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Personalized Medicine in NSCLC

Posted in Biomarkers & Medical Diagnostics, CANCER BIOLOGY & Innovations in Cancer Therapy, Chemical Genetics, Computational Biology/Systems and Bioinformatics, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Genome Biology, Genomic Testing: Methodology for Diagnosis, Health Economics and Outcomes Research, Health Law & Patient Safety, Imaging-based Cancer Patient Management, International Global Work in Pharmaceutical, Molecular Genetics & Pharmaceutical, Nanotechnology for Drug Delivery, Personalized and Precision Medicine & Genomic Research, Pharmaceutical Industry Competitive Intelligence, Pharmacogenomics, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Technology Transfer: Biotech and Pharmaceutical, tagged American Society of Clinical Oncology, AstraZeneca, EGFR, Epidermal growth factor receptor, Gefitinib, KRAS, Lung cancer, National Comprehensive Cancer Network, Non-small-cell lung carcinoma, NSCLC, progression-free survival, The New England Journal of Medicine on March 3, 2013| 2 Comments »

Personalized Medicine in NSCLC

Reviewer: Larry H Bernstein, MD, FCAP

Introduction

Early in the 21st century, gefitinib, an epi­dermal growth factor receptor (EGFR) tyrosine kinase inhibitor became available  for the treatment of non-small cell lung can­cer (NSCLC). Over 80% of selected patients

• EGFR mutation-positive patients, respond to gefitinib treatment;
• most patients develop acquired resistance to gefitinib within a few years.

Recently, many studies have been performed to determine precisely how to select patients who will respond to gefitinib, the best timing for its administration, and how to avoid the development of acquired resistance as well as adverse drug effects.

Lung cancers are classified according to their his­tological type. Because each variant has different bio­logical and clinical properties, including response to treatment, a precise classification is essential to pro­vide appropriate therapy for individual patients. Lung cancer consists of two broad categories—non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC).

NSCLC  – 20%–40% RR to chemotherapy

• ade­nocarcinoma (AC),  40%–50% ( most common form)
  • higher sensitivity to chemotherapy than SCC or LC
• squamous cell carcinoma (SCC),  ∼30%
•  large cell carcinoma (LCC). 10%

The majority of patients with SCLC are diagnosed with

• advanced cancer with distant metastasis
• high sensitivity to chemotherapy.
• response rate (RR) for SCLC is reportedly 60%–80%
• complete remission is observed in only 15%–20% of patients

The Potential of Personalized Medicine in Advanced NSCLC
Personalized medicine—

• matching a patient’s unique molecular profile with an appropriate targeted therapy—
• is transforming the diagnosis and treatment of non–small-cell lung cancer (NSCLC).

Through molecular diagnostics, tumor cells may be differentiated based on the presence or absence of

• receptor proteins,
• driver mutations, or
• oncogenic fusion/rearrangements.

The convergence of advancing research in drug development and genetic sequencing has permitted the development of therapies specifically targeted to certain biomarkers, which may offer a differential clinical benefit.

Putting personalized medicine in NSCLC into practice
With the data on the prognostic and predictive biomarkers EGFR and ALK, biomarker testing is increasingly important in therapy decisions in NSCLC.1,2
Biomarker Testing in Advanced NSCLC: Evolution in Pathology Clinical Practice
http://www.medscape.com/infosite/letstest/article-3
Multidisciplinary Approaches in the Changing Landscape of Advanced NSCLC
http://www.medscape.com/infosite/letstest/article-4
Oncology Perspectives on Biomarker Testing
http://www.medscape.com/infosite/letstest/article-1

References
1. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology™: Non-Small Cell Lung Cancer. Version 2.2012.
http://www.nccn.org/professionals/physician_gls/PDF/nscl.pdf.                   August 6, 2012.
2. Gazdar AF. Epidermal growth factor receptor inhibition in lung cancer: the evolving role of individualized therapy. Cancer Metastasis Rev. 2010;29(1):37-48.

Over the last decade, a growing number of biomarkers have been identified in NSCLC.3,4 To date, 2 of these molecular markers have been shown to have both prognostic and predictive value in patients with advanced NSCLC: epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements.5-8 Testing for these biomarkers may provide physicians with more information on which to base treatment decisions, and reflex testing may permit consideration of appropriate therapy from the outset of treatment.2,9,10

References:
Lovly CM, Carbone DP. Lung cancer in 2010: one size does not fit all. Nat Rev Clin Oncol. 2011;8(2):68-70.
Dacic S. Molecular diagnostics of lung carcinomas. Arch Pathol Lab Med. 2011;135(5):622-629.
Herbst RS, Heymach JV, Lippman SM. Lung cancer. N Engl J Med. 2008;359(13):1367-1380.
Quest Diagnostics. Lung Cancer Mutation Panel (EGFR, KRAS, ALK).                       Sept 17, 2012
http://questdiagnostics.com/hcp/intguide/jsp/showintguidepage.jsp?fn=Lung/TS_LungCancerMutation_Panel.htm.

Rosell R, Gervais R, Vergnenegre A, et al. Erlotinib versus chemotherapy (CT) in advanced non-small cell lung cancer (NSCLC) patients (p) with epidermal growth factor receptor (EGFR) mutations: interim results of the European Erlotinib Versus Chemotherapy (EURTAC) phase III randomized trial. Presented at: 2011 American Society of Clinical Oncology (ASCO) Annual Meeting, J Clin Oncol. 2011;29(suppl). Abstract 7503.                        Aug 6, 2012.                    http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=102&abstractID=78285.
Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361(10):947-957.
Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non–small-cell lung cancer. N Engl J Med. 2010;363(18):1693-1703.
National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology™: Non-Small Cell Lung Cancer. Version 2.2012.
http://www.nccn.org/professionals/physician_gls/PDF/nscl.pdf.                        Aug 6, 2012
College of American Pathologists (CAP)/International Association for the Study of Lung Cancer (IASLC)/Association for Molecular Pathology (AMP) expert panel. Lung cancer biomarkers guideline draft recommendations. http://capstaging.cap.org/apps/docs/membership/transformation/new/lung_public_comment_supporting_materials.pdf.      Aug 6, 2012.
Gazdar AF. Epidermal growth factor receptor inhibition in lung cancer: the evolving role of individualized therapy. Cancer Metastasis Rev. 2010;29(1):37-48.

 Background Studies

In 2002, gefitinib (ZD1839; AstraZeneca) , the first epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, became available as an innovative molecular-targeted drug for the treatment of unresectable NSCLC. Initially, many NSCLC patients were expected to respond to gefitinib because many solid tumors, including NSCLC, are known to overexpress EGFR, which has a role in tumor pro­liferation and is used as a biomarker to predict poor prognosis. Gefitinib was shown to have a dra­matic effect on a limited number of patients; but  it was ineffective in 70%–80% of patients with NSCLC. There have been reports of death caused by interstitial pneumonia (IP), one of the critical adverse drug reactions (ADRs) associated with gefitinib use. Therefore, there is a need for  predicting the effects of gefitinib, and criteria for select­ing patients who could be treated with gefitinib.

 In 2004, Lynch et al. and Paez et al. each pub­lished, on the same day, sensational reports in the New England Journal of Medicine and Science, identifying somatic mutations in the tyrosine kinase domain of the EGFR gene in patients with gefitinib-sensitive lung cancer, as compared with none of the patients who had no response. Therefore, screening for EGFR mutations in lung cancer showed potential for identifying patients who would respond to gefi­tinib therapy. It then was found that patients with EGFR mutations in the area of the gene cod­ing for the ATP-binding pocket of the tyrosine kinase domain responded to gefitinib. Consequently, the EGFR genotyping has been used to select patients who will respond to gefitinib. Other genetic mutations have also been reported as indicators of the response or resistance to gefitinib; for example, mutations of the KRAS gene are associated with primary resistance to gefitinib. Thus, screening of EGFR and KRAS is used to

• predict the effects of gefi­tinib and
• to select patients who will respond to gefitinib in the clinical setting.

Until now, the effects of gefitinib have been predicted only by genotyping factors, such as EGFR and KRAS mutations. However, Nakamura et al showed a relationship between the blood concentration of gefitinib and its clinical effects. In their study of 23 NSCLC patients with EGFR mutations, the ratio of the gefitinib concentration on day 8 to that on day 3 after the first administration of gefitinib (C8/C3) correlated with the progression-free survival (PFS) period. Patients with a higher C8/C3 ratio had a significantly lon­ger PFS (P = 0.0158, 95% confidence interval [CI]: 0.237–0.862), which  suggests the importance of the PK of gefitinib on its clinical outcome.   Chmielecki et al. concurrently reported that maintain­ing a high concentration of erlotinib, another EGFR tyrosine kinase inhibitor (EGFR-TKIs) with the same mechanism of action as gefitinib, could

1. delay the establishment of drug-resistant tumor cells and
2. decrease the proliferation rate of drug-resistant cells compared to

• treatment using a lower concentration of erlotinib.

Pharmacogenetic profile

Initially, gefitinib was expected to induce a response in patients with tumors that overexpressed EGFR because it exerts its antineoplastic effects by com­petitively inhibiting the binding of ATP to the ATP-binding site of EGFR.  A number of studies contradict this hypothesis:
(1) while approxi­mately 40%–80% of NSCLC overexpress EGFR, only 10%–20% of NSCLC patients respond to gefi­tinib;5,6 and
(2) while EGFR overexpression is known to be more common in SCC than AC, gefitinib shows a higher antineoplastic effect on AC than on SCC, while other reports indicated no correlation between the expression levels of EGFR and clinical outcomes.

In 2004, somatic mutations were identified in the EGFR tyrosine kinase domain of patients with gefitinib-responsive lung cancer, as compared with no mutations in patients exhibiting no response, and the presence of an EGFR mutation was highly correlated with a good response to gefitinib.The conformational change of the EGFR ATP-binding site caused by genetic mutations constitutively acti­vates the EGFR downstream signaling pathway and increases the malignancy of cancer. Conversely, the conformational change of the ATP-binding site can also increase its affinity for gefitinib; therefore, gefi­tinib can inhibit the downstream signaling pathway more easily, strongly induces apoptosis, and reduces the proliferation of cancer cells.

Mutations in exons 18–21 of EGFR are predictive factors for the clinical efficacy of gefitinib;

• deletions in exon 19 and missense mutations in exon 21 account for ∼90% of these mutations.

The detection of EGFR muta­tions in exons 19 and 21 is considered to be essential to predict the clinical efficacy of gefitinib.
Acquired resistance
All responders eventually develop resistance to gefitinib but in 2005, an EGFR mutation in exon 20, which substitutes methionine for threonine at amino acid position 790 (T790M), was reported to be one of the main causes of acquired resistance to gefitinib. The EGFR T790M vari­ant

1. changes the structural conformation of the ATP-binding site, thereby
2. increasing the affinity of ATP to EGFR, while
3. the affinity of gefitinib to ATP is unchanged.

Screening methods for EGFR and KRAS mutations
The detection of EGFR and KRAS mutations has been usually achieved by sequencing DNA amplified from tumor tissues; however, sequencing techniques are too complex, time-consuming, and expensive.  The selection of an appropri­ate method to detect EGFR and KRAS mutations is essential to make an exact prediction of the efficacy of gefitinib in individual patients. Advances in diagnostics and treatments for NSCLC have led to better outcomes and higher standards of what outcomes are expected. These new understandings and treatments have raised multiple new questions and issues with regard to the decisions on the appropriate treatment of NSCLC patients.

• Biomarkers are increasingly recognized and applied for guidance in diagnosis, prognosis and treatment decisions and evaluation.
• Biologics and newer cancer treatments are enabling the possibility for new combined treatment modalities in earlier stage disease
• Maintenance therapy has been shown to be useful, but optimal therapy choices before and after maintenance therapy need clarification
• The importance of performance status on treatment decisions
• Comparative effectiveness is becoming an expectation across all treatments and diseases, and will prove difficult to accomplish within the complexity of cancer diseases

NCCN Molecular Testing White Paper: Effectiveness, Efficiency, and Reimbursement

PF Engstrom, MG Bloom,GD Demetri, PG Febbo, et al.
Personalized medicine in oncology is maturing and evolving rapidly, and the use of molecular biomarkers in clinical decisionmaking is growing. This raises important issues regarding the safe, effective, and efficient deployment of molecular tests to guide appropriate care, specifically regarding laboratory-developed tests and companion diagnostics. In May 2011, NCCN assembled a work group composed of thought leaders from NCCN Member Institutions and other organizations to identify challenges and provide guidance regarding molecular testing in oncology and its corresponding utility. The NCCN Molecular Testing Work Group identified

challenges surrounding molecular testing, including health care provider knowledge, determining clinical utility, coding and billing for molecular tests, maintaining clinical and analytic validity of molecular tests, efficient use of specimens, and building clinical evidence. (JNCCN 2011;9[Suppl 6]:S1–S16)

Executive Summary

The FDA recently announced plans for oversight of laboratory-developed tests (LDTs) and released draft guidance regarding the development of companion diagnostics concurrently with therapeutics, both areas over which the FDA has regulatory authority. As recognized by the FDA, these types of diagnostic tests are used increasingly to directly inform treatment decisions, and this especially impacts patients with cancer and their oncologists. However, because of the increasing complexity of some LDTs and increasing commercial interest in oncology-related LDTs in general, the FDA is considering whether its policy of exercising “enforcement discretion”

for LDTs is still appropriate. To provide guidance regarding challenges of molecular testing to health care providers and other stakeholders, NCCN assembled a work group composed of thought leaders from NCCN Member Institutions and other organizations external to NCCN.  The NCCN Molecular Testing Work Group agreed to define molecular testing in oncology as

• procedures designed to detect somatic or germline mutations in DNA and
• changes in gene or protein expression that could impact the
  • diagnosis,
  • prognosis,
  • prediction, and
  • evaluation of therapy of patients with cancer.

Therefore, the discussion focused on molecular tests that predict outcomes for therapy.
Realizing the importance of personalized medicine in advanced NSCLC

E Topol, B Buehler, GS Ginsburg.       Medscape Molec Medicine

With the data on the prognostic and predictive biomarkers EGFR and ALK, biomarker testing is increasingly important in therapy decisions in NSCLC
http://www.nccn.org/professionals/physician_gls/PDF/nscl.pdf/

Lung Cancer in the Never Smoker Population: An Expert Interview With Dr. Nasser Hanna

Lung cancer in the never smoker population is a distinct disease entity with specific molecular changes, offering the potential for targeted therapy.
Experts And Viewpoint, Medscape Hematology-Oncology, December 2007

An Update on New and Emerging Therapies for NSCLC

Simon L. Ekman, MD, PhD; Fred R. Hirsch, MD, PhD

On completion of these readings participants will be thoroughly familiar with these issues:

1. The influence of histologic types and genetic and molecular markers on choosing and personalizing therapy in patients with advanced NSCLC
2. The role of the pathologist in properly classifying subtypes of NSCLC and reporting the presence of molecular markers in tumor samples
3. Familiarize themselves with effective methods of obtaining adequate tissue samples from patients and recognize the importance of accurate pathologic assessment of NSCLC

The rapid developments in molecular biology have opened up new possibilities for individualized treatment of non-small cell lung cancer (NSCLC), and, in recent years, has mainly focused on the epidermal growth factor receptor (EGFR). A greater understanding of the molecular mechanisms behind

• tumorigenesis and
• the identification of new therapeutic targets
  • have sparked the development of novel agents

• • intended to improve the standard chemotherapy regimens for NSCLC.

Along with the advent of targeted therapy, identifying biomarkers to predict the subset of patients more likely to benefit from a specific targeted intervention has become increasingly important.

EGFR TYROSINE KINASE INHIBITORS 

tumor-associated mutations in the tyrosine kinase domain of EGFR have been associated with response to EGFR TKIs

The most common EGFR-sensitizing mutations encompass deletions in exon 19 and a point mutation at L858R in exon 21; together,

• they account for approximately 85% of EGFR mutations in NSCLC.
• Other EGFR mutations have been detected, particularly in exon 20.
  •  mutations identified in exon 20 have been linked to resistance to EGFR TKIsNon-Small Cell Lung Cancer: Biologic and Therapeutic Considerations for Personalized Management
    Taofeek K. Owonikoko, MD, PhD

What is the role and application of molecular profiling in the management of NSCLC?

It is essential to:

1. Identify advances in the understanding of molecular biology and histologic profiling in the treatment of NSCLC
2. Summarize clinical data supporting the use of tumor biomarkers as predictors of therapeutic efficacy of targeted agents in NSCLC
3. Devise an individualized treatment plan for patients with advanced NSCLC based on a tumor’s molecular profile
4. Identify methods for overcoming barriers to effective incorporation of molecular profiling for the management of NSCLC into clinical practice

Non-small cell lung cancer (NSCLC),the most common type of lung cancer, usually grows and spreads more slowly than small cell lung cancer.

The three common forms of NSCLC are:

1. Adenocarcinomas are often found in an outer area of the lung.
2. Squamous cell carcinomas are usually found in the center of the lung next to an air tube (bronchus).
3. Large cell carcinomas occur in any part of the lung and tend to grow and spread faster than the other two types

Smoking causes most cases of lung cancer. The risk depends on the number of cigarettes you smoke every day and for how long you have smoked. Some people who do not smoke and have never smoked develop lung cancer.

Working with or near the following cancer-causing chemicals or materials can also increase your risk:

• Asbestos
• Chemicals such as uranium, beryllium, vinyl chloride, nickel chromates, coal products, mustard gas, chloromethyl ethers, gasoline, and diesel exhaust
• Certain alloys, paints, pigments, and preservatives
• Products using chloride and formaldehyde

Non-small cell lung c

ancer

(NSCLC) accounts for

• approximately 85% of all lung cancers.

Lung cancer  may produce no symptoms until the disease is well advanced, so early recognition of symptoms may be beneficial to outcome.

At initial diagnosis,

• 20% of patients have localized disease,
• 25% of patients have regional metastasis, and
• 55% of patients have distant spread of disease.

Revisiting Doublet Maintenance Chemo in Advanced NSCLC 

H. Jack West, MD

• Pemetrexed Versus Pemetrexed and Carboplatin as Second-Line Chemotherapy In Advanced Non-Small-Cell Lung Cancer

Ardizzoni A, Tiseo M, Boni L, et al

J Clin Oncol. 2102;30:4501-4507

Historically, our second-line therapy has evolved into a strategy of pursuing single-agent therapies for patients with advanced non-small cell lung cancer (NSCLC) who have received prior chemotherapy. This approach was developed on the basis of benefits conferred by such established treatments as docetaxel, pemetrexed, and erlotinib — each well-tested as single agents — and evidence indicating a survival benefit in previously treated patients.

A study out of Italy by Ardizzoni and colleagues published in the Journal of Clinical Oncology directly compares carboplatin/pemetrexed with pemetrexed alone, and

• it provides more evidence that our current approach of sequential singlet therapy remains appropriate.

This randomized phase 2 trial enrolled 239 patients with advanced NSCLC, initially of any histology, then later amended (September 2008) to enroll

• only patients with non-squamous NSCLC because of mounting evidence that pemetrexed is not active in patients with the squamous subtype of advanced NSCLC.

Patients must have received prior chemotherapy (without restriction on regimen except that it could not include pemetrexed). Participants were randomly assigned 1:1 to receive pemetrexed at the standard dose of 500 mg/m2 IV every 21 days or the same chemotherapy with carboplatin at an area under the curve of 5, also IV every 21 days.
The primary endpoint for the trial was progression-free survival (PFS), and the trial was intended to have results pooled with a nearly identically designed trial that was done in The Netherlands. The Dutch trial compared pemetrexed with carboplatin/pemetrexed at the same dose and schedule. The vast majority of patients (97.5%) had a performance status of 0 or 1, and the median age was 64 years.

The Italian study found no evidence to support a benefit in efficacy from the more aggressive doublet regimen. Specifically,

• median PFS was 3.6 months with pemetrexed alone vs 3.5 months with carboplatin/pemetrexed.
• Response rate (RR) and median overall survival (OS) were also no better with the doublet regimen
  • RR 12.6% vs 12.5%, median OS 9.2 vs 8.8 months, for pemetrexed and carboplatin/pemetrexed.

Moreover, pooling the data from the Italian trial with the Dutch trial demonstrated no significant differences between the 2 strategies. Subgroup analysis showed that

• the patients with squamous NSCLC had a superior median PFS of 3.2 months with the carboplatin doublet vs 2.0 months with pemetrexed alone.

Unfortunately, this only confirms that adding a second agent is beneficial for patients receiving an agent previously shown to be ineffective in that population.

Viewpoint

Putting it in the context of previous data, these results only provide further confirmation that more is not better.

• combinations are associated with more toxicity than single-agent therapy, and
• this is likely to be especially relevant in previously treated patients whose ability to tolerate ongoing therapy over time may be reduced.

It is critical to balance efficacy with tolerability to enable us to deliver the treatment over a prolonged period. We need to recognize the importance of pacing ourselves if our goal is to administer treatments in a palliative setting for an increasingly longer duration.

 http://www.medscape.com/viewarticle/777367

Epidermal growth factor receptor (EGFR) signaling pathway. (Photo credit: Wikipedia)

EGFR structure (Photo credit: Wikipedia)

ATP synthase (Photo credit: Ethan Hein)

Non-small cell carcinoma – FNA (Photo credit: Pulmonary Pathology)

Articles on NSCLC in Pharmaceutical Intelligence:

http://pharmaceuticalintelligence.com/2012/11/08/lung-cancer-nsclc-drug-administration-and-nanotechnology/

http://pharmaceuticalintelligence.com/2012/09/18/personalized-rx-decisions-in-nsclc-treatments-symposium-in-thoracic-oncology/

http://pharmaceuticalintelligence.com/2013/01/23/state-of-the-art-in-oncologic-imaging-of-lungs/

http://pharmaceuticalintelligence.com/2013/01/03/differentiation-therapy-epigenetics-tackles-solid-tumors/

http://pharmaceuticalintelligence.com/2012/12/19/nanotechnology-detecting-and-treating-metastatic-cancer-in-the-lymph-node/

http://pharmaceuticalintelligence.com/2012/11/06/non-small-cell-lung-cancer-drugs-where-does-the-future-lie/

http://pharmaceuticalintelligence.com/2012/11/02/cancer-innovations-from-across-the-web/

http://pharmaceuticalintelligence.com/2012/10/22/advances-in-separations-technology-for-the-omics-and-clarification-of-therapeutic-targets/

Key Sources:

1. Realizing the importance of personalized medicine in advanced NSCLC
   E Topol, B Buehler, GS Ginsburg. 
   Medscape Molec Medicine The Potential of Personalized Medicine in Advanced NSCLC
   With the data on the prognostic and predictive biomarkers EGFR and ALK, biomarker testing is increasingly important in therapy decisions in NSCLC

   http://www.nccn.org/professionals/physician_gls/PDF/nscl.pdf/
2. Revisiting Doublet Maintenance Chemo in Advanced NSCLC
   H. Jack West, MD     http://www.medscape.com/viewarticle/777367
   Pemetrexed Versus Pemetrexed and Carboplatin as Second-Line Chemotherapy In Advanced Non-Small-Cell Lung Cancer
   Ardizzoni A, Tiseo M, Boni L, et al
   J Clin Oncol. 2102;30:4501-4507
3. Lung Cancer in the Never Smoker Population: An Expert Interview With Dr. Nasser Hanna
   Experts And Viewpoint, Medscape Hematology-Oncology, December 2007
4. Non-Small Cell Lung Cancer: Biologic and Therapeutic Considerations for Personalized Management
   Taofeek K. Owonikoko, MD, PhD   August 24, 2011.   Medscape
5. An Update on New and Emerging Therapies for NSCLC
   Simon L. Ekman, MD, PhD; Fred R. Hirsch, MD, PhD     Medscape
6. Lovly CM, Carbone DP. Lung cancer in 2010: one size does not fit all. Nat Rev Clin Oncol. 2011;8(2):68-70.

7. Dacic S. Molecular diagnostics of lung carcinomas. Arch Pathol Lab Med. 2011;135(5):622-629.

8. Herbst RS, Heymach JV, Lippman SM. Lung cancer. N Engl J Med. 2008;359(13):1367-1380.

9. Gazdar AF. Epidermal growth factor receptor inhibition in lung cancer: the evolving role of individualized therapy.

   Cancer Metastasis Rev. 2010;29:37-48.

10. NCCN Oncology Insights Report on Non-Small Cell Lung Cancer 1.2010
11.   Review of the Treatment of Non-Small Cell Lung Cancer with Gefitinib
    T Araki, H Yashima, K Shimizu, T Aomori
    Clinical Medicine Insights: Oncology 2012:6 407–421  http://dx.doi.org/10.4137/CMO.S7340

Related articles

• Detection and Clinical Significance of Intratumoral EGFR Mutational Heterogeneity in Chinese Patients with Advanced Non-Small Cell Lung Cancer (plosone.org)
• Patients with EGFR exon 20 insertions have poorer prognosis (medicalxpress.com)
• The Latest Biological Research Featured at ScienceAlerts.com (prweb.com)
• FDA Approves Supplemental New Drug Application for Tarceva: Now, AttorneyOne Can Provide Advice for Legal Counsel in Case of Side Effects (prweb.com)
• By determining structural effects of tumor-causing mutations, scientists obtain valuable information for drug discovery (medicalxpress.com)
• Oncology Learning Network Continuing Education Course to Offer Certificate in Lung Cancer Decision-Making (prweb.com)
• Predictors of Survival in Patients with Non-Small Cell Lung Cancer [Article A Week] (nursetopia.net)
• Multiple Marker Detection in Peripheral Blood for NSCLC Diagnosis (plosone.org)
• The Prognostic Value of Epigenetic Silencing of p16 Gene in NSCLC Patients: A Systematic Review and Meta-Analysis (plosone.org)
• Peripheral Immune Cell Gene Expression Changes in Advanced Non-Small Cell Lung Cancer Patients Treated with First Line Combination Chemotherapy (plosone.org)

 

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Nanotechnology and Ocular Drug Delivery: Part I

Posted in Advanced Drug Manufacturing Technology, BioSimilars, Disease Biology, Drug Delivery Platform Technology, Nanotechnology for Drug Delivery, Pharmaceutical R&D Investment, Small Molecules in Development of Therapeutic Drugs, Technology Transfer: Biotech and Pharmaceutical, tagged anterior chamber, Ciprofloxacin, colloidal carriers, Drug delivery, Human eye, liposome, liposomes, nanoparticles, nanotechnology, Ocular drug delivery, Ophthalmology, posterior chamber, prodrug, Tilda Barliya, Time release technology, Topical on February 23, 2013| Leave a Comment »

Author: Tilda Barliya PhD

Ocular drug delivery is a very challenging field for pharmaceutical scientists.  The unique structure of the eye restricts the entry of drug molecules at the required site of action. The eye and its drugs are classically divided into : Anterior and Posterior segments (1).

Conventional systems like eye drops, suspensions and ointments cannot be considered optimal in  the treatment of vision threatening ocular diseases yet  more than 90% of the marketed ophthalmic formulations are in the form of eye drops.

In the majority of these topical  formulations which target the anterior chamber (the front of the eye) are washed off from the eye by various mechanisms:

• lacrimation,
• tear dilution
• tear turnover
• Moreover, human cornea comprising of epithelium, substantia propria and endothelium also restricts the ocular entry of drug molecules

Under normal condition the human eye can hold about 25–30 μl of an ophthalmic solution; however after a single blink the volume is reduced to 7–10 μl through nasolacrimal drainage which cause the drug to be systemically absorbed across the nasal mucosa or the gastrointestinal tract. A significant systemic loss from topically applied drugs also occurs from conjunctival absorption into the local circulation (4)

Thus resulting in low ocular  bioavailability of drugs with less than 5% of the drugs entering the eye.   Recently many drug efflux pumps have been identified and significant  enhancement in ocular drug absorption was achieved following their inhibition or evasion. But prolonged use of such inhibitors may result in undesirable effects.

Targeting the posterior chamber is even more difficult due to the tight junctions  of blood retinal barrier (BRB) restrict the entry of systemically administered drugs into the retina. Drugs are therefore delivered to the posterior chamber via:

• Intravitreal injections
• Implants
• periocular injections

Here’s an illustration of the several ocular drug and their administration path

The success of nanoparticle systems for ocular drug delivery may depend on optimizing lipophilic-hydrophilic properties of the polymer-drug system, optimizing rates of biodegradation, and safety. Polymers used for the preparation of nanoparticles should be mucoadhesive and biocompatible. The choice of polymer plays an important role in the release kinetics of the drug from a nanoparticle system (4).

The choice of polymer plays an important role in the release kinetics of the drug from a nanoparticle system. Ocular bioavailability from a mucoadhesive dosage form will depend on the polymer’s bioadhesion characteristics, which are affected by its swelling properties, hydration time, molecular weight, and degree of crosslinking. The binding of drug depends on the physicochemical properties of the molecule as well as of the nanoparticle polymer, and also on the manufacturing process for these nanoparticle systems (4).

Other areas in which nanotechnology may be used is the use as biosensors, cell delivery and scaffolds etc (2)

Delivery of a drug via nanotechnology based product fulfills mainly three  objectives as follows:

1. enhances drug permeation
2. controls the release of drug
3. targets drug

Tiwari et al (1) nicely covered different ocular delivery systems available. In this section we’ll review only few of the these drug products:

Viscosity improver:

The viscosity enhancers used are hydrophilic polymers such as cellulose, polyalcohol and polyacrylic acid. Sodium carboxy methyl cellulose is one of the most important mucoadhesion polymers having mono adhesive strength. Viscosity vehicles increases the contact time and no marked sustaining effect are seen.

Prodrugs:

Prodrugs enhance comeal drug permeability through modification of the hydrophilic or lipophilicity of the drug . The method includes modification of chemical structure of the drug molecule, thus making it selective, site specific and a safe ocular drug delivery system. Drugs with increased penetrability through prodrug formulations are epinephrine1, phenylephrine, timolol, and pilocarpine. The main indication of these drugs is to treat glaucoma thought epinephrine1 and phenylephrine are also being used to treat redness of the eye  and/or part of dialing eye-drops.

Colloidal Carriers:
Nanoparticles  provide sustained release-and prolonged therapeutic activity when retained in the cul-de-sac after  topical administration and the entrapped drug must be released from the particles at an appropriate rate. Most commonly used polymers are venous poly (alkyl cyanoacrylates), poly Scaprolactone and polylactic-co-glycolic acid, which undergo hydrolysis in tears. Enhanced permeation across the cornea was also observed when poly (epsilon-caprolactone) nanoparticles were coated with polyethylene glycol.

Liposomes:

Liposomes are lipid vesicles containing aqueous core which have been widely exploited in ocular delivery for various drug molecules.Liposomes are favorable for lipophilic drugs and not for-hydrophilic drugs. liposomes has an affinity to bind to, ocular surfaces, and release contents at optimal rates. Coating with bioadhesive polymers to liposomes, prolong the  precomea retention of liposomes. Carbopol 1342-coated pilocarpine containing liposomes were  shown to produce a longer duration of action. Ciprofloxacin (CPFX) was also formulated in  liposomal environmental which lowered tear-driven dilution in the conjunctival sac.  Multilamellar vesicles from lecithin and alpha-L-dipalmithoyl-phosphatidylcholine were used to prepare liposome containing CPFX. This approach produced sustained release of the drug  depending on the nature of the lipid composition selected.

There are many other known forms used in the industry to enhance drug penetration and bioavailability such as dendrimers, bioadhesive polymers, niosomes and microemulsions which will be discussed elsewhere.

Summary:

Drug delivery by topical and intravitreal routes cannot always be considered safe, effective and patient friendly. Drug delivery by periocular route can potentially overcome many of these limitations and also can provide sustained drug levels in  ocular pathologies affecting both segments. Transporter targeted delivery can be a promising  strategy for many drug molecules. Colloidal carriers can substantially improve the current therapy and may emerge as an alternative following their periocular administration. Ophthalmic drug delivery, more than any other route of administration, may benefit to a full extent from the characteristics of nano-sized drug particles. Other aspect of nanotechnology and ocular drug delivery will be discussed in the next chapter.

REFERENCES

1. Tiwari A and Shukla KR. Novel ocular drug delivery systems: An overview. J. Chem. Pharm. Res., 2010, 2(3):348-355

Click to access JOCPR-2010-2-3-348-355.pdf

2. Kalishwaralal K., Barathmanikanth S., Pandian SR, Deepak V and Gurunathan S.  Silver nano-a trove for retinal therapies. J Control Release  2010 Jul 14;145(2):76-90. http://www.ncbi.nlm.nih.gov/pubmed/20359511

3.Cholkar K., Patel SP., Vadlapudi AD and Mitra AK. Novel Strategies for Anterior Segment Ocular Drug Delivery. J Ocul Pharmaco Ther  2012 Dec 5. [Epub ahead of print]

4. Bucolo C., Drago F and Salomone S. Ocular drug delivery: a clue from nanotechnology. Front Pharmacol. 2012; 3: 188.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3486627/

5. Vega E., Gamisans F., García M. L., Chauvet A., Lacoulonche F., Egea M. A. (2008). PLGA nanospheres for the ocular delivery of flubiprofen: drug release and interactions. J. Pharm. Sci.97, 5306–5317.

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Prostate Cancer: Androgen-driven “Pathomechanism” in Early-onset Forms of the Disease

Posted in CANCER BIOLOGY & Innovations in Cancer Therapy, Chemical Genetics, Computational Biology/Systems and Bioinformatics, Drug Delivery Platform Technology, Genome Biology, Genomic Testing: Methodology for Diagnosis, Health Economics and Outcomes Research, Imaging-based Cancer Patient Management, Molecular Genetics & Pharmaceutical, Nanotechnology for Drug Delivery, Personalized and Precision Medicine & Genomic Research, Population Health Management, Genetics & Pharmaceutical, Reproductive Andrology, Embryology, Genomic Endocrinology, Preimplantation Genetic Diagnosis and Reproductive Genomics, tagged Cancer - General, Cancer cell, Conditions and Diseases, European Molecular Biology Laboratory, Genitourinary, health, Prostate cancer on February 14, 2013| 7 Comments »

Curator: Aviva Lev-Ari, PhD, RN

Word Cloud By Danielle Smolyar

A new etiology for Prostate Cancer based on Integrative Genomic Analyses reveals difference in Pathomechanism between Early onset and and Non-Early onset  was reported this week in Cancer Cell, Volume 23, Issue 2, 159-170, 11 February 2013

Early Onset: Androgen-Driven Somatic Alteration Landscape in Early-Onset Prostate Cancer

Median age of 47: EO-PCAs harbored a prevalence of balanced SRs, with a specific abundance of androgen-regulated ETS gene fusions including TMPRSS2:ERG

Non Early onset:

Around 65 years of age at onset:  elderly-onset PCAs displayed primarily non-androgen-associated structural rearrangement (SR) formations.

Treatment Comparison for Clinically Localized Primary Prostate Cancer Therapies

Treatment	Description	Selected Risks	Recovery	Selected Outcomes
HIFU – (high intensity focused ultrasound)	Minimally invasive use of focused ultrasound waves to ablate diseased tissue	Incontinence: 0-10% 1-3 Impotence: 8-50%4,5 Rectal Injury: <3% 4-6	Catheter worn for approximately 2-3 weeks; can return to normal activities within a few days	55-95% biochemical disease-free survival rate at 5 years; 55-98% negative biopsy1-9
Cryotherapy	Minimally invasive procedure using controlled freeze and thaw cycles to destroy the prostate	Incontinence: 3-10% 10 Impotence: 40-100% 10 Rectal Injury: 0-3% 10	2-3 hour procedure with possible overnight stay; return to normal activities within a few days	50-92% biochemical disease-free survival at 5 years; 87-98% negative biopsy 11,12
Radical Prostatectomy	Surgery to remove prostate, open or laparoscopic	Incontinence: 9-20% 13 Impotence: 4-85%13 Rectal Injury:0-5%14	2-3 day hospital stay, catheter for 2-3 weeks for open surgery; shorter hospitalization and fewer postoperative complications for laparoscopic procedure	68–98% biochemical disease-free survival15,16
External Beam Radiation	6-8 week treatment; external machine concentrating radiation beams to the prostate	Incontinence: 4-15% 17 Impotence: 41-62% 17 Rectal Injury: 15%17	Five treatments per week for 6-8 weeks, up to 2 months fatigue after full course of treatment	55–86% biochemical disease-free survival18-19
Brachytherapy	Minimally invasive implants of radiation seeds in the prostate	Incontinence: 3-18% 20 Impotence: 14-82% 20 Rectal Injury: 3%21	1-2 hour procedure with possible overnight stay	78–89% biochemical disease-free survival22

Data presented are for clinically localized, low-high risk primary prostate cancer. The information provided in the chart is therapy and not device specific and may not include all potential risks, recovery and outcome information. For further information please see references.

The Sonablate^® 500 is approved for investigational use within the U.S. and is being studied for the treatment of prostate cancer in clinical trials in the U.S. The FDA has made no decision as to the safety or efficacy of the Sonablate^® 500 for the treatment of prostate cancer. Currently, the device is available for the treatment of prostate cancer outside the U.S. in more than 30 countries.

http://www.internationalhifu.com/treatment-options/treatment-comparison.html?kmas=1&kmkw=prostate%20cancer%20treatment&gclid=CJbo37P0trUCFQdU4AodWhkAxQ

http://www.internationalhifu.com/treatment-options/treatment-comparison.html?kmas=1&kmkw=prostate%20cancer%20treatment&gclid=CJbo37P0trUCFQdU4AodWhkAxQ#ixzz2KuxByzdV

Prostate Cancer and Nanotecnology

Dr. T. Barlyia summaried:

Early detection of prostate cancer increased dramatically the five-year survival of patients. “This study demonstrates for the first time that it is possible to generate medicines with both targeted and programmable properties that can concentrate the therapeutic effect directly at the site of disease, potentially revolutionizing how complex diseases such as cancer are treated”. The Phase I clinical trial is still ongoing and continued dose escalation is underway; BIND Biosciences is now planning Phase II trials, which will further investigate the treatment’s effectiveness in a larger number of patients.

http://pharmaceuticalintelligence.com/2013/02/07/prostate-cancer-and-nanotecnology/

BIND-014 is a programmable nanomedicine that combines a targeting ligandand a therapeutic nanoparticle.  BIND-014 contains docetaxel, a proven cancer drug which is approved in major cancer indications including breast, prostate and lung, encapsulated in FDA-approved biocompatible and biodegradable polymers. BIND-014 is targeted to prostate specific membrane antigen (PSMA), a cell surface antigen abundantly expressed on the surface of cancer cells and on new blood vessels that feed a wide array of solid tumors.  In preclinical cancer models, BIND-014 was shown to deliver up to ten-fold more docetaxel to tumors than an equivalent dose of conventional docetaxel.  The increased accumulation of docetaxel at the site of disease translated to marked improvements in antitumor activity and tolerability.  BIND-014 is currently in Phase 1 human clinical testing in cancer patients with advanced or metastatic solid tumor cancers (NCT01300533). The early development of BIND-014 was funded in part by the National Cancer Institute and the U.S. National Institutes of Standards and Technology (NIST) under its Advanced Technology Program (ATP).

http://www.bindbio.com/content/pages/news/news_detail.jsp/q/news-id/70

State of the art in oncologic imaging of Prostate

Dr. D. Nir summarizes:

In regards to treatment choice: “active surveillance, focal therapy, radical prostatectomy, and radiation therapy represent a range of treatments with varying degrees of invasiveness for men with different disease grades and stages. Active surveillance and focal therapy, which are relatively new options, are promising but are complicated by uncertainties in risk stratification that affect treatment decision-making, as well as by uncertainties regarding the definition of appropriate outcome measures. Biopsy, which leaves the possibility of under sampling, is not sufficient to resolve these uncertainties. Novel biomarkers and modern imaging are expected to play increasingly important roles in facilitating broader acceptance of both active surveillance and focal therapy. Further research, particularly involving prospective validation, is needed to facilitate standardization and establish the roles of advanced imaging tools in routine prostate cancer management.”

My summary: Prostate cancer is a disease managed by urologists, not radiologists. This disease’s multi-choice of pathways is “craving” for tissue characterization. Nothing could fit the urologist’s work-flow better than ultrasound-based tissue characterization!

http://pharmaceuticalintelligence.com/2013/01/28/state-of-the-art-in-oncologic-imaging-of-prostate/

Age-related differences in structural rearrangement (SR) formation became evident, suggesting distinct disease pathomechanisms. 

Early Onset:

Median age of 47: EO-PCAs harbored a prevalence of balanced SRs, with a specific abundance of androgen-regulated ETS gene fusions including TMPRSS2:ERG,

Non Early onset:

Around 65 years of age at onset:  elderly-onset PCAs displayed primarily non-androgen-associated SRs.

Integrative Genomic Analyses Reveal an Androgen-Driven Somatic Alteration Landscape in Early-Onset Prostate Cancer

Joachim Weischenfeldt,Ronald Simon,Lars Feuerbach,Karin Schlangen,Dieter Weichenhan,Sarah Minner,Daniela Wuttig,Hans-Jörg Warnatz,Henning Stehr,Tobias Rausch,Natalie Jäger,Lei Gu,Olga Bogatyrova,Adrian M. Stütz,Rainer Claus,Jürgen Eils,Roland Eils,Clarissa Gerhäuser,Po-Hsien Huang,Barbara Hutter,Rolf Kabbe,Christian Lawerenz,Sylwester Radomski,Cynthia C. Bartholomae,Maria Fälth,Stephan Gade,Manfred Schmidt,Nina Amschler,Thomas Haß,Rami Galal,Jovisa Gjoni,Ruprecht Kuner,Constance Baer,Sawinee Masser,Christof von Kalle,Thomas Zichner,Vladimir Benes,Benjamin Raeder,Malte Mader,Vyacheslav Amstislavskiy,Meryem Avci,Hans Lehrach,Dmitri Parkhomchuk,Marc Sultan,Lia Burkhardt,Markus Graefen,Hartwig Huland,Martina Kluth,Antje Krohn,Hüseyin Sirma,Laura Stumm,Stefan Steurer,Katharina Grupp,Holger Sültmann,Guido Sauter,Christoph Plass,Benedikt Brors,Marie-Laure Yaspo,Jan O. Korbel,Thorsten SchlommSee Affiliations

• Genome sequencing revealed age-related genetic alterations in PCA
• Early-onset PCAs display a specific abundance of androgen-driven rearrangements
• These age-linked alterations coincide with activity levels of the androgen receptor
• This is an observation of age-specific DNA alterations in a common cancer

Summary

Early-onset prostate cancer (EO-PCA) represents the earliest clinical manifestation of prostate cancer. To compare the genomic alteration landscapes of EO-PCA with “classical” (elderly-onset) PCA, we performed deep sequencing-based genomics analyses in 11 tumors diagnosed at young age, and pursued comparative assessments with seven elderly-onset PCA genomes. Remarkable age-related differences in structural rearrangement (SR) formation became evident, suggesting distinct disease pathomechanisms. Whereas EO-PCAs harbored a prevalence of balanced SRs, with a specific abundance of androgen-regulated ETS gene fusions includingTMPRSS2:ERG, elderly-onset PCAs displayed primarily non-androgen-associated SRs. Data from a validation cohort of > 10,000 patients showed age-dependent androgen receptor levels and a prevalence of SRs affecting androgen-regulated genes, further substantiating the activity of a characteristic “androgen-type” pathomechanism in EO-PCA.

---

Early onset prostate cancer tumors tend to have a propensity for containing balanced structural rearrangements, particularly involving genes regulated by the androgen hormone, according to a study in Cancer Cell. As part of the International Cancer Genome Project’s Early-Onset Prostate Cancer project, researchers from Germany and the UK performed whole-genome sequencing on tumor and matched normal samples from 11 individuals who were surgically treated for prostate cancer at a median age of 47 years old. The tumors were also subjected to transcriptome and methylome sequencing.

When they compared sequences from these tumors with sequences from a previously described set of samples taken from seven individuals diagnosed with prostate cancer at around 65 years of age, investigators saw a rise in gene fusion-producing structural changes in the early onset samples.

Those fusions often affected ETS family genes and other genes prone to androgen-related regulation, researchers reported. In contrast, tumors from individuals whose prostate cancer appeared later in life were more apt to contain structural rearrangements affecting genes without any androgen ties.

Follow-up tests using samples from more than 10,000 other patients seemed to support this link between age at prostate cancer diagnosis and androgen receptor rearrangement, study authors said, pointing to a distinct, androgen-driven “pathomechanism” in early-onset forms of the disease.

SOURCE:

http://www.genomeweb.com//node/1191311?hq_e=el&hq_m=1498692&hq_l=5&hq_v=5f2bf80408

Cancer Cell, Volume 23, Issue 2, 159-170, 11 February 2013
Copyright © 2013 Elsevier Inc. All rights reserved.
10.1016/j.ccr.2013.01.002

http://www.internationalhifu.com/treatment-options/treatment-comparison.html?kmas=1&kmkw=prostate%20cancer%20treatment&gclid=CJbo37P0trUCFQdU4AodWhkAxQ#ixzz2KuxrkZbB

REFERENCES

1. Uchida T, Ohkusa H, Nagata Y, Hyodo T, Satoh T, Irie A. Treatment of localized prostate cancer using high-intensity focused ultrasound. BJU international 2006;97:56-61.
2. Uchida T, Ohkusa H, Yamashita H, et al. Five years experience of transrectal high-intensity focused ultrasound using the Sonablate device in the treatment of localized prostate cancer. International journal of urology : official journal of the Japanese Urological Association 2006;13:228-33.
3. Muto S, Yoshii T, Saito K, Kamiyama Y, Ide H, Horie S. Focal therapy with high-intensity-focused ultrasound in the treatment of localized prostate cancer. Japanese journal of clinical oncology 2008;38:192-9.
4. Ahmed HU, Zacharakis E, Dudderidge T, et al. High-intensity-focused ultrasound in the treatment of primary prostate cancer: the first UK series. British journal of cancer 2009;101:19-26.
5. Inoue Y, Goto K, Hayashi T, Hayashi M. Transrectal high-intensity focused ultrasound for treatment of localized prostate cancer. International journal of urology : official journal of the Japanese Urological Association 2011;18:358-62.
6. Uchida T, Shoji S, Nakano M, et al. Transrectal high-intensity focused ultrasound for the treatment of localized prostate cancer: eight-year experience. International journal of urology : official journal of the Japanese Urological Association 2009;16:881-6.
7. Sumitomo M, Hayashi M, Watanabe T, et al. Efficacy of short-term androgen deprivation with high-intensity focused ultrasound in the treatment of prostate cancer in Japan. Urology 2008;72:1335-40.
8. Sumitomo M, Asakuma J, Yoshii H, et al. Anterior perirectal fat tissue thickness is a strong predictor of recurrence after high-intensity focused ultrasound for prostate cancer. International journal of urology : official journal of the Japanese Urological Association 2010;17:776-82.
9. Dudderidge T, Ahmed H, Emberton M. High-intensity focused ultrasound for localized prostate cancer: initial experience with a 2-year follow-up. BJU international 2009;104:1170-1; author reply 1.
10. Shelley M, Wilt TJ, Coles B, Mason MD. Cryotherapy for localised prostate cancer. Cochrane Database Syst Rev 2007:CD005010.
11. Cheetham P, Truesdale M, Chaudhury S, Wenske S, Hruby GW, Katz A. Long-term cancer-specific and overall survival for men followed more than 10 years after primary and salvage cryoablation of the prostate. Journal of endourology / Endourological Society 2010;24:1123-9.
12. Jones JS, Rewcastle JC, Donnelly BJ, Lugnani FM, Pisters LL, Katz AE. Whole gland primary prostate cryoablation: initial results from the cryo on-line data registry. The Journal of urology 2008;180:554-8.
13. Hu JC, Gu X, Lipsitz SR, et al. Comparative effectiveness of minimally invasive vs open radical prostatectomy. JAMA : the journal of the American Medical Association 2009;302:1557-64.
14. Williams SB, Prasad SM, Weinberg AC, et al. Trends in the care of radical prostatectomy in the United States from 2003 to 2006. BJU international 2011;108:49-55.
15. Mullins JK, Feng Z, Trock BJ, Epstein JI, Walsh PC, Loeb S. The impact of anatomical radical retropubic prostatectomy on cancer control: the 30-year anniversary. The Journal of urology 2012;188:2219-24.
16. Loeb S, Zhu X, Schroder FH, Roobol MJ. Long-term radical prostatectomy outcomes among participants from the European Randomized Study of Screening for Prostate Cancer (ERSPC) Rotterdam. BJU international 2012.
17. Budaus L, Bolla M, Bossi A, et al. Functional outcomes and complications following radiation therapy for prostate cancer: a critical analysis of the literature. European urology 2012;61:112-27.
18. Grimm P, Billiet I, Bostwick D, et al. Comparative analysis of prostate-specific antigen free survival outcomes for patients with low, intermediate and high risk prostate cancer treatment by radical therapy. Results from the Prostate Cancer Results Study Group. BJU international 2012;109 Suppl 1:22-9.
19. Wilt TJ, MacDonald R, Rutks I, Shamliyan TA, Taylor BC, Kane RL. Systematic review: comparative effectiveness and harms of treatments for clinically localized prostate cancer. Annals of internal medicine 2008;148:435-48.
20. Buckstein M, Kerns S, Forysthe K, Stone NN, Stock RG. Temporal patterns of selected late toxicities in patients treated with brachytherapy or brachytherapy plus external beam radiation for prostate adenocarcinoma. BJU international 2012.
21. Orio PF, 3rd, Merrick GS, Galbreath RW, Butler WM, Lief J, Wallner KE. Patient-reported long-term rectal function after permanent interstitial brachytherapy for clinically localized prostate cancer. Brachytherapy 2012;11:341-7.
22. Critz FA, Benton JB, Shrake P, Merlin ML. 25 year disease free survival rate after irradiation of prostate cancer calculated with the prostate specific antigen definition of recurrence used for radical prostatectomy. The Journal of urology 2012.

http://www.internationalhifu.com/treatment-options/treatment-comparison.html?kmas=1&kmkw=prostate%20cancer%20treatment&gclid=CJbo37P0trUCFQdU4AodWhkAxQ#ixzz2KuxrkZbB

Other research papers related to the management of Prostate cancer were published on this One Access Online Scientific Journal

Imaging agent to detect Prostate cancer-now a reality

Scientists use natural agents for prostate cancer bone metastasis treatment

Today’s fundamental challenge in Prostate cancer screening

ROLE OF VIRAL INFECTION IN PROSTATE CANCER

Men With Prostate Cancer More Likely to Die from Other Causes

New Prostate Cancer Screening Guidelines Face a Tough Sell, Study Suggests

New clinical results supports Imaging-guidance for targeted prostate biopsy

Prostate Cancer and Nanotecnology

http://pharmaceuticalintelligence.com/2013/02/07/prostate-cancer-and-nanotecnology/

State of the art in oncologic imaging of Prostate

http://pharmaceuticalintelligence.com/2013/01/28/state-of-the-art-in-oncologic-imaging-of-prostate/

Genomically Guided Treatment after CLIA Approval: to be offered by Weill Cornell Precision Medicine Institute
http://pharmaceuticalintelligence.com/2013/02/06/genomically-guided-treatment-after-clia-approval-to-be-offered-by-weill-cornell-precision-medicine-institute/

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State of the art in oncologic imaging of breast.

Posted in Bio Instrumentation in Experimental Life Sciences Research, Biomarkers & Medical Diagnostics, CANCER BIOLOGY & Innovations in Cancer Therapy, Computational Biology/Systems and Bioinformatics, Ecosystems & Industrial Concentration in the Medical Device Sector, FDA Regulatory Affairs, Health Economics and Outcomes Research, HealthCare IT, Imaging-based Cancer Patient Management, Medical Devices R&D and Inventions, Medical Devices R&D Investment, Nanotechnology for Drug Delivery, Personalized and Precision Medicine & Genomic Research, Population Health Management, Genetics & Pharmaceutical, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Reproductive Biology & Bio Instrumentation, Technology Transfer: Biotech and Pharmaceutical, tagged American Society of Clinical Oncology, Biology, breast cancer, Cancer - General, Clinical trial, Conditions and Diseases, FDA, FDG PET, Food and Drug Administration, health, medicine, MRI, National Institutes of Health, oncologic imaging, oncology, PEM, Personalized medicine, PET/MRI, Proceedings of the National Academy of Sciences of the United States of America, research, United States on January 21, 2013| 2 Comments »

State of the art in oncologic imaging of breast.

Author-Writer: Dror Nir, PhD

Word Cloud By Danielle Smolyar

In the coming posts I will address the state of the art in oncologic imaging based on a review paper; Advances in oncologic imaging^†‡ that provides updates on the latest approaches to imaging of 5 common cancers: breast, lung, prostate, colorectal cancers, and lymphoma. This paper is published at CA Cancer J Clin 2012. © 2012 American Cancer Society.

The paper gives a fair description of the use of imaging in interventional oncology based on literature review of more than 200 peer-reviewed publications.

In this post I summaries the chapter on breast cancer imaging.

Breast Cancer Imaging

As a start the authors describes the evolution in the ACS imaging guidelines for breast cancer screening. Most interesting to learn is how age limits are changing. The most recent: “In 2010, the Society of Breast Imaging and the Breast Imaging Commission of the ACS issued recommendations for breast cancer screening to provide guidance in light of the controversies and emerging technologies.5 These recommendations were based on multiple prospective randomized trials as well as population-based experience.

Recommendations for screening with non-mammographic imaging are based not on evidence showing mortality reduction but largely on surrogate indicators, i.e., tumor size and nodal status, suggesting improved survival compared with women who are not screened.” I have referred to these guidelines in my recent post: Not applying evidence-based medicine drives up the costs of screening for breast-cancer in the USA.

As long as imaging interpretation is based mainly on observations related to lesion morphology:

“The imaging characteristics of malignant lesions are nonspecific and usually do not allow a definitive diagnosis. When a biopsy is recommended based on mammography, it has a 25% to 45% likelihood of resulting in a diagnosis of carcinoma.11 Similar positive predictive values are reported for biopsies recommended based on MRI.”

It is worthwhile noting that these results do not reflect purely the specificity of the imaging device but rather the specificity of the whole workflow; i.e imaging, biopsy and histopathology. All imaging techniques have false negatives: Mammography screening of general population misses approximately 20% of the cancers. This rate increases as breast density increases. MRI is not applied to general population. When applied to highly suspicious cases MRI misses ~10% of the invasive cancers. Although ultrasound has proven to be useful in detecting cancer especially in women with dense breasts: Automated Breast Ultrasound System (‘ABUS’) for full breast scanning: The beginning of structuring a solution for an acute need! Based on the literature reviewed by the authors of this paper they do not recommend routine sonography for these women.

For women with locally advanced breast cancer (Fig. 2) who undergo neoadjuvant therapy before breast surgery, the authors recommends post-treatment staging using MRI, which has been found to predict complete response with sensitivity above 60% and specificity as high as 90%.26

A 27-year-old female with locally advanced poorly differentiated invasive ductal carcinoma underwent evaluation of extent of disease before starting neoadjuvant chemotherapy. Sagittal fat-suppressed T1-weighted postcontrast MR images demonstrate an almost 6-cm heterogeneously enhancing mass (A) involving the skin of the lower breast (arrow) with (B) right axillary (arrow) and (C) right internal mammary adenopathy (arrow).

Same is recommended for women who have undergone lumpectomy if the surgical margins are positive. As post therapy follow-up, a new baseline mammogram of the treated breast is recommended followed by annual mammography.

In regards to emerging technology the following are discussed: Mammographic tomosynthesis – see also Improving Mammography-based imaging for better treatment planning

Contrast-enhanced digital mammography – “involves the injection of iodinated contrast material, as is done for computed tomography (CT); this enables hypervascular lesions to be seen with modified mammography technology, potentially providing the same information obtained through MRI. Little has been published on the clinical application of this technology, but diagnostic accuracy better than that of mammography and approaching that of MRI has been reported.31, 32”

MR choline spectroscopy – has been shown to improve the positive predictive value of breast MRI and may be useful in reducing the number of lesions that require biopsy (Fig. 4).33 Studies of spectroscopy have reported sensitivities of 70% to 100% and specificities of 67% to 100% in the detection of breast cancer. Decreasing choline concentrations may also be a useful indication of tumor response to treatment before any change in tumor volume can be detected.34, 35 Technical factors have limited the use of spectroscopy to lesions 1 cm in size or larger.”

Sagittal fat-suppressed T1-weighted postcontrast MR image is shown (A) of the right breast of a 48-year-old female who was status post–contralateral mastectomy for DCIS with the spectroscopy voxel placed over an enhancing mass (arrow). The magnified spectrum (B) demonstrated no choline peak. Biopsy yielded fibroadenoma.

Diffusion-weighted MRI (DW-MRI) – “adding DW-MRI data to other imaging characteristics of lesions on breast MRI may increase the positive predictive value of the examination, in turn decreasing the number of benign lesions requiring biopsy for diagnosis.” See also Imaging: seeing or imagining? (Part 2).

Axial T1-weighted fat-suppressed postcontrast MR image is shown (A) of the left breast of a 42-year-old female with biopsy-proven contralateral cancer undergoing evaluation of disease extent. An enhancing mass (arrow) was seen in the left breast. This mass (arrow) was also demonstrated on the axial diffusion-weighted MR image (B). Biopsy yielded fibroadenoma with atypical ductal hyperplasia and lobular carcinoma in situ.

Ultrasound-elastography – “Ultrasound elastography has been reported to differentiate benign from malignant breast lesions with sensitivities of 78% to 100% and specificities of 21% to 98%.39 When added to other US techniques, it may improve radiologists’ performance in distinguishing malignant breast lesions.”

Positron emission tomography (PET) – “alone or combined with CT, allows noninvasive, quantitative assessment of biochemical and functional processes at the molecular level in the body. It is most often performed with the radiolabeled glucose analogue [18F] fluorodeoxyglucose ([18F]FDG) to detect the elevated glucose metabolism that is a hallmark of cancer. In breast cancer, its utility depends on the pretest probability for advanced disease, and thus the clinical stage.” The authors found that the use of [18F] FDG PET to patients with stage I and II disease is “limited”. Specifically, they claim that it is not sufficiently accurate for axillary nodal staging in this subset of patients.40 The did find enough evidence to recommend the use of FDG PET in patients with advanced disease: “where it accurately defines disease extent,41 and frequently eliminates the need for other imaging tests, and provides an early readout of treatment response as well as prognostic information.”

Combined PET/MRI is mentioned as a promising technology for predicting response to therapy “but this remains to be proven”.

Positron emission mammography (PEM) – “adapts full-body PET imaging to the breast. In a multicenter study, the interpretation of PEM in conjunction with mammographic and clinical findings yielded a sensitivity of 91% and a specificity of 93% for breast cancer.47 “. However, the authors mention that its use for screening (applying to healthy women) has been criticized because of the need to administer a radioactive tracer.

Lung Cancer Imaging

To be followed…

Other research papers related to the management of breast cancer were published on this Scientific Web site:

The unfortunate ending of the Tower of Babel construction project and its effect on modern imaging-based cancer patients’ management

 Automated Breast Ultrasound System (‘ABUS’) for full breast scanning: The beginning of structuring a solution for an acute need!

Introducing smart-imaging into radiologists’ daily practice.

Will Bio-Tech make Medical Imaging redundant?

Improving Mammography-based imaging for better treatment planning

Not applying evidence-based medicine drives up the costs of screening for breast-cancer in the USA.

New Imaging device bears a promise for better quality control of breast-cancer lumpectomies – considering the cost impact

Harnessing Personalized Medicine for Cancer Management, Prospects of Prevention and Cure: Opinions of Cancer Scientific Leaders @ http://pharmaceuticalintelligence.com

Predicting Tumor Response, Progression, and Time to Recurrence

“The Molecular pathology of Breast Cancer Progression”

Personalized medicine gearing up to tackle cancer

Whole-body imaging as cancer screening tool; answering an unmet clinical need?

What could transform an underdog into a winner?

Mechanism involved in Breast Cancer Cell Growth: Function in Early Detection & Treatment

Nanotech Therapy for Breast Cancer

A Strategy to Handle the Most Aggressive Breast Cancer: Triple-negative Tumors

Optical Coherent Tomography – emerging technology in cancer patient management

Breakthrough Technique Images Breast Tumors in 3-D With Great Clarity, Reduced Radiation

Closing the Mammography gap

Imaging: seeing or imagining? (Part 1)

Imaging: seeing or imagining? (Part 2)

 

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AAAS February 14-18, 2013, Boston: Symposia – The Science of Uncertainty in Genomic Medicine

Posted in Genome Biology, Nanotechnology for Drug Delivery, tagged AAAS on January 20, 2013| Leave a Comment »

Reporter: Aviva Lev-Ari, PhD, RN

What is AAAS?

The American Association for the Advancement of Science, “Triple A-S” (AAAS), is an international non-profit organization dedicated to advancing science around the world by serving as an educator, leader, spokesperson and professional association. In addition to organizing membership activities, AAAS publishes the journal Science, as well as many scientific newsletters, books and reports, and spearheads programs that raise the bar of understanding for science worldwide.

AAAS History
Founded in 1848, AAAS serves some 261 affiliated societies and academies of science, serving 10 million individuals. Science has the largest paid circulation of any peer-reviewed general science journal in the world, with an estimated total readership of one million. The non-profit AAAS is open to all and fulfills its mission to “advance science and serve society” through initiatives in science policy; international programs; science education; and more. For the latest research news, log onto EurekAlert!, the premier science-news Web site, a service of AAAS.

AAAS is a global organization, with offices in Washington, D.C. and Cambridge, U.K., and award-winning news correspondents reporting from an array of countries. The U.S. headquarters facility, designed by renowned architect Henry N. Cobb of Pei Cobb Freed & Partners, was dedicated in September 1997 as the William T. Golden Center for Science and Engineering, in honor of the Association’s long-time treasurer. In 2009, the AAAS headquarters facility became the first existing, not newly constructed facility in the District of Columbia to earn a gold-level certification through the U.S. Green Building Council‘s Leadership Environmental & Energy Design program.

Membership and Programs
Open to all, AAAS membership includes a subscription to Science. Four primary program areas fulfill the AAAS mission:

• Science and Policy
• International Activities
• Education and Human Resources
• Project 2061

AAAS Mission
AAAS seeks to “advance science, engineering, and innovation throughout the world for the benefit of all people.” To fulfill this mission, the AAAS Board has set these broad goals:

• Enhance communication among scientists, engineers, and the public;
• Promote and defend the integrity of science and its use;
• Strengthen support for the science and technology enterprise;
• Provide a voice for science on societal issues;
• Promote the responsible use of science in public policy;
• Strengthen and diversify the science and technology workforce;
• Foster education in science and technology for everyone;
• Increase public engagement with science and technology; and
• Advance international cooperation in science.

Symposia – The Science of Uncertainty in Genomic Medicine

Friday, February 15, 2013: 10:00 AM-11:30 AM

Room 313 (Hynes Convention Center)

The notion of “personalizing” health care through the use of an individual’s genetic code has attracted considerable enthusiasm and investment. Impressive examples, confirmed through formal studies of clinical validity and utility, suggest that we have only scratched the surface of applications to treat disease more precisely, identify risk factors for complex disease, and guide preventative measures. As the cost of sequencing entire exomes and genomes falls, the opportunities for people around the world to take possession of their entire genetic code will proliferate. However, one irony of the precise determination of all 3.2 billion nucleotide pairs is the lack of understanding of the meaning of many sequence variations. More than 1,500 single nucleotide variations are associated with risks for more than 200 complex diseases, but despite their commercialization, these account for a small proportion of heritability. Thus, in both translational science and clinical practice, the substantial uncertainty in interpreting genomic information serves as an important barrier to application. Coping with uncertainty can be addressed quantitatively, but how the information is understood, presented, and interpreted has best been addressed qualitatively. Transdisciplinary teams of professionals may be best suited to study the many facets of uncertainty in genomic medicine.

Organizer:

Reed E. Pyeritz, University of Pennsylvania

Co-Organizer:

Shili Lin, Ohio State University

Moderator:

Reed E. Pyeritz, University of Pennsylvania

Speakers:

 

Giovanni Parmigiani, Harvard Medical School

How Useful Is It to Know Your Genome?

James P. Evans, University of North Carolina

Genomics in Clinical Medicine: Navigating the Spectrum from Certainty to Uncertainty

ert C. Green, Partners Center for Personalized Genetic Medicine

 

A Data-Driven Pathway to Genomic Medicine

Friday, February 15, 2013

Room 313 (Hynes Convention Center)

Robert C. Green , Partners Center for Personalized Genetic Medicine, Boston, MA

Physicians and other health care professionals, including medical geneticists, have little understanding or experience in applying information about a person’s entire genome to risk prediction for complex diseases. We have been studying what patients are interested in knowing and how they would like data presented and discussed.

 

The Architecture of the Cell Nucleus

Friday, February 15, 2013: 10:00 AM-11:30 AM

Room 203 (Hynes Convention Center)

The cell nucleus in humans and other higher organisms is filled with chromatin, the protein-DNA complex in which the genome is packaged. However, the arrangement of chromatin within the nucleus is not random. Entire specific regions of the genome are localized near the nuclear periphery; others are sequestered in “organelles” such as the nucleolus. In each case, the location may control the activity of the gene. Certain chromosomes contain genes that control sex-specific features of the organism. Genes on these chromosomes may be specifically silenced or activated by structures that propagate and extend over the entire chromosome. It has been known for a long time that the expression of genes is controlled by DNA sequence elements located close to the genes themselves. However, striking results obtained over the last several years show that important contributions to this regulation are also made by DNA sequences far away from the target gene: within the nucleus, distant sites on chromatin make many specific and preferred long-range contacts. Many of these are associated with previously unsuspected regulatory pathways. All these results lead to a revised view of the nucleus, which contains both complex networks of interacting sites and highly organized substructures.

Organizer:

Gary Felsenfeld, National Institute of Diabetes and Digestive and Kidney Diseases

Moderator:

Gary Felsenfeld, National Institute of Diabetes and Digestive and Kidney Diseases

Speakers:

 

Mitzi Kuroda, Harvard Medical School

Chromosome-Specific Targeting of Dosage Compensation in Drosophila

 

Thomas A. Misteli, National Cancer Institute

Nuclear Architecture and Disease

 

Job Dekker, University of Massachusetts Medical School

3D Folding of Genomes

New Frontiers in Single Molecule Detection and Single Cell Analysis

Saturday, February 16, 2013: 8:30 AM-11:30 AM

Room 206 (Hynes Convention Center)

Single molecule detection (SMD) and single cell analysis (SCA) offer unique opportunities for detection of biomarkers for early disease diagnosis, for ultrasensitive assessing of environmental impacts, and for probing distinctive functions of individual molecules in single live cells. Smart functions of single live cells have also inspired designs of intelligent bio-inspired devices. At the cellular level, a small number of biomolecules can induce drastic cellular responses and lead to disease, emphasizing the importance of molecular detection of trace amounts of biomolecules in single live cells. This symposium is structured to showcase the latest advances in SMD and SCA and their applications.

Organizer:

X. Nancy Xu, Old Dominion University

Moderator:

X. Nancy Xu, Old Dominion University

Speakers:

 

Robert Singer, Albert Einstein College of Medicine

Following Single mRNA Molecules in Living Cells and Tissues

 

George Church, Harvard Medical School

In Situ Sequencing

 

Linda B. McGown, Rensselaer Polytechnic Institute

Investigating Protein Capture at Aptamer‑Coated Surfaces

 

X. Nancy Xu, Old Dominion University

Nanoparticle Biosensors for Mapping Single‑Molecule Functions in Single Live Cells

 

Scott Fraser, California Institute of Technology

Imaging the Cellular and Molecular Dynamics That Pattern Embryos

 

Xiaowei Zhuang, Harvard University

Single‑Molecule and Super‑Resolution Imaging of Cells and Tissues

Confluence of Streams of Knowledge: Biotechnology and Nanotechnology

How Macro-Evolutionary Studies Call for an Extended Synthesis

Sunday, February 17, 2013: 8:30 AM-11:30 AM

Room 203 (Hynes Convention Center)

When Eldredge and Gould formulated the punctuated equilibria theory, they put several macroevolutionary phenomena on the agenda that were not addressed by the early population geneticists and the founders of the Modern Synthesis. Their theory provides alternative scientific interpretations for the mode and tempo of evolution. Occurring gaps in the fossil record, or the lack of evidence for the existence of intermediate species, are understood as real. And some (living) fossils do not appear to undergo any significant evolutionary change for millions of years, which necessitates the study of stasis. Acknowledging that evolution can occur faster or slower than predicted by Neodarwinians has consequences for how we define species and for determining the levels of evolution. Macroevolutionary studies provide different species concepts and argue that evolution can occur at levels higher than the pheno- or genotype. Today, multiple scholars investigate the causes of evolutionary stasis as well as punctuations, macroevolutionary trends, and how evolution occurs at different hierarchies. In recent years, evidence for macroevolution is also provided from within the field of molecular biology, and the pattern of punctuated equilibrium has been proven to be present in neontological and even sociocultural evolutionary phenomena. The session will examine how macroevolutionary studies call for an extension of the Modern Synthesis and which methodologies and techniques enable the study of macroevolutionary events.

Organizer:

Nathalie L. Gontier, University of Lisbon

Co-Organizer:

Emanuele Serrelli, University of Milan-Bicocca

Moderator:

Emanuele Serrelli, University of Milan-Bicocca

Speakers:

 

David Sepkoski, Max Planck Institute for the History of Science

Stephen Jay Gould’s Hierarchical Alternative to Neodarwinism

 

Douglas H. Erwin, Smithsonian Institution

The Evolution of Evolution: Changing Dynamics in Macroevolution

 

Derek Turner, Connecticut College

Contingency and the Explanation of Macroevolutionary Trends

 

Folmer Bokma, Umeå University

Complexity and Limits to Change

 

Nathalie L. Gontier, University of Lisbon

Punctuated Equilibria: A Universal Pattern in Life and Culture

 

Alycia L. Stigall, Ohio University

Expanding the Role of Biogeography and Niche Evolution in Macroevolutionary Theory

How Macro-Evolutionary Studies Call for an Extended Synthesis

Sunday, February 17, 2013: 8:30 AM-11:30 AM

Room 203 (Hynes Convention Center)

When Eldredge and Gould formulated the punctuated equilibria theory, they put several macroevolutionary phenomena on the agenda that were not addressed by the early population geneticists and the founders of the Modern Synthesis. Their theory provides alternative scientific interpretations for the mode and tempo of evolution. Occurring gaps in the fossil record, or the lack of evidence for the existence of intermediate species, are understood as real. And some (living) fossils do not appear to undergo any significant evolutionary change for millions of years, which necessitates the study of stasis. Acknowledging that evolution can occur faster or slower than predicted by Neodarwinians has consequences for how we define species and for determining the levels of evolution. Macroevolutionary studies provide different species concepts and argue that evolution can occur at levels higher than the pheno- or genotype. Today, multiple scholars investigate the causes of evolutionary stasis as well as punctuations, macroevolutionary trends, and how evolution occurs at different hierarchies. In recent years, evidence for macroevolution is also provided from within the field of molecular biology, and the pattern of punctuated equilibrium has been proven to be present in neontological and even sociocultural evolutionary phenomena. The session will examine how macroevolutionary studies call for an extension of the Modern Synthesis and which methodologies and techniques enable the study of macroevolutionary events.

Organizer:

Nathalie L. Gontier, University of Lisbon

Co-Organizer:

Emanuele Serrelli, University of Milan-Bicocca

Moderator:

Emanuele Serrelli, University of Milan-Bicocca

Speakers:

 

David Sepkoski, Max Planck Institute for the History of Science

Stephen Jay Gould’s Hierarchical Alternative to Neodarwinism

 

Douglas H. Erwin, Smithsonian Institution

The Evolution of Evolution: Changing Dynamics in Macroevolution

 

Derek Turner, Connecticut College

Contingency and the Explanation of Macroevolutionary Trends

 

Folmer Bokma, Umeå University

Complexity and Limits to Change

 

Nathalie L. Gontier, University of Lisbon

Punctuated Equilibria: A Universal Pattern in Life and Culture

 

Alycia L. Stigall, Ohio University

Expanding the Role of Biogeography and Niche Evolution in Macroevolutionary Theory

Monday, February 18, 2013: 9:45 AM-12:45 PM

Room 300 (Hynes Convention Center)

As scientists are able to understand and manipulate ever-smaller scales of matter, a confluence of research streams in the fields of biotechnology and nanotechnology has enabled such innovations as lab-on-a-chip devices, targeted drug delivery, and other forms of minimally invasive therapy and diagnostics. As an example of the confluence of technology streams, the tissue-engineering field combines advances in developmental biology with engineering and materials methods to replace or improve tissue, organs, and other biological functions. This is not a typical interdisciplinary situation where a cell type can be given over to an engineer or an engineer can guess what kind of scaffold will work in a biological system. Rather, there must be a multidisciplinary collaboration from the start, with all participants having common reference points and language. Although there are challenges for managing research and development at the confluence of research streams, there is also greater opportunity for radical innovation. Research at confluence of biotechnology and nanotechnology is producing great benefits for society — biomedical innovations and clean energy innovations  — and is stimulating an emerging industrial sector. In this symposium, the challenges and opportunities of such research will be explored, with implications for the organization of research in universities, research institutes, technology ventures, and multinational organizations.

Organizer:

Elicia M.A. Maine, Simon Fraser University

Co-Organizer:

James M. Utterback, Massachusetts Institute of Technology

Moderator:

James M. Utterback, Massachusetts Institute of Technology

Speakers:

 

Robert S. Langer, Massachusetts Institute of Technology

Challenges and Opportunities at the Confluence of Biotechnology and Nanomaterials

 

Nathan Lewis, California Institute of Technology

Clean Energy Innovation from the Confluence of Technologies

 

Sarah Kaplan, University of Toronto

The Process and Practice of Interdisciplinary Research

 

Elicia M.A. Maine, Simon Fraser University

Global Bio-Nano Firms: Exploiting the Confluence of Technologies

 

Han Cao, BioNano Genomics Inc.

Commercializing Innovation: Applying Nanotechnology to Genomics

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