source: National Cancer Institute.

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