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Posts Tagged ‘Clinical Trials’


Hormonal Therapy, Complementary and Alternative Therapies – 9.4

Writer and Curator: Larry H. Bernstein, MD, FCAP

The following material has been covered from a different vantage point in previous writings. In the previous articles the focus was both antibacterial and anticancer resistance.  Much of the focus was on the metabolomic studies of substrate fluxes across cells and extracellular analyses to determine differences between cancer cell types in vitro.  This time I shall cover some of the selected ground with a different perspective.  Alternative medicines have been around for thousands of years. Much of it was based on readily available plants that had a pharmacological action.  This also gave rise to pharmaceuticals by extraction of the active compound. Such was the case with digitalis and also with Warfarin.

9.4.1 Use of complementary medicine by adult patients participating in cancer clinical trials

9.4.2 Complementary/Alternative Medicine Use in a Comprehensive Cancer Center and the Implications for Oncology

9.4.3 Trends in Alternative Medicine Use in the United States, 1990-1997 Results of a Follow-up National Survey

9.4.4 Courses Involving Complementary and Alternative Medicine at US Medical Schools

9.4.5 38% of Adults Use Alternative Medicine

9.4.6 Wheat germ extract (Avemar, Avé, AvéULTRA, AWGE, OncoMAR)

9.4.7 How Avemar Helps Fight Cancer

9.4.8  The anti-cancer action of curcumin (turmeric)

Introduction – PENDING

9.4.1 Use of complementary medicine by adult patients participating in cancer clinical trials
Sparber ABauer LCurt GEisenberg DLevin TParks SSteinberg SMWootton J
Oncology Nursing Forum [2000, 27(4):623-630]
http://europepmc.org/abstract/med/10833691

PURPOSE/OBJECTIVES: To document the prevalence, demographic correlates, patterns of use, and beliefs about complementary and alternative medicine (CAM) therapies of adult patients enrolled in National Cancer Institute (NCI) clinical trials. DESIGN: Prospective, cross-sectional, descriptive survey.
SETTING: W.G. Magnuson Clinical Center of the National Institutes of Health in Bethesda, MD. SAMPLE: Convenience sample of 100 English-speaking, adult patients with cancer admitted to intramural clinical trials.
METHODS: A standardized, 99-item questionnaire assessing use of CAM therapies pre- and postcancer diagnosis was administered by face-to-face interview. MAIN RESEARCH VARIABLES: Use of CAM therapies, beliefs, communication with physician. FINDINGS: 63% used at least one CAM therapy, with an average use of two therapies per patient. Men were significantly less likely to use a therapy than women; women were more likely to use numerous therapies. Cancer diagnosis seems to have had no influence overall on the frequency of use of CAM therapies. The major reasons stated for CAM use were for treatment-related medical conditions as well as depression, anxiety, and insomnia. The most frequently reported therapies were spiritual, relaxation, imagery, exercise, lifestyle diet (e.g., macrobiotic, vegetarian), and nutritional supplementation. Patients unanimously believed that these complementary therapies helped to improve their quality of life through more effective coping with stress, decreasing the discomforts of treatment and illness, and giving them a sense of control. CONCLUSIONS: Patients with cancer use various complementary therapies to cope with their disease and the rigors of clinical trials. Women and those with higher educational backgrounds were more frequent users.
IMPLICATIONS FOR NURSING PRACTICE: Nurses who provide care to subjects of biomedical research have an opportunity and responsibility regarding their patients’ use of CAM therapies. Nurses may use in-house resources to help evaluate subjects’ use of a CAM modality or to provide quality-of-life therapies such as relaxation, imagery, or healing touch. Discussing these health practices in a nonjudgmental manner adds to the assessment of patients’ coping skills and ability to make decisions about their health care.

9.4.2 Complementary/Alternative Medicine Use in a Comprehensive Cancer Center and the Implications for Oncology
MA Richardson, T Sanders, JL Palmer, A Greisinger, and SE Singletary
J Clin Oncol 18:2505-2514.
http://www.integratedhealthclinic.com/assets/byTopic/IntegrativeOncology/3-CAM%20Use%20in%20MD%20Anderson-J%20Clin%20Oncol%202000.pdf

Purpose: Oncologists are aware that their patients use complementary/ alternative medicine (CAM). As cancer incidence rates and survival time increase, use of CAM will likely increase. This study assessed the prevalence and predictors of CAM use in a comprehensive cancer center. Subjects and Methods: Subjects were English-speaking cancer patients at least 18 years of age, attending one of eight outpatient clinics at The University of Texas M.D. Anderson Cancer Center, Houston, TX, between December 1997 and June 1998. After giving written informed consent, participants completed a self-administered questionnaire. Differences between CAM users and nonusers were assessed by Chi square and univariate logistic regression analysis. A multivariate logistic regression model identified the simultaneous impact of demographic, clinical, and treatment variables on CAM use; P values were two-sided. Results: Of the 453 participants (response rate, 51.4%), 99.3% had heard of CAM. Of those, 83.3% had used at least one CAM approach. Use was greatest for spiritual practices (80.5%), vitamins and herbs (62.6%), and movement and physical therapies (59.2%) and predicted (P < .001) by sex (female), younger age, indigent pay status, and surgery. After excluding spiritual practices and psychotherapy, 95.8% of participants were aware of CAM and 68.7% of those had used CAM. Use was predicted (P < .0001) by sex (female), education, and chemotherapy. Conclusion: In most categories, CAM use was common among outpatients. Given the number of patients combining vitamins and herbs with conventional treatments, the oncology community must improve patient provider communication, offer reliable information to patients, and initiate research to determine possible drug-herb-vitamin interactions.

9.4.3 Trends in Alternative Medicine Use in the United States, 1990-1997 Results of a Follow-up National Survey
DM Eisenberg, RB Davis, SL Ettner, S Appel, S Wilkey, M Van Rompay; RC Kessler
JAMA. 1998; 280(18):1569-1575.
http://dx.doi.org:/10.1001/jama.280.18.1569

Context.  A prior national survey documented the high prevalence and costs of alternative medicine use in the United States in 1990. Objective. To document trends in alternative medicine use in the United States between 1990 and 1997. Design. Nationally representative random household telephone surveys using comparable key questions were conducted in 1991 and 1997 measuring utilization in 1990 and 1997, respectively. Participants. A total of 1539 adults in 1991 and 2055 in 1997. Main Outcomes Measures. Prevalence, estimated costs, and disclosure of alternative therapies to physicians.
Results. Use of at least 1 of 16 alternative therapies during the previous year increased from 33.8% in 1990 to 42.1% in 1997 (P≤.001). The therapies increasing the most included: herbal medicine, massage, megavitamins, self-help groups, folk remedies, energy healing, and homeopathy. The probability of users visiting an alternative medicine practitioner increased from 36.3% to 46.3% (P=.002). In both surveys alternative therapies were used most frequently for chronic conditions, including back problems, anxiety, depression, and headaches. There was no significant change in disclosure rates between the 2 survey years; 39.8% of alternative therapies were disclosed to physicians in 1990 vs 38.5% in 1997. The percentage of users paying entirely out-of-pocket for services provided by alternative medicine practitioners did not change significantly between 1990 (64.0%) and 1997 (58.3%) (P=.36). Extrapolations to the US population suggest a 47.3% increase in total visits to alternative medicine practitioners, from 427 million in 1990 to 629 million in 1997, thereby exceeding total visits to all US primary care physicians. An estimated 15 million adults in 1997 took prescription medications concurrently with herbal remedies and/or high-dose vitamins (18.4% of all prescription users). Estimated expenditures for alternative medicine professional services increased 45.2% between 1990 and 1997 and were conservatively estimated at $21.2 billion in 1997, with at least $12.2 billion paid out-of-pocket. This exceeds the 1997 out-of-pocket expenditures for all US hospitalizations. Total 1997 out-of-pocket expenditures relating to alternative therapies were conservatively estimated at $27.0 billion, which is comparable with the projected 1997 out-of-pocket expenditures for all US physician services. Conclusions. Alternative medicine use and expenditures increased substantially between 1990 and 1997, attributable primarily to an increase in the proportion of the population seeking alternative therapies, rather than increased visits per patient.

9.4.4 Courses Involving Complementary and Alternative Medicine at US Medical Schools
Miriam S. Wetzel, David M. Eisenberg, Ted J. Kaptchuk
JAMA. 1998; 280(9):784-787.
http://dx.doi.org:/10.1001/jama.280.9.784

Context. With the public’s increasing use of complementary and alternative medicine, medical schools must consider the challenge of educating physicians about these therapies. Objectives. To document the prevalence, scope, and diversity of medical school education in complementary and alternative therapy topics and to obtain information about the organizational and academic features of these courses. Design. Mail survey and follow-up letter and telephone survey conducted in 1997-1998. Participants. Academic or curriculum deans and faculty at each of the 125 US medical schools.
Main Outcome Measures. Courses taught at US medical schools and administrative and educational characteristics of these courses.
Results. Replies were received from 117 (94%) of the 125 US medical schools. Of schools that replied, 75 (64%) reported offering elective courses in complementary or alternative medicine or including these topics in required courses. Of the 123 courses reported, 84 (68%) were stand-alone electives, 38 (31%) were part of required courses, and one (1%) was part of an elective. Thirty-eight courses (31%) were offered by departments of family practice and 14 (11%) by departments of medicine or internal medicine. Educational formats included lectures, practitioner lecture and/or demonstration, and patient presentations. Common topics included chiropractic, acupuncture, homeopathy, herbal therapies, and mind-body techniques.
Conclusions. There is tremendous heterogeneity and diversity in content, format, and requirements among courses in complementary and alternative medicine at US medical schools.

9.4.5  38% of Adults Use Alternative Medicine
Rob Stein – Washington Post Staff Writer Dec 11, 2008
http://washingtonpost.com/wp-dyn/content/article/2008/12/10/AR2008121001601.html

More than one-third of adults and nearly 12 percent of children in the United States use alternatives to traditional medicine, according to a large federal survey released today that documents how entrenched acupuncture, herbal remedies and other once-exotic therapies have become.

The 2007 survey of more than 32,000 Americans, which for the first time included children, found that use of yoga, “probiotics,” fish oil and other “complementary and alternative” therapies held steady among adults since the last national survey five years earlier, and that such treatments have become part of health care for many youngsters.

“It’s clear that millions of Americans every year are turning to complementary and alternative medicine,” said Richard L. Nahin of the National Institutes of Health’s National Center for Complementary and Alternative Medicine, which released the survey. “The use of complementary and alternative medicine seems to have stabilized in the United States.”

The most commonly used are dietary supplements and herbal products such as echinacea, flaxseed oil and ginseng, followed by deep-breathing exercises, meditation, chiropractic therapy, massage and yoga. Although fewer Americans were using certain diets and trying herbal remedies such as echinacea to cure colds, the popularity of acupuncture, meditation, yoga and massage grew.
9.4.6 Wheat germ extract (Avemar, Avé, AvéULTRA, AWGE, OncoMAR)
http://mskcc.org/cancer-care/herb/wheat-germ-extract

Fermented wheat germ extract (WGE) was developed in the 1990s by Hungarian chemist Mate Hidvegi. It should not be confused with wheat germ oil. WGE is used as a dietary supplement by cancer patients in Hungary to improve quality of life (QoL).

Results from in vitro studies show that WGE has anticancer (1) (2) (3) (4) (5) (19), antimetastatic (6), and immunomodulatory (2) (7) effects. Although it appears to increase estrogen receptor (ER) activity, WGE enhanced efficacy of tamoxifen, an ER antagonist, in ER+ breast cancer cells (8) as well as cisplatin in ovarian cancer cell lines (5). Animal models suggest WGE can reduce cardiovascular symptoms due to chronic hypertension, diabetes, and obesity (9), mitigate symptoms associated with lupus (10), and that its antitumor effect is comparable to other endocrine treatments (11).

Data from pilot studies indicate a beneficial role for WGE in patients with colorectal cancer (12) and in reducing treatment-associated febrile neutropenia in pediatric cancer patients (13). It also prolonged survival of patients with melanoma when used with chemotherapy (14) (15). However, these effects must be confirmed by large-scale, well-designed clinical trials.

Because it potentiates estrogen receptor activity, patients with hormone-sensitive cancers should use WGE with caution.

What is Avemar?
http://avemar.info/what_is_avemar

Avemar is an all-natural, clinically proven, dietary supplement for cancer patients. Medical experts recognize Avemar as an effective supportive cancer treatment and recommend complementing the diet of concerned patients with Avemar.Scientific studies showed that Avemar also enhances the efficacy of conventional oncological treatments (surgery, radio-, chemo- and immunotherapy). With regular intake of Avemar, patients can relish a better quality of life and can enjoy a better lifestyle. Avemar is available in granulate and film-coated tablet form.

The active ingredient is Avemar pulvis, an all-natural compound made from fermented wheat germ extract using patented biotechnological processes. Since the invention of Avemar pulvis significant research has been undertaken – not only in the laboratory, but in test animals and human cancer patients as well. Numerous scientific studies have been conducted to study its safety profile and its effectiveness, including in vitroin vivo and human clinical research. Over 100 reports have been written for presentation or publication since 1998, and over 33 peer-reviewed scientific papers are currently accessible at PubMed database. All scientific publications are accessible at the official Avemar Research website.

9.4.7 How Avemar Helps Fight Cancer
Dr. David Williams
http://drdavidwilliams.com/avemar-cancer

Avemar is a naturally fermented wheat germ extract that has been subjected to a great deal of research scrutiny, particularly in the area of cancer treatment. What makes Avemar stand out among other known therapies is the fact that its effectiveness isn’t limited to any one specific type of cancer. So far it has exhibited positive effects against all forms of cancer cell lines tested.

Whether cancer cells proceed to replicate, grow, and eventually spread throughout the body is determined by enzymatic activity and their accessibility to various nutrients.

Pharmaceutical companies have focused their efforts to find cures for various forms of cancer. One of their top priorities (and one area with the greatest potential) has always been to uncover compounds that inhibit glucose metabolism in tumor cells.

Every form of cancer cell utilizes glucose at rates 10 to 50 times higher than that of normal healthy cells (a well-known phenomenon referred to as “the Warburg effect”). Unlike normal, healthy cells that utilize glucose primarily for energy, tumor cells use glucose to replicate cells. They convert glucose to nucleic acids (necessary for the formation of additional RNA) by a hexose monophosphate pathway. They also have to break down tissue in order to make proteins (needed for the cancer to continue to grow). This is termed cachexia.  In this sense the behavior of cancer proliferation is like a systemic infection.

In simple terms, cancer cells have only one function: proliferation. To achieve this function, cancer cells need large amounts of glucose that they can convert into building materials for new cells. As the tumor grows, more and more glucose is consumed.

Research indicates that Avemar works through several different mechanisms. One of its most unique benefits, however, is its ability to inhibit glucose metabolism in cancer cells.

Research at UCLA has demonstrated that Avemar reduces glucose flow into cancer cells—which inhibits their ability to produce additional nucleic acids and subsequently reduces their proliferation or growth. In the presence of Avemar compounds, cancer cells begin to utilize the available glucose to produce substances that actually inhibit cell division and stimulate programmed cell death (apoptosis) within the tumor.

As one report explains, decreased glucose consumption of the tumors results in a harmonizing of the patient’s metabolism—as well as weight gain, even in people with advanced cancers. As a result, patients treated with Avemar also have improved tolerance for surgery, radiation, and chemotherapy. Further, Avemar achieves these results without creating any toxicity or damage to normal, healthy cells. (Ann N Y Acad Sci. 07;1110:348–61)

This particular feature of Avemar explains why cancer patients using the product routinely experience an improved quality of life. They have less fatigue, pain, and depression, and experience an increase in appetite that can help them regain lost weight. (Medicus Anonymus/Pulmono 03;11 (Suppl 1):13–14) (24th Congress of the Hungarian Cancer Society, Budapest, Hungary 2001)

9.4.8  The anti-cancer action of curcumin (turmeric)
http://canceractive.com/cancer-active-page-link.aspx?n=1571

* Importantly, the spice can stop the action of the enzyme COX-2 known to produce negative, inflammation causing localised enzymes (eicosanoids). Such inflammation is a known precursor to cancer.

* It has also been shown to inhibit vascular epithelial growth factors. Every tumor needs a blood supply – the growth factors build one, but curcumin seems to stop them.

* It has been shown to ´re-awaken´ a key tumor suppressor gene.

* It has been shown to inhibit metastases.

* It has been shown to kill cancer cells (B lymphoma cells).

* It prevents regrowth of cancer stem cells which lie at the heart of many tumors

In the journal ´Genes and Nutrition´ (2011; 6(2):93-108) the whole issue of ´Epigenetics´ was exposed. It used to be thought that your genes controlled all and a problem in a gene meant you were in some way ´doomed´. This theory has been disproven and replaced by one that shows genes are just your blueprint; these blueprints are controlled, activated or suppressed by the localized environment. So hormones can affect their action, as can natural compounds in food. And curcumin seems to affect gene expression significantly. Such ´signaling pathways´ have been shown to be affected by curcumin.

An example of this ´signaling pathway´ modification came in research from the Ludwig-Maximilians University in Munich, Germany in 2012 which showed that curcumin can inhibit the formation of metastases in both prostate and breast cancer.  Both cancers spread throughout the body through the release of chemical messengers, pro-inflammatory cytokines CXCL1 and CXCL2, but curcumin alters the expression of these two damaging proteins.

Next, Cheryl Myers (head of Scientific Affairs and Education for EuroPharma Inc.) refers to curcumin as ´the anti-cancer herb´ because of its success in stopping cancer formation, replication and spread. Research also shows that curcumin increases the activity of certain anti-cancer drugs while protecting healthy cells and organs. It has been proven to reduce systemic inflammation and oxidative stress.

And researchers from the Dept. of Natural Science at Middlesex University have shown that curcumin and chokeberry can work together to induce cancer cell death (apoptosis) and stop the spread of malignant cancer cells. Their report (in Oncology Reports) was for brain tumors.

Dr Young S. Kim leading a team at the National Cancer Institute in America showed that curcumin was one of the natural compounds that could prevent cancer stem cells from re-growing and re-forming the cancer. Her conclusion even suggested patients could supplement!

The University of Missouri has shown curcumin can counter the dangerous effects of HRT and its link to breast cancer cause.  “The results of the study show that women could potentially take curcumin to protect themselves from developing progestin-accelerated tumors,” said the lead researcher. Synthetic progestin increases VEGF a protein that helps form blood supplies to developing tumors. Curcumin inhibits VEGF and thus reduces the potential of breast cancer to grow.

Professor Bharat Aggarwal Ph. D. in MD Anderson Department of Therapeutics has conducted a number of studies, for example showing that in a Phase II clinical trial, pancreatic cancer patients having no chemotherapy, it reduced tumor size. He believes it is effective against many types of cancer because it suppresses angiogenesis (the growth of blood vessels essential to a tumor). “The reason curcumin is so effective against cancer is that it hits not just a single target or cell signaling pathway but dozens of targets implicated in cancer.” It has also been shown to have a strong synergistic effect against cancer with resveratrol, and also with EGCG in green tea.

What is exciting the experts in cancer centers in America is that it can play a role against several of the steps in what is a multi-step cancer process. As such it would seem stupid to ignore it as a part of an Integrative or holistic cancer treatment program.

What are curcumin and turmeric?

Curcumin is the active ingredient of the Indian/Asian curry spice Turmeric.  To put this technically, curcumin is the principal curcuminoid in turmeric.  Curcuminoids are polyphenols.  Turmeric powder is ground from the root of a plant called Curcuma Longa, which is a member of the ginger family and is found throughout Southern Asia, even growing wild in the Himalayas.

This vivid yellow to brown spice was used, like many Asian spices and chillies, to hide the taste of stronger tasting meats and fish even those that might have gone a little off in such hot climates.  Like many such spices, it also performed a necessary and functional role it was a cleanser, a bacteria-killer in the stomach, protecting against tainted foods!

Curcumin/turmeric has been used in Ayurvedic medicine for thousands of years as a cleanser of the body.  It appears to work at a number of levels:

  1. It can inhibit unwanted bacterial action in the stomach and intestine:

For example (i) , University of Chicago researchers have shown it inhibits Helicobacter pylori, a bacterium known to be responsible for stomach ulcers and some stomach cancers.  In Ayurvedic medicine, curcumin was used in poultices for this same reason to kill unwanted bacteria.

  1. It is a significant anti-inflammatory:

Arachidonic acid is a precursor/stimulator of the production of bad eicosancids (see our reviews of omega 3 and vitamin D) and thus to inflammation, which is itself a precursor to certain cancers.  Curcumin has been found to inhibit several of the pre-inflammatory enzymes (e.g. COX2 and iNOS) in vitro and in vivo with animals.  Japanese research suggests it works in much the same way as salicylin.

  1. It boosts crucial cellular glutathione levels:

Glutathione is a crucial intracellular antioxidant, helping the cell maintain its correct oxygen levels and fight off the effects of stress hormones.  Research has shown that curcumin can prevent the action of an enzyme that limits glutathione production.

  1. It is a powerful antioxidant:

Turmeric extract tested more potent than garlic, omega 3 and cat´s claw (devil´s claw) said German research.

  1. It can help prevent liver damage

2010 research from St Louis has shown that it can turn off a protein called Leptin, which causes liver damage. It has also been shown to be capable of detoxifying the liver. Thus curcumin may be of help in keeping the liver healthy during chemotherapy cancer treatments.

  1. It can prevent and even ´treat´ cancer:

As we have covered above, curcumin can suppress tumor initiation, promotion and metastasis.  Extensive research over the last 50 years has indicated it can prevent and treat cancer. The anti-cancer potential stems from its ability to control gene signaling, and affect a wide variety of tumor cells, down-regulate transcription factors, down-regulate enzymes such as COX-2 and other inflammatories, cytokines, chemokines, cell-surface adhesion molecules, down-regulate growth factors, etc., etc.

Tufts have conducted research with breast cancer patients concluding that curcumin and isoflavanoids seem to inhibit the action of environmental estrogens.

UCLA have researched its potential with colorectal cancer (San Diego, Chauhen). And there are Clinical Trials underway (according to the Mayo Clinic to investigate curcumin as a way to prevent cancer in people with precancerous conditions, as a cancer treatment, and as a remedy for signs and symptoms caused by cancer treatments.

Much of the work original used cell cultures.  Increasingly studies use a variety of animals, and there have been human trials, even clinical trials, primarily with cervical cancer lesions and with gastrointestinal cancers.  So, although the biochemical knowledge is vast, the use of oral curcumin to prevent and treat cancer is still in its infancy.

Next, there is a problem maintaining effectiveness inside the cells; there are several studies that show oral consumption needs to be maintained in order to maintain blood and cellular levels.  But it is not as simple as curry every day!

Curcumin supplements may be heavily contaminated with everything from pesticides to other spices so you must choose a reliable supplier, ideally of curcuma longa. If you are thinking of buying Curcuma Longa you might like to look at the Natural Selection as they are based in the UK and they tend to have natural compounds that avoid pesticides. Click here. Alternatively in the USA you might like to go to the Natural News or Dr Mercola websites.

Counter indications

Some supplements contain piperine, supposedly to increase bio-availability.  This can interfere with certain drugs.

Curcumin can inhibit coagulation in vitro and so may be inadvisable if you are taking anti-coagulants.  It might increase the risk of bleeding.

It might also be advisable not to take it if you are pregnant or lactating.

In summary

Clearly there is a huge enthusiasm, even expectation, overseas for curcumin, if not in British hospitals and oncology departments.  But the real issue is can you take enough of it orally to deliver it in adequate doses to your breast or prostate cells?  Certainly curcumin (curcuma longa) was seen to be an important herb in the natural and successful treatment of prostate cancer that we covered in Cancer Watch (icon 2006, issue 3 ).  We will just have to wait and see whether this longstanding Ayurvedic medicine will curry favour with the UK medical fraternity.

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Notes from Opening Plenary Session – The Genome and Beyond from the 2015 AACR Meeting in Philadelphia PA; Sunday April 19, 2015

 

Reporter: Stephen J. Williams, Ph.D.

The following contain notes from the Sunday April 19, 2015 AACR Meeting (Pennsylvania Convention Center, Philadelphia PA) 9:30 AM Opening Plenary Session

The Genome and Beyond

Session Chairperson: Lewis C. Cantley, Ph.D.

Speakers: Michael R. Stratton, Tyler Jacks, Stephen B. Baylin, Robert D. Schreiber, Williams R. Sellers

  1. A) Insights From Cancer Genomes: Michael R. Stratton, Ph.D.; Director of the Wellcome Trust Sanger Institute
  • How do we correlate mutations with causative factors of carcinogenesis and exposure?
  • Cancer was thought as a disease of somatic mutations
  • UV skin exposure – see C>T transversion in TP53 while tobacco exposure and lung cancer see more C>A transversion; Is it possible to determine EXPOSURE SIGNATURES?
  • Use a method called non negative matrix factorization (like face pattern recognition but a mutation pattern recognition)
  • Performed sequence analysis producing 12,000 mutation catalogs with 8,000 somatic mutation signatures
  • Found more mutations than expected; some mutation signatures found in all cancers, while some signatures in half of cancers, and some signatures not found in cancer
  • For example found 3 mutation signatures in ovarian cancer but 13 for breast cancers (80,000 mutations); his signatures are actually spectrums of mutations
  • kataegis: defined as localized hypermutation; an example is a signature he found related to AID/APOBEC family (involved in IgG variability); kataegis is more prone in hematologic cancers than solid cancers
  • recurrent tumors show a difference in mutation signatures than primary tumor before drug treatment

 

  1. B) Engineering Cancer Genomes: Tyler Jacks, Ph.D.; Director, Koch Institute for Integrative Cancer Research
  • Cancer GEM’s (genetically engineered mouse models of cancer) had moved from transgenics to defined oncogenes
  • Observation that p53 -/- mice develop spontaneous tumors (lymphomas)
  • then GEMs moved to Cre/Lox systems to generate mice with deletions however these tumor models require lots of animals, much time to create, expensive to keep;
  • figured can use CRSPR/Cas9 as rapid, inexpensive way to generate engineered mice and tumor models
  • he used CRSPR/Cas9 vectors targeting PTEN to introduce PTEN mutations in-vivo to hepatocytes; when they also introduced p53 mutations produced hemangiosarcomas; took ONLY THREE months to produce detectable tumors
  • also produced liver tumors by using CRSPR/Cas9 to introduce gain of function mutation in β-catenin

 

See an article describing this study by MIT News “A New Way To Model Cancer: New gene-editing technique allows scientists to more rapidly study the role of mutations in tumor development.”

The original research article can be found in the August 6, 2014 issue of Nature[1]

And see also on the Jacks Lab site under Research

  1. C) Above the Genome; The Epigenome and its Biology: Stephen B. Baylin
  • Baylin feels epigenetic therapy could be used for cancer cell reprogramming
  • Interplay between Histone (Movers) and epigenetic marks (Writers, Readers) important for developing epigenetic therapy
  • Difference between stem cells and cancer: cancer keeps multiple methylation marks whereas stem cells either keep one on or turn off marks in lineage
  • Corepressor drugs are a new exciting class in chemotherapeutic development
  • (Histone Demythylase {LSD1} inhibitors in clinical trials)
  • Bromodomain (Brd4) enhancers in clinical trials
  1. D) Using Genomes to Personalize Immunotherapy: Robert D. Schreiber, Ph.D.,
  • The three “E’s” of cancer immunoediting: Elimination, Equilibrium, and Escape
  • First evidence for immunoediting came from mice that were immunocompetent resistant to 3 methylcholanthrene (3mca)-induced tumorigenesis but RAG2 -/- form 3mca-induced tumors
  • RAG2-/- unedited (retain immunogenicity); tumors rejected by wild type mice
  • Edited tumors (aren’t immunogenic) led to tolerization of tumors
  • Can use genomic studies to identify mutant proteins which could be cancer specific immunoepitopes
  • MHC (major histocompatibility complex) tetramers: can develop vaccines against epitope and personalize therapy but only good as checkpoint block (anti-PD1 and anti CTLA4) but personalized vaccines can increase therapeutic window so don’t need to start PD1 therapy right away
  • For more details see references Schreiker 2011 Science and Shankaran 2001 in Nature
  1. E) Report on the Melanoma Keynote 006 Trial comparing pembrolizumab and ipilimumab (PD1 inhibitors)

Results of this trial were published the morning of the meeting in the New England Journal of Medicine and can be found here.

A few notes:

From the paper: The anti–PD-1 antibody pembrolizumab prolonged progression-free survival and overall survival and had less high-grade toxicity than did ipilimumab in patients with advanced melanoma. (Funded by Merck Sharp & Dohme; KEYNOTE-006 ClinicalTrials.gov number, NCT01866319.)

And from Twitter:

Robert Cade, PharmD @VTOncologyPharm

KEYNOTE-006 was presented at this week’s #AACR15 conference. Pembrolizumab blew away ipilimumab as 1st-line therapy for metastatic melanoma.

2:02 PM – 21 Apr 2015

Jeb Keiper @JebKeiper

KEYNOTE-006 at #AACR15 has pembro HR 0.63 in OS over ipi. Issue is ipi is dosed only 4 times over 2 years (per label) vs Q2W for pembro. Hmm

11:55 AM – 19 Apr 2015

OncLive.com @OncLive

Dr Antoni Ribas presenting data from KEYNOTE-006 at #AACR15 – Read more about the findings, at http://ow.ly/LMG6T 

11:25 AM – 19 Apr 2015

Joe @GantosJ

$MRK on 03/24 KEYNOTE-006 vs Yervoy Ph3 stopped early for meeting goals of PFS, OS & full data @ #AACR15 now back to weekend & family

9:05 AM – 19 Apr 2015

Kristen Slangerup @medwritekristen

Keytruda OS benefit over Yervoy in frontline #melanoma $MRK stops Ph3 early & data to come @ #AACR15 #immunotherapy http://yhoo.it/1EYwwq8 

2:40 PM – 26 Mar 2015

Yahoo Finance @YahooFinance

Merck’s Pivotal KEYNOTE-006 Study in First-Line Treatment for…

Merck , known as MSD outside the United States and Canada, today announced that the randomized, pivotal Phase 3 study investigating KEYTRUDA® compared to ipilimumab in the first-line treatment of…

View on web

 

Stephen J Williams @StephenJWillia2

Progression free survival better for pembrolzumab over ipilimumab by 2.5 months #AACR15 @Pharma_BI #Cancer #Immunotherapy

11:56 AM – 19 Apr 2015

 

Stephen J Williams @StephenJWillia2

Melanoma Keynote 006 trial PD1 inhibitor #Immunotherapy 80% responders after 1 year @Pharma_BI #AACR15

 

References

  1. Xue W, Chen S, Yin H, Tammela T, Papagiannakopoulos T, Joshi NS, Cai W, Yang G, Bronson R, Crowley DG et al: CRISPR-mediated direct mutation of cancer genes in the mouse liver. Nature 2014, 514(7522):380-384.

 

Other related articles on Cancer Genomics and Social Media Coverage were published in this Open Access Online Scientific Journal, include the following:

Cancer Biology and Genomics for Disease Diagnosis

Introduction – The Evolution of Cancer Therapy and Cancer Research: How We Got Here?

Methodology for Conference Coverage using Social Media: 2014 MassBio Annual Meeting 4/3 – 4/4 2014, Royal Sonesta Hotel, Cambridge, MA

List of Breakthroughs in Cancer Research and Oncology Drug Development by Awardees of The Israel Cancer Research Fund

2013 American Cancer Research Association Award for Outstanding Achievement in Chemistry in Cancer Research: Professor Alexander Levitzki

Genomics and Epigenetics: Genetic Errors and Methodologies – Cancer and Other Diseases

Cancer Genomics – Leading the Way by Cancer Genomics Program at UC Santa Cruz

Genomics and Metabolomics Advances in Cancer

Pancreatic Cancer: Genetics, Genomics and Immunotherapy

Multiple Lung Cancer Genomic Projects Suggest New Targets, Research Directions for Non-Small Cell Lung Cancer

 

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Imaging-guided cancer treatment


Imaging-guided cancer treatment

Writer & reporter: Dror Nir, PhD

It is estimated that the medical imaging market will exceed $30 billion in 2014 (FierceMedicalImaging). To put this amount in perspective; the global pharmaceutical market size for the same year is expected to be ~$1 trillion (IMS) while the global health care spending as a percentage of Gross Domestic Product (GDP) will average 10.5% globally in 2014 (Deloitte); it will reach ~$3 trillion in the USA.

Recent technology-advances, mainly miniaturization and improvement in electronic-processing components is driving increased introduction of innovative medical-imaging devices into critical nodes of major-diseases’ management pathways. Consequently, in contrast to it’s very small contribution to global health costs, medical imaging bears outstanding potential to reduce the future growth in spending on major segments in this market mainly: Drugs development and regulation (e.g. companion diagnostics and imaging surrogate markers); Disease management (e.g. non-invasive diagnosis, guided treatment and non-invasive follow-ups); and Monitoring aging-population (e.g. Imaging-based domestic sensors).

In; The Role of Medical Imaging in Personalized Medicine I discussed in length the role medical imaging assumes in drugs development.  Integrating imaging into drug development processes, specifically at the early stages of drug discovery, as well as for monitoring drug delivery and the response of targeted processes to the therapy is a growing trend. A nice (and short) review highlighting the processes, opportunities, and challenges of medical imaging in new drug development is: Medical imaging in new drug clinical development.

The following is dedicated to the role of imaging in guiding treatment.

Precise treatment is a major pillar of modern medicine. An important aspect to enable accurate administration of treatment is complementing the accurate identification of the organ location that needs to be treated with a system and methods that ensure application of treatment only, or mainly to, that location. Imaging is off-course, a major component in such composite systems. Amongst the available solution, functional-imaging modalities are gaining traction. Specifically, molecular imaging (e.g. PET, MRS) allows the visual representation, characterization, and quantification of biological processes at the cellular and subcellular levels within intact living organisms. In oncology, it can be used to depict the abnormal molecules as well as the aberrant interactions of altered molecules on which cancers depend. Being able to detect such fundamental finger-prints of cancer is key to improved matching between drugs-based treatment and disease. Moreover, imaging-based quantified monitoring of changes in tumor metabolism and its microenvironment could provide real-time non-invasive tool to predict the evolution and progression of primary tumors, as well as the development of tumor metastases.

A recent review-paper: Image-guided interventional therapy for cancer with radiotherapeutic nanoparticles nicely illustrates the role of imaging in treatment guidance through a comprehensive discussion of; Image-guided radiotherapeutic using intravenous nanoparticles for the delivery of localized radiation to solid cancer tumors.

 Graphical abstract

 Abstract

One of the major limitations of current cancer therapy is the inability to deliver tumoricidal agents throughout the entire tumor mass using traditional intravenous administration. Nanoparticles carrying beta-emitting therapeutic radionuclides [DN: radioactive isotops that emits electrons as part of the decay process a list of β-emitting radionuclides used in radiotherapeutic nanoparticle preparation is given in table1 of this paper.) that are delivered using advanced image-guidance have significant potential to improve solid tumor therapy. The use of image-guidance in combination with nanoparticle carriers can improve the delivery of localized radiation to tumors. Nanoparticles labeled with certain beta-emitting radionuclides are intrinsically theranostic agents that can provide information regarding distribution and regional dosimetry within the tumor and the body. Image-guided thermal therapy results in increased uptake of intravenous nanoparticles within tumors, improving therapy. In addition, nanoparticles are ideal carriers for direct intratumoral infusion of beta-emitting radionuclides by convection enhanced delivery, permitting the delivery of localized therapeutic radiation without the requirement of the radionuclide exiting from the nanoparticle. With this approach, very high doses of radiation can be delivered to solid tumors while sparing normal organs. Recent technological developments in image-guidance, convection enhanced delivery and newly developed nanoparticles carrying beta-emitting radionuclides will be reviewed. Examples will be shown describing how this new approach has promise for the treatment of brain, head and neck, and other types of solid tumors.

The challenges this review discusses

  • intravenously administered drugs are inhibited in their intratumoral penetration by high interstitial pressures which prevent diffusion of drugs from the blood circulation into the tumor tissue [1–5].
  • relatively rapid clearance of intravenously administered drugs from the blood circulation by kidneys and liver.
  • drugs that do reach the solid tumor by diffusion are inhomogeneously distributed at the micro-scale – This cannot be overcome by simply administering larger systemic doses as toxicity to normal organs is generally the dose limiting factor.
  • even nanoparticulate drugs have poor penetration from the vascular compartment into the tumor and the nanoparticles that do penetrate are most often heterogeneously distributed

How imaging could mitigate the above mentioned challenges

  • The inclusion of an imaging probe during drug development can aid in determining the clearance kinetics and tissue distribution of the drug non-invasively. Such probe can also be used to determine the likelihood of the drug reaching the tumor and to what extent.

Note: Drugs that have increased accumulation within the targeted site are likely to be more effective as compared with others. In that respect, Nanoparticle-based drugs have an additional advantage over free drugs with their potential to be multifunctional carriers capable of carrying both therapeutic and diagnostic imaging probes (theranostic) in the same nanocarrier. These multifunctional nanoparticles can serve as theranostic agents and facilitate personalized treatment planning.

  • Imaging can also be used for localization of the tumor to improve the placement of a catheter or external device within tumors to cause cell death through thermal ablation or oxidative stress secondary to reactive oxygen species.

See the example of Vintfolide in The Role of Medical Imaging in Personalized Medicine

vinta

Note: Image guided thermal ablation methods include radiofrequency (RF) ablation, microwave ablation or high intensity focused ultrasound (HIFU). Photodynamic therapy methods using external light devices to activate photosensitizing agents can also be used to treat superficial tumors or deeper tumors when used with endoscopic catheters.

  • Quality control during and post treatment

For example: The use of high intensity focused ultrasound (HIFU) combined with nanoparticle therapeutics: HIFU is applied to improve drug delivery and to trigger drug release from nanoparticles. Gas-bubbles are playing the role of the drug’s nano-carrier. These are used both to increase the drug transport into the cell and as ultrasound-imaging contrast material. The ultrasound is also used for processes of drug-release and ablation.

 HIFU

Additional example; Multifunctional nanoparticles for tracking CED (convection enhanced delivery)  distribution within tumors: Nanoparticle that could serve as a carrier not only for the therapeutic radionuclides but simultaneously also for a therapeutic drug and 4 different types of imaging contrast agents including an MRI contrast agent, PET and SPECT nuclear diagnostic imaging agents and optical contrast agents as shown below. The ability to perform multiple types of imaging on the same nanoparticles will allow studies investigating the distribution and retention of nanoparticles initially in vivo using non-invasive imaging and later at the histological level using optical imaging.

 multi

Conclusions

Image-guided radiotherapeutic nanoparticles have significant potential for solid tumor cancer therapy. The current success of this therapy in animals is most likely due to the improved accumulation, retention and dispersion of nanoparticles within solid tumor following image-guided therapies as well as the micro-field of the β-particle which reduces the requirement of perfectly homogeneous tumor coverage. It is also possible that the intratumoral distribution of nanoparticles may benefit from their uptake by intratumoral macrophages although more research is required to determine the importance of this aspect of intratumoral radionuclide nanoparticle therapy. This new approach to cancer therapy is a fertile ground for many new technological developments as well as for new understandings in the basic biology of cancer therapy. The clinical success of this approach will depend on progress in many areas of interdisciplinary research including imaging technology, nanoparticle technology, computer and robot assisted image-guided application of therapies, radiation physics and oncology. Close collaboration of a wide variety of scientists and physicians including chemists, nanotechnologists, drug delivery experts, radiation physicists, robotics and software experts, toxicologists, surgeons, imaging physicians, and oncologists will best facilitate the implementation of this novel approach to the treatment of cancer in the clinical environment. Image-guided nanoparticle therapies including those with β-emission radionuclide nanoparticles have excellent promise to significantly impact clinical cancer therapy and advance the field of drug delivery.

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Dompe’ Receives FDA orphan drug designation for rhNGF in the treatment of Neurotrophic Keratitis (NK).

Reporter: Stephen J Williams, PhD

 

The U.S. FDA granted Dompe’ an orphan drug designation for rhNGF (recombinant human nerve growth factor) in the treatment of Neurotrophic Keratitis (NK).

Neurotrophic Keratitis (NK) is a rare, degenerative corneal disease caused by an impairment of corneal innervation (the distribution or supply of nerves), leading to a decrease or absence of corneal sensation and dysfunction of the corneal epithelium and abnormal corneal epithelial healing. The development of persistent epithelial defects or corneal ulcers can result in vision loss.

Severe NK is consistently recognized by clinicians as a serious condition lacking a highly effective treatment option.

The epidemiology of NK has not been well-defined. The estimated prevalence of patients with moderate-to-severe NK (stage 2-3) is less than 1 person in 5,000 globally.

Clinical trials in the U.S. are expected to begin in the next few months in leading research centers.

Dompé will be present at the American Association of Ophthalmology Annual meeting (Chicago, October 18-21). Currently, the enrollment is ongoing for the company’s Phase II trial with rhNGF in the treatment of NK.
Background – Dompé and its R&D

  • Dompé is a leading Italian biopharmaceutical company (with headquarters in Milan) committed to the development of innovative treatment solutions for rare, often orphan, diseases that have a high social impact, in areas where unmet treatment needs still exist.
  • The Company focuses its R&D activities in diabetes, ophthalmology, oncology and organ transplants.
  • The R&D activities are carried out in the Dompé biotech plant located in L’Aquila (Abruzzo), which has an internationally recognized expertise in the field of rare diseases.  
  • This year (2014), Dompé opened an office in New York, staffed with scientists and R&D teams in order to carry out and coordinate the scientific activities in the U.S.

 

Dompé commitment in ophthalmology – rhNGF

  • In ophthalmology, Dompé is promoting the research and development of Nerve Growth Factor (NGF), a soluble protein that stimulates the growth, maintenance and survival of neurons, whose discovery led to Prof. Rita Levi Montalcini being awarded the Nobel Prize in 1986.
  • Recombinant human Nerve Growth Factor (rhNGF) has been studied and produced exclusively at Dompé’s production site in L’Aquila, Italy, and is undergoing an international Phase II trial, called “REPARO”, to evaluate its efficacy and safety in the treatment of Neurotrophic Keratitis, a rare orphan disease. The trial is being conducted in 39 centers and nine European countries.

The medicine recently has been designated an orphan drug for the treatment of Retinitis Pigmentosa (RP), a severe, genetic rare disease that can lead to blindness for which there is currently no treatment available. A clinical trial in the EU, involving patients with RP, started in the first quarter of 2014 with the enrolment of the first patient.

SOURCE

From: Gail Thornton <gailsthornton@yahoo.com>
Reply-To: Gail Thornton <gailsthornton@yahoo.com>
Date: Wed, 23 Jul 2014 07:02:05 -0700
To: Aviva Lev-Ari <avivalev-ari@alum.berkeley.edu>
Subject: Dompe’ Receives FDA orphan drug designation for rhNGF

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Improving imaging based assessment of tumours’ response to treatment

Writer: Dror Nir, PhD.

The protocol for imaging-based assessment of cancer patients’ response to oncological drugs is known as the RECIST 1.1 criteria; The Role of Medical Imaging in Personalized Medicine . RECIST is mainly relying on morphological evaluation of tumors’ size . I recently participated to a webinar organised by Oncodesign which presented the potential use of more advanced imaging techniques as tools to improve the assessment of cancer patients’ response during oncological clinical trials.

It’s first part, describes a methodology developed based on the original approach of the DITEP* at the “Institut Gustave Roussy”. A method that takes into account kinetics of tumor growth at the pre-treatment phase and along the entire treatment sequence. The conclusion is that adding Tumor Growth Rate (TGR) assessment in Phase I and Phase III clinical trials is simple and provides clinically relevant information: (i) It allows for an early and precise assessment of the tumor growth, (ii) It reveals drug-specific profiles, suggesting its potential use for the early assessment of drug activity, (iii)TGR is independently associated with prognosis both in early clinical trials and in phase III setting.

The second part  presents two functional imaging modalities based on MRI: diffusion-weighted imaging (Dw-MRI) and Dynamic Contrast-Enhanced MRI (DCE-MRI). Dw-MRI gives measures of tissue architecture at the cellular level, whereas DCE-MRI provides information on the vascular status of tumors. Both methods have been standardized and used extensively as early PD biomarkers of the efficacy of anticancer therapies. The presentation goes through preclinical and clinical case studies illustrating how these two techniques can be used to evaluate the activity of novel drug candidates.

I recommend watching a recording of this webinar on YouTube . Note, the voice recording is not so good but, the effort is worthwhile….

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Intracoronary Transplantation of Progenitor Cells after Acute MI

Curators: Larry H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

 

Transcoronary Transplantation of Progenitor Cells after Myocardial Infarction

Birgit Assmus, M.D., Jörg Honold, M.D., Volker Schächinger, M.D., Martina B. Britten, M.D., Ulrich Fischer-Rasokat, M.D., et al.
From the Division of Cardiology and Mo­lecular Cardiology, Department of Medi­cine III (B.A., J.H., V.S., M.B.B., U.F.-R., R.L., C.T., K.P., S.D., A.M.Z.), Division of He­matology, Department of Medicine II (H.M.), and the Department of Diagnos­tic and Interventional Radiology (N.D.A.), Johann Wolfgang Goethe University; and the Institute for Transfusion Medicine and Immunohematology, Red Cross Blood Donor Service, Baden–Württem-berg–Hessen (T.T.) — both in Frankfurt, Germany.

N Engl J Med 2006;355:1222-32.

Background

Pilot studies suggest that intracoronary transplantation of progenitor cells derived from bone marrow (BMC) or circulating blood (CPC) may improve left ventricular function after acute myocardial infarction. The effects of cell transplantation in patients with healed myocardial infarction are unknown.

METHODS

After an initial pilot trial involving 17 patients, we randomly assigned, in a controlled crossover study, 75 patients with stable ischemic heart disease who had had a myo­cardial infarction at least 3 months previously to receive either no cell infusion (23 patients) or infusion of CPC (24 patients) or BMC (28 patients) into the patent coro­nary artery supplying the most dyskinetic left ventricular area. The patients in the control group were

  • subsequently randomly assigned to receive CPC or BMC, and
  • the patients who initially received BMC or CPC crossed over to receive CPC or BMC, respectively, at 3 months’ follow-up.

RESULTS

The absolute change in left ventricular ejection fraction was significantly greater among patients receiving BMC (+2.9 percentage points) than among those receiving CPC (−0.4 percentage point, P = 0.003) or no infusion (−1.2 percentage points, P<0.001). The increase in global cardiac function was related to significantly

  • en­hanced regional contractility in the area targeted by intracoronary infusion of BMC.

The crossover phase of the study revealed that intracoronary infusion of BMC was associated with a significant increase in global and regional left ventricular func­tion, regardless of whether patients crossed over from control to BMC or from CPC to BMC.

CONCLUSIONS

Intracoronary infusion of progenitor cells is safe and feasible in patients with healed myocardial infarction. Transplantation of BMC is associated with moderate but significant improvement in the left ventricular ejection fraction after 3 months. (ClinicalTrials.gov number, NCT00289822.)

Introduction

HRONIC HEART FAILURE IS COMMON, and its prevalence continues to increase.1 Ischemic heart disease is the principal cause of heart failure.2 Although myocardial salvage due to early reperfusion therapy has significantly re­duced early mortality rates,3

  • postinfarction heart failure resulting from ventricular remodeling re­mains a problem.4

One possible approach to re­versing postinfarction heart failure is

  • enhance­ment of the regeneration of cardiac myocytes as well as
  • stimulation of neovascularization within the infarcted area.

Initial clinical pilot studies have suggested that

  • intracoronary infusion of pro­genitor cells is feasible and may
  • beneficially af­fect postinfarction remodeling processes in pa­tients with acute myocardial infarction.5-9

However, it is currently unknown whether such a treatment strategy may also be associated with

  • improvements in cardiac function in patients with persistent left ventricular dysfunction due to healed myocardial infarction with established scar formation.

Therefore, in the prospective TOPCARE-CHD (Transplantation of Progenitor Cells and Recovery of LV [Left Ventricular] Function in Patients with Chronic Ischemic Heart Disease) trial, we inves­tigated

  • whether intracoronary infusion of pro­genitor cells into the infarct-related artery at least 3 months after myocardial infarction improves global and regional left ventricular function.

Patient Outcome Criteria

The primary end point of the study was the absolute change in global left ventricular ejection fraction (LVEF) as measured by quantitative left ventricular angiography 3 months after cell infu­sion. Secondary end points included quantitative variables relating to the regional left ventricular function of the target area, as well as left ven­tricular volumes derived from serial left ventric­ular angiograms. In addition, functional status was assessed by NYHA classification. Finally, event-free survival was defined as freedom from death, myocardial infarction, stroke, or rehospi­talization for worsening heart failure. Causes of rehospitalization during follow-up were verified by review of the discharge letters or charts of hospital stays.

DETECTION OF VIABLE MYOCARDIUM

All patients underwent low-dose dobutamine stress echocardiography, combined thallium sin­gle-photon-emission computed tomography and [18F]fluorodeoxyglucose positron-emission tomog­raphy, or both, as previously described.6 It was pos­sible to analyze regional left ventricular viability in 80 patients (87%).

RESULTS

BASELINE CHARACTERISTICS OF THE PATIENTS

A total of 92 patients were enrolled in the study. Of these, 35 patients received BMC as their ini­tial treatment (in phases 1 and 2 of the trial), 34 patients received CPC (in phases 1 and 2), and 23 patients received no intracoronary cell infu­sion (in phase 2, as the control group). Table 1 illustrates that the three groups of patients were well matched.

EFFECTS OF PROGENITOR-CELL INFUSION

Quantitative Characteristics of Left Ventricular Function

Patients with an adverse clinical event (six), sub­total stenosis of the target vessel at follow-up (three), an intraventricular thrombus precluding performance of left ventricular angiography (one), or atrial flutter or fibrillation at follow-up (one) were excluded from the exploratory analysis. In addition, of the 81 eligible patients, left ventricu­lar angiograms could not be quantitatively ana­lyzed in 4 because of inadequate contrast opaci-fication, in 1 because of ventricular extrasystoles, and in 4 because of the patients’ refusal to un­dergo invasive follow-up. Thus, a total of 72 of 81 serial paired left ventricular angiograms were available for quantitative analysis (28 in the BMC group, 26 in the CPC group, and 18 in the control group).

Table 2 summarizes the angiographic charac­teristics of the 75 patients included in the ran­domized phase of the study. At baseline, the three groups did not differ with respect to global LVEF, the extent or magnitude of regional left ventricu­lar dysfunction, left ventricular volumes, or stroke volumes.

The absolute change in global LVEF from base­line to 3 months did significantly differ among the three groups of patients. Patients receiving BMC had a significantly larger change in LVEF than patients receiving CPC (P = 0.003) and those in the control group (P<0.001). Similar results were ob­tained when patients from the first two phases of the study (the pilot phase and the randomized phase) were pooled. The results did not differ when patients without evidence of viable myo­cardium before inclusion were analyzed sepa­rately. The change in LVEF was −0.3±3.4 percent­age points in the control group (9 patients), +0.4±3.0 percentage points in the CPC group (18 patients), and +3.7±4.0 percentage points in the BMC group (18 patients) (P = 0.02 for the com­parison with the control group and P = 0.02 for the comparison with the CPC group).

In the subgroup of 35 patients who underwent serial assessment of left ventricular function by MRI, MRI-derived global LVEF increased signifi­cantly, by 4.8±6.0% (P = 0.03) among those receiv­ing BMC (11 patients) and by 2.8±5.2% (P = 0.02) among those receiving CPC (20 patients), where­as no change was observed in 4 control patients (P = 0.14). Thus, MRI-derived assessment of left ventricular function further corroborated the re­sults obtained from the total patient population.

Analysis of regional left ventricular function revealed that BMC treatment significantly in­creased contractility in the center of the left ven­tricular target area (Table 2). Likewise, MRI-derived regional analysis of left ventricular function re­vealed that the number of hypocontractile seg­ments was significantly reduced, from 10.1±3.6 to 8.7±3.6 segments (P = 0.02), and the number of normocontractile segments significantly in­creased, from 3.8±4.5 to 5.4±4.6 segments (P = 0.01), in the BMC group, whereas no significant changes were observed in the CPC group. MRI-derived infarct size, as measured by late enhance­ment volume normalized to left ventricular mass, remained constant both in the CPC group (25± 18% at baseline and 23±14% at 3 months,13 patients) and in the BMC group (20±10% at both time points, 9 patients). Thus, taken together, the data suggest that intracoronary infusion of BMC is associated with significant improvements in global and regional left ventricular contractile function among patients with persistent left ven­tricular dysfunction due to prior myocardial in­farction.

To identify independent predictors of improved global LVEF, a stepwise multivariate regression analysis was performed; it included classic deter­minants of LVEF as well as various baseline characteristics of the three groups (Table 3). The multivariate analysis identified the type of pro­genitor cell infused and the baseline stroke vol­ume as the only statistically significant indepen­dent predictors of LVEF recovery.

Functional Status

The functional status of the patients, as assessed by NYHA classification, improved significantly in the BMC group (from 2.23±0.6 to 1.97±0.7, P = 0.005). It did not improve significantly either in the CPC group (class, 2.16±0.8 at baseline and 1.93±0.8 at 3 months; P = 0.13) or in the control group (class, 1.91±0.7 and 2.09±0.9, respectively; P = 0.27).

RANDOMIZED CROSSOVER PHASE

Of the 24 patients who initially were randomly assigned to CPC infusion, 21 received BMC at the time of their first follow-up examination. Likewise, of the 28 patients who initially were randomly assigned to BMC infusion,

  • 24 received CPC after 3 months.

Of the 23 patients of the control group, 10 patients received CPC and 11 received BMC at their reexamination at 3 months (Fig. 1). As illustrated in Figure 2, regardless of whether patients received BMC as initial treatment, as crossover treatment after CPC infusion, or as crossover treatment after no cell infusion,

  • glob­al LVEF increased significantly after infusion of BMC. In contrast,
  • CPC treatment did not significantly alter LVEF when given either before or after BMC.

Thus, the intrapatient comparison of the dif­ferent treatment strategies not only documents the superiority of intracoronary infusion of BMC over the infusion of CPC for improving global left ventricular function, but also corroborates our findings in the analysis of data according to initial treatment assignment. The

  • preserved im­provement in cardiac function observed among patients who initially received BMC treatment and
  • then crossed over to CPC treatment demon­strates that the initially achieved differences in cardiac function persisted for at least 6 months after intracoronary infusion of BMC.
 Table 1. Baseline Characteristics of the Patients.* (not copied)  

Table 2. Quantitative Variables Pertaining to Left Ventricular Function, as Assessed by Left Ventricular Angiography.*

copy protected

Figure 2. Absolute Change in Quantitative Global Left Ventricular Ejection Fraction (LVEF) during the Crossover Phase of the Trial.

Data at 3 and 6 months are shown for all patients crossing over from BMC to CPC infusion (18 patients), from CPC to BMC infusion
(18 patients), and from no cell infusion to either CPC infusion (10 patients) or BMC infusion (11 patients). I bars represent standard
errors.

Table 3. Stepwise Linear Regression Analysis for Predictors of Improvement in Global Left Ventricular Ejection Fraction.*

Variable Nonstandardized Coefficient B

95% CI for B

P Value

Treatment group

1.49

0.53 to 2.46

0.003
Baseline stroke volume

−0.13

−0.22 to –0.05

0.002
No. of cardiovascular risk factors 0.76
Time since most recent MI 0.48
Concomitant PCI 0.60
Age 0.82
Baseline ejection fraction 0.72
Baseline end-diastolic volume 0.88

* Values are shown only for significant differences. MI denotes myocardial infarc­tion, and PCI percutaneous coronary intervention. For the overall model, the ad­justed R2 was 0.29; P<0.001 by analysis of variance.

 

DISCUSSION

Intrapatient comparison in the crossover phase of the trial rules out the possibility that differences in the patient populations studied may have affected outcomes. However, the mechanisms involved in mediating improved contractile function after intracoronary progenitor-cell infusion are not well understood.

Experimentally, although there is no definitive proof that cardiac myocytes may be regenerated, BMC were shown to contribute to functional re­covery of left ventricular contraction when in­jected into freshly infarcted hearts,13-15 whereas CPC profoundly stimulated ischemia-induced neovascularization.16,17 Both cell types were shown to prevent cardiomyocyte apoptosis and reduce the development of myocardial fibrosis and there­by improve cardiac function after acute myocar­dial infarction.18,19 Indeed, in our TOPCARE-AMI (Transplantation of Progenitor Cells and Regen­eration Enhancement in Acute Myocardial Infarc­tion) studies,6,7,9 intracoronary infusion of CPC was associated with functional improvements similar to those found with the use of BMC im­mediately after myocardial infarction. In the cur­rent study, however, which involved patients who had had a myocardial infarction at least 3 months before therapy,

  • transcoronary adminis­tration of CPC was significantly inferior to administration of BMC in altering global left ven­tricular function.

CPC obtained from patients with chronic ischemic heart disease show pro­found functional impairments,20,21 which might limit their recruitment, after intracoronary infu­sion, into chronically reperfused scar tissue many months or years after myocardial infarction. Thus, additional studies in which larger numbers of functionally enhanced CPC are used will be re­quired to increase the response to intracoronary infusion of CPC.

The magnitude of the improvement after in-tracoronary infusion of BMC, with absolute increases in global LVEF of approximately 2.9 percentage points according to left ventricular angiography and 4.8 percentage points accord­ing to MRI, was modest. However, it should be noted that the improvement in LVEF occurred in the setting of full conventional pharmacologic treatment: more than 90% of the patients were receiving beta-blocker and angiotensin-convert-ing–enzyme inhibitor treatment. Moreover, results from trials of contemporary reperfusion for the treatment of acute myocardial infarction, which is regarded as the most effective treatment strat­egy for improving left ventricular contractile per­formance after ischemic injury, have reported in­creases in global LVEF of 2.8% (in the CADILLAC [Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications] trial) and 4.1% (in the ADMIRAL [Abciximab before Direct Angioplasty and Stenting in Myocardial Infarction Regarding Acute and Long-Term Fol­low-up] trial).22,23

The number of patients, as well as the dura­tion of follow-up, is not sufficient to address the question of whether the moderate improvement in LVEF associated with one-time intracoronary BMC infusion is associated with reduced mortal­ity and morbidity among patients with heart fail­ure secondary to previous myocardial infarction. We conclude that intracoronary infusion of BMC is associated with persistent improvements in regional and global left ventricular function and improved functional status among patients who have had a myocardial infarction at least 3 months previously. Given the reasonable short-term safety profile of this therapeutic ap­proach, studies on a larger scale are warranted to examine its potential effects on morbidity and mortality among patients with postinfarction heart failure.

REFERENCES (1-8/23)

  1. 2001 Heart and stroke statistical up­date. Dallas: American Heart Association, 2000.
  2. Braunwald E. Cardiovascular medicine at the turn of the millennium: triumphs, concerns, and opportunities. N Engl J Med 1997;337:1360-9.
  3. Lange RA, Hillis LD. Reperfusion ther­apy in acute myocardial infarction. N Engl J Med 2002;346:954-5.
  4. Sutton MG, Sharpe N. Left ventricular remodeling after myocardial infarction: pathophysiology and therapy. Circulation 2000;101:2981-8.
  5. Strauer BE, Brehm M, Zeus T, et al. Re­pair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans. Circula­tion 2002;106:1913-8.
  6. Assmus B, Schachinger V, Teupe C, et al. Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myo­cardial Infarction (TOPCARE-AMI). Circu­lation 2002;106:3009-17.
  7. Britten MB, Abolmaali ND, Assmus B, et al. Infarct remodeling after intra-coronary progenitor cell treatment in pa­tients with acute myocardial infarction (TOPCARE-AMI): mechanistic insights from serial contrast-enhanced magnetic resonance imaging. Circulation 2003;108: 2212-8.
  8. Wollert KC, Meyer GP, Lotz J, et al. In-tracoronary autologous bone-marrow cell transfer after myocardial infarction: the BOOST randomised controlled clinical trial. Lancet 2004;364:141-8.

 

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Author: Tilda Barliya PhD

Photoacoustic Tomography (PAT), also called the optoacoustic or thermoacoustic (TA), is a materials analysis technique based on the reconstruction of an internal photoacoustic source distribution from measurements acquired by scanning ultrasound detectors over a surface that encloses the source under study. Moreover, it is non-ionizing and non-invasive, and is the fastest growing new biomedical method, with clinical applications on the way.

Dr. Lihong Wang, a Distinguished Professor of Biomedical Engineering in the School of Engineering and Applied Science at Washington University in St. Louis, summarizes the state of the art in photoacoustic imaging (1).

The photoacoustic (PA) effect:

The fundamental principle of the PA effect can be simply described: an object absorbs EM radiation energy, the absorbed energy converts into heat and the temperature of the object increases. As soon as the temperature increases, thermal expansion takes place, generating acoustic pressure in the medium. However, a steady thermal expansion (time invariant heating) does not generate acoustic waves; thus, the heating source is required to be time variant.

Dr. Wang explains that “the trick of photoacoustic tomography is to convert light absorbed at depth to sound waves, which scatter a thousand times less than light, for transmission back to the surface. The tissue to be imaged is irradiated by a nanosecond-pulsed laser at an optical wavelength”.

Absorption by light by molecules beneath the surface creates a thermally induced pressure jump that launches sound waves that are measured by ultrasound receivers at the surface and reassembled to create what is, in effect, a photograph.

When comparing to other modalities, PAT has several great advantages:

Table 1 Comparison of imaging modalities.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Dr. Wang is already working with physicians at the Washington University School of Medicine to move four applications of photoacoustic tomography into clinical trials (2).

  • One is to visualize the sentinel lymph nodes that are important in breast cancer staging;
  • A second to monitor early response to chemotherapy;
  • A third to image melanomas;
  • The fourth to image the gastrointestinal tract.

Sentinel node biopsy provides a good example of the improvement photoacoustic imaging promises over current imaging practice. Sentinel nodes are the nodes nearest a tumor, such as a breast tumor, to which cancerous cells would first migrate.

Currently, sentinel node biopsy, includes injection of  a radioactive substance, a dye or both near a tumor. The body treats both substances as foreign, so they flow to the first draining node to be filtered and flushed from the body. A gamma probe or a Geiger counter is used to locate the radioactive particles and the surgeon must cut open the area and follow the dye visually to the sentinel lymph node.

Dr. Wang however, offers a simpler method: injecting an optical dye that shows up so clearly in photoacoustic images that a hollow needle can be guided directly to the sentinel lymph node and a sample of tissue taken through the needle.

Contrast agents:

Most photoacoustic (PA) contrast agents are designed for absorbing laser, especially in the NIR spectral range. However, RF contrast agents are also desirable due to the superior penetration depth of RF in the body (1).  A typical example is indocyanine green (ICG), a dye approved by FDA. ICG has high absorption in the NIR spectral region, and it has already been proved to increase the PA signal when it is injected in blood vessels. Most recently, methyline blue was used as the contrast agent to detect the sentinel lymph node (SLN) (4).

Compared with dyes, nanoparticles possess a high and tunable absorption spectrum, and longer circulation time (1). The absorption peak is tunable by changing the shape and size of the particle. In addition, nanoparticles can be used to target certain diseases by bio-conjugating them with proteins, such as antibodies.  Among different nanoparticles, gold nanoparticles are favored in optical imaging due to their exceptional optical properties in the visible and NIR spectral ranges, including scattering, absorption and photoluminescence. So far, none of the gold nanoparticles have been approved by FDA (1).

One exciting aspect of photoacoustic tomography is that images contain functional as well as structural information because color reflects the chemical composition and chemistry determines function. Photoacoustic tomography, for example, can detect the oxygen saturation of hemoglobin, which is bright red when it is carrying oxygen and turns darker red when it releases it (3), that is important, since almost all diseases, especially cancer and diabetes, cause abnormal oxygen metabolism.  For example see image 1.

Image courtesy of Junjie Yao/Lihong Wang

Image 1: melanoma tumor (MT) cells were injected into a mouse ear on day 1. By day 7, there were noticeable changes in the blood flow rate (top graph, right) and the metabolic rate of oxygen usage (bottom graph, right). Counterintuitively, the tumor did not increase the oxygen extraction fraction (middle graph). The colors correspond to depth, with blue being superficial and red deep (3).

Wang’s team demonstrated that oxygen metabolism betrayed the presence of a melanoma within few days of injections in animal models, where as Oxygen use doubled in a week.

In this aspect: photoacoustic images,  can offer several parameters such as;

  • Vessel cross-section,
  • Concentration of hemoglobin and blood flow speed,
  • and The gradient of oxygen saturation can be used to calculate the oxygen use by a region of tissue.

Analysis of oxygen use is not necessarily new and is frequently measured by positron emission tomography (PET), which requires the injection or inhalation of a radioactively labeled tracer and undesirable radiation exposure.

Photoacoustic Tomography is currently being investigated for (5):

  1. Breast cancer (microvascular).  Additionally, for further information on photoacoustic tomography please read the article by Dr. Venkat Karra (I).
  2. Skin cancer (melanin)
  3. Brain tumors
  4. Cardiac disease – myocardial infraction (6)
  5. Ophthalmology – retinal disease (7)
  6. Ostheoarthrities (8)

Summary

photoacoustic tomography perfectly complements other biomedical imaging modalities by providing unique optical absorption contrast with highly scalable spatial resolution, penetration depth, and imaging speed. In light of its capabilities and flexibilities, PAT is expected to play a more essential role in biomedical studies and clinical practice.

Reference:

1.  Changhui Li and Lihong V Wang. Photoacoustic tomography and sensing in biomedicine. Phys. Med. Biol. 2009 54 R59 doi:10.1088/0031-9155/54/19/R01  http://iopscience.iop.org/0031-9155/54/19/R01 http://iopscience.iop.org/0031-9155/54/19/R01/pdf/0031-9155_54_19_R01.pdf

2. Jiecheny Yin. Photoacoustic tomography in cancer detection. http://bme240.eng.uci.edu/students/08s/jiecheny/index.htm

3. Jim Goodwin. NEW IMAGING TECHNIQUE COULD SPEED CANCER DETECTION. http://www.siteman.wustl.edu/ContentPage.aspx?id=5788

4.  Song K H, Stein E W, Margenthaler J A and Wang L V. Noninvasive photoacoustic identification of sentinel lymph nodes containing methylene blue in vivo in a rat model J. Biomed. Opt. 2008: 13 054033–6.  http://oilab.seas.wustl.edu/epub/SongK_2008_J_Biomed_Opt_13_054033.pdf

5. Junjie Yao and Lihong V Wang.  Photoacoustic tomography: fundamentals, advances and prospects. Contrast Media Mol Imaging. 2011 September; 6(5): 332–345. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3205414/

6. Holotta M, Grossauer HKremser CTorbica PVölkl JDegenhart GEsterhammer RNuster RPaltauf GJaschke W. Photoacoustic tomography of ex vivo mouse hearts with myocardial infarction. J. Biomed Opt. 2011 Mar;16(3):036007. doi: 10.1117/1.3556720. http://www.ncbi.nlm.nih.gov/pubmed/21456870

7. Hao F. ZhangCarmen A. Puliafito, and Shuliang Jiao, Photoacoustic Ophthalmoscopy for In Vivo Retinal Imaging: Current Status and Prospects.  Ophthalmic Surg Lasers Imaging. 2011 July; 42(0): S106–S115.  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3291958/

8. Yao Sun, Eric S. Sobel, and Huabei Jiang. First assessment of three-dimensional quantitative photoacoustic tomography for in vivo detection of osteoarthritis in the finger joints.  Med. Phys. 38, 4009 (2011); http://dx.doi.org/10.1118/1.3598113 . http://online.medphys.org/resource/1/mphya6/v38/i7/p4009_s1?isAuthorized=no

Other articles from our Open Access Journal:

I. By : Venkat Karra. Visualizing breast cancer without X-rays. https://pharmaceuticalintelligence.com/2012/05/08/visualizing-breast-cancer-without-x-rays/

II. By: Dr. Dror Nir. Ultrasound in Radiology – Results of a European Survey. https://pharmaceuticalintelligence.com/2013/07/21/ultrasound-in-radiology-results-of-a-european-survey/

III.  By: Dr. Dror Nir. Causes and imaging features of false positives and false negatives on 18F-PET/CT in oncologic imaging. https://pharmaceuticalintelligence.com/2013/05/18/causes-and-imaging-features-of-false-positives-and-false-negatives-on-18f-petct-in-oncologic-imaging/

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