Cleveland Clinic researcher discovers genetic cause of thyroid cancer

Genetic analysis revises treatment recommendations related to thyroid cancer

Friday, December 23, 2011, Cleveland: Cleveland Clinic researchers have discovered three genes that increase the risk of thyroid cancer, which is has the largest incidence increase in cancers among both men and women.

Research led by Charis Eng, M.D., Ph.D., Chair and founding Director of the Genomic Medicine Institute of Cleveland Clinic's Lerner Research Institute, included nearly 3,000 patients with Cowden syndrome (CS) or CS-like disease, which is related to an increased risk of breast and thyroid cancer.

Mutations in the PTEN gene are the foundation of Cowden syndrome. PTEN is a tumor suppressor gene, helping to direct the growth and division of cells. Inherited mutations in the PTEN gene have been found in approximately 80 percent of Cowden syndrome patients. These mutations prevent the PTEN protein from effectively regulating cell survival and division, which can lead to the formation of tumors.

"Our investigation into the genetics behind thyroid disease raises important details relevant to diagnosis and treatment," said Dr. Eng. "We hope to promote the earliest diagnosis and most targeted treatment possible."

The conclusions of this research, published in the Journal of Clinical Endocrinology & Metabolism, found that all six patients under age 18 had pathogenic PTEN mutations. The researchers recommend that the thyroids of children with PTEN mutation-causing CS-related disease receive increased surveillance.

Children with thyroid cancer are recommended to have testing for PTEN mutations, which could warrant surveillance for additional cancers or maladies. In contrast, alterations in the SDH and KLLN genes did not associate with thyroid cancer in children.

PTEN gene testing in the setting of genetic counseling is already routinely practiced, and has been a powerful gene-enabled diagnostic test which then personalizes clinical screening and treatment. Once SDH and KLLN findings are independently validated, the tests could be implemented as a clinical routine test as well. Importantly, these three genes belong to different cell pathways so that specific molecular-targeted treatments can be utilized depending on which gene is involved.

CureToday.com: Winter 2011 Article - "Patients on Angiogenesis Inhibitors Should Be Monitored for Heart Issues"

Patients on Angiogenesis Inhibitors (Including Sutent - jhh) Should Be Monitored for Heart Issues

BY KATHY LATOUR
PUBLISHED DECEMBER 21, 2011

Researchers studying the side effects of new cancer treatments have determined that patients taking a class of drugs that target the VEGF pathway should be monitored for cardiac issues that include high blood pressure, heart attack and congestive heart failure.

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The issue is not to stop the drugs’ use but to make oncologists aware that patients taking these drugs need monitoring, says Javid Moslehi, MD, co-director of the Cardio-Oncology Program at the Brigham and Women’s Hospital and Dana-Farber Cancer Institute in Boston.

VEGF, or vascular endothelial growth factor, is a protein released more abundantly by tumors, which signals the growth of blood vessels to feed the tumor, a process called angiogenesis. The increasing numbers of angiogenesis inhibitors in development have made this an important area of research, Moslehi says. During the past seven years, four drugs that target the VEGF pathway have been approved by the Food and Drug Administration for use in a number of cancers, including brain, colon, lung, kidney, liver and gastrointestinal tumors. In addition to Avastin (bevacizumab), the FDA has approved Nexavar (sorafenib), Sutent (sunitinib) and Votrient (pazopanib).

“It has been recognized that these drugs cause hypertension,” Moslehi says, “but it was often ignored because they were treating the patient for cancer. But hypertension can be a long-term issue and lead to a number of cardiovascular diseases, including heart failure and stroke.”

A study reported earlier this year in the Journal of Clinical Oncology examined five randomized trials, which compared 3,784 women with metastatic breast cancer who received chemotherapy regimens containing Avastin with women given regimens that did not include the drug.

“This analysis showed a significant increase in [risk for] high-grade congestive heart failure in women taking Avastin—almost five times higher,” says Toni Choueiri, MD, assistant professor of medicine at Harvard Medical School and lead researcher. “This is clinically significant.” Only 1.6 percent of women taking Avastin actually had high-grade congestive heart failure, so while it’s important to note there is a significantly increased risk, there is still a low incidence overall.

In the study, Choueiri points to research on mice indicating that those lacking the VEGF gene have thinned myocardial walls. “What we know is that VEGF may have cardioprotective effects, and when you block it you may get a certain cardiac toxicity,” Choueiri says, adding that physicians may not have attributed symptoms associated with heart failure to Avastin since symptoms could be attributed to other causes, particularly in the breast cancer population where women may have received other treatments recognized as having cardiac toxicity. For this reason, he says, incidents may not have been cited in the studies.

Moslehi and Choueiri point to the trial process for the newer drugs as a time to identify potential cardiac side effects, learn how they can be managed and determine whether they are reversible.

In October, Moslehi and colleagues published a letter in The New England Journal of Medicine that indicated in certain cases that the heart failure seen with Nexavar and Sutent is reversible. “But more studies are needed that prospectively examine these unwarranted side effects.”

Moslehi and Choueiri have joined forces and combined their expertise—cardiology and oncology—to examine the effects of VEGF inhibitors on the cardiovascular system.

“Ultimately, treating the cardiovascular effects of novel chemotherapies requires a team effort between various physicians working together for the benefit of the patient,” Moslehi says.

Health News - Removal of lymph nodes during surgery for thyroid cancer may be beneficial

Procedure may reduce recurrence rates, lower tumor marker levels

By Rachel Champeau

Papillary thyroid cancer accounts for the majority of all thyroid malignancies, which primarily impact women. A new study indicates that routinely removing lymph nodes in the neck in these cancer patients may help prevent the disease from coming back.

When thyroid cancer metastasizes, lymph nodes in the neck may be affected, but these lymph-node tumors can be tiny and may not be detected by ultrasounds done before surgery to remove the diseased thyroid — or even during the procedure itself.

In an international academic study published in the December issue of the journal Surgery, UCLA researchers and colleagues demonstrate that routine removal of neck lymph nodes during initial thyroid surgery for papillary cancer may lead to lower disease recurrence rates and lower levels of thyroglobulin, a thyroid tumor marker that can be an indicator of disease when elevated.

Although it is standard procedure in some cancer centers, there has been debate in the worldwide surgical community about the benefits of routinely removing neck lymph nodes, a procedure known as prophylactic central neck lymph-node dissection, or CLND.

"We found that re-operation rates due to cancer were lower in patients who had routine removal of these lymph nodes, which suggests a more thorough surgical clearance of disease," said the study's senior author, Dr. Michael Yeh, an associate professor of surgery at the David Geffen School of Medicine at UCLA. "Our findings may help add to growing evidence that this additional procedure, performed during initial thyroid surgery, may be helpful in management of papillary thyroid cancer."

For the study, researchers examined data on 606 patients who received care in one of three endocrine surgical units in the U.S., England and Australia. Patients were divided into two groups: Group A patients had undergone total thyroid removal alone; Group B patients had undergone both thyroid removal and dissection of central neck lymph nodes. Patients were followed for an average of three-and-a-half years following surgery.

The standard pre-operative evaluation of all patients included a fine-needle biopsy of the primary thyroid tumor and determination of neck lymph-node disease status through physical examination and ultrasound of the neck.

The rate of disease recurrence in the entire study population was 6.9 percent. The researchers found that the need for central neck re-operation was significantly lower among patients who had undergone the routine initial central neck lymph-node dissection, compared with those who had undergone only thyroid removal (1.5 percent vs. 6.1 percent).

Stimulated thyroglobulin levels were also lower among patients in Group B, which may demonstrate a more thorough clearing of disease in the patients who had both thyroid and neck lymph-node removal procedures, the researchers said.

"This significant reduction in the need for further surgery in the critical central area of the neck is important, since it reduces risk to the many vital structures housed here, such as the nerves supplying the voice," said study co-author Dr. Mark Sywak of the University of Sydney in Australia.

UCLA's Yeh noted that blood thyroglobulin levels are a useful and sensitive measure in tracking disease recurrence, especially when many tumors in this area are too tiny to be detected using a physical exam or ultrasound.

Rates of temporarily low calcium levels, a common side effect, were significantly higher in Group B patients (9.7 percent), who had neck lymph nodes removed, than in Group A patients (4.1 percent) who had thyroid-removal surgery alone. The rate of long-term complications was low for both groups — about 1 percent.

The researchers said the next step may be to conduct a prospective, randomized clinical trial to further assess the impact of routinely removing central neck lymph nodes during initial surgery for papillary thyroid cancer.

The study took place at UCLA Medical Center; the University of Sydney, Australia; and Hammersmith Hospital at Imperial College London.

Other study authors included Aleksandra Popadich, James C. Lee, Stan Sidhu, Leigh Delbridge and Mark Sywak from the University of Sydney endocrine surgical unit; Olga Levin and Kevin Ro, both students at the David Geffen School of Medicine at UCLA; Stephanie Smooke-Praw from the department of medicine at the Geffen School of Medicine; Maisam Fazel, Asit Arora, Neil S. Tolley and F. Fausto Palazzo from the department of thyroid and endocrine surgery at Hammersmith Hospital in London; and Diana L. Learoyd from the department of endocrinology at Royal North Shore Hospital in New South Wales, Australia.

Clinical Trial Update following Cycles 39 and 40

Hi, Everyone - I made my 12-weekly visit to St. Louis on December 14 for my quarterly poking and prodding.  I got good news again - no new tumors and no growth in the existing ones.  Yea!  There was no shrinkage, but the point of the study is to try for no growth. They are now calling me a Progression Free Survivor (PFS).  Rather an impressive-sounding label, isn't it?  I got no new details about how the study is going from St. Louis, not even hints, but my Lincoln oncologist told me that I'm the longest surviving person with this type of cancer that he's ever heard of.  I hope they say that at my funeral in about 40 years! The side effects, etc., have been about the same but I'm getting used to them after 4-and-a-half years on Sutent.  (That doesn't mean I still don't look for ways to minimize them!) Christopher flew down with me this trip, which was nice.  He's a senior and Washington University in St. Louis is a school he's interested in.  They seem to be interested in him as well.  He came down to be interviewed by their admissions department.  He left feeling pretty good about how things went.  It would be nice if it went so well that they offered him lots and lots of financial aid to attend, but we'll have to wait and see. While Christopher was interviewed in one room, a few other admission people came out and talked to me about him.  They were all familiar with his activities and academics, oddly enough.   They wanted to talk to me mainly about Show Choir and Band and how he managed to do both while taking as many AP classes as he did.  They were really impressed that he chose to take summer classes to free up time during the school year for those other activities.  (And here I thought it was just to avoid mowing the lawn!) He's been admitted to the U of Nebraska and Nebraska Wesleyan here in Lincoln as well as Iowa State (which should make his mother's side of the family happy).  There are a few other schools he's applied to but hasn't heard back from.  I'm not sure to what college he's leaning at the moment, but he has plenty of time to make a decision. Sara and Matthew are both fine.  Matthew's been singing a lot this month with the Lincoln Boys Choir, among other things.  He's about ready for everything to be over though.  His final concert is Sunday, December 18, at 5:00 at St. Paul Church, for all you Lincoln people. My next trip will be March 7.  I bet the daffodils will be up down there by then. Thanks again for all your continuing prayers and support.  Hope you all have a very Merry Christmas and a Great 2012! John

BRAF addiction of thyroid cancers makes them therapeutically vulnerable

Papillary carcinoma is the most common form of thyroid cancer. Approximately one quarter of these carcinomas have mutations in the BRAF gene. The prevalence of such mutations is even greater in high-grade carcinomas, particularly those that are refractory to standard treatment, which is radioactive iodine (RAI). A team of researchers led by James Fagin, at Memorial Sloan-Kettering Cancer Center, New York, has now identified a way to potentially exploit the expression of BRAF by such cancers for therapeutic purposes.
Despite the prevalence of BRAF mutations in papillary carcinoma it has remained unclear how dependent thyroid cancers are on BRAF expression. Fagin and colleagues first showed that thyroid tumors in mice expressing one of the most commonly detected BRAF mutations in human papillary thyroid carcinomas were exquisitely dependent on BRAF for viability. Of therapeutic significance, treating thyroid tumor–bearing mice with drugs that inhibited the BRAF signaling pathway rendered the tumor cells susceptible to a therapeutic dose of RAI. Fagin and colleagues therefore suggest that their data provide rationale for clinical trials testing whether such drugs can restore the efficacy of RAI therapy in patients with papillary thyroid carcinomas expressing BRAF mutations.

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TITLE: Small-molecule MAPK inhibitors restore radioiodine incorporation in mouse thyroid cancers with conditional BRAF activation
AUTHOR CONTACT:
James A. Fagin
Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
Phone: 646-888-2136; Fax: 646-422-0890; E-mail: faginj@mskcc.org.

Overcoming Thyroid Cancer Resistance | www.dailyrx.com

Overcoming Thyroid Cancer Resistance

BRAF mutations may restore RAI efficacy in papillary carcinomas

Reviewed By: Joseph V. Madia, MD

By: Laurie Stoneham

Published: Nov 21, 2011 11:18 am

(dailyRx)
Thyroid cancer is usually successfully treated with surgery. The problem is - this is one of the cancers that tends to reappear. New research has uncovered a means for overcoming a common obstacle in treating thyroid cancer.
BRAF gene mutations occur in about 25 percent of thyroid cancers, particularly high-grade tumors that often become resistant to standard treatments with radioactive iodine (RAI). Researchers have found that targeting the BRAF mutations may help these tumors become more responsive to therapy.

Work with your healthcare team to develop a comprehensive cancer care plan.

Researchers, led by James Fagin, M.D., chief of Endocrinology Service at Memorial Sloan-Kettering Cancer Center, have found a way to work with BRAF mutations in papillary carcinoma, the most common type of thyroid cancer.
Dr. Fagin and his team first discovered that thyroid cancers were what they called "exquisitely dependent on BRAF for viability."
Next, the team treated mice with thyroid tumors with drugs that blocked the BRAF signaling pathway. They found that this therapy made the tumor cells more responsive to therapeutic doses of RAI.
Researchers suggest this data provides enough evidence for clinical trials to be conducted which will focus on restoring RAI therapy efficacy in patients with papillary thyroid cancers who have BRAF mutations.
This research was published in November, 2011 edition of Journal of Clinical Investigation.

Cancer

Cancer is diagnosed in over 12 million people each year, kills over 7 million and one out of every three people will be diagnosed with an invasive cancer at some point in their lifetime in the United States. Cancer is a group of diseases classified by abnormal and uncontrolled cellular growth in a particular organ or tissue type in the body.
Cancer is caused by a multitude of factors including genetics and infections, but a majority of cancers can be attributed to environmental causes, such as smoking, and being exposed to carcinogens or radiation.

Cancer will produce symptoms that affect the organ it is located in, such as coughing and shortness of breath from a lung cancer, constipation and bloody stools from colon cancer, or headaches and cognitive problems from a brain cancer. Other cancers such as leukemia and blood cancers may produce flu-like symptoms and sudden infections. Some cancers may be discovered by physical evidence, such as feeling a lump in breast cancer.
Treatment is usually one of, or a combination of, surgery, radiation therapy, and chemotherapy. Newer treatments such as hormonal drugs and targeted drugs (Herceptin in breast cancer, Erbitux in colon cancer, Avastin in several) are making cancer treatment even more specific to the patient and the disease. Diagnosis is based off of physical examination and several imaging techniques such as MRI, PET scan laparoscopy and when a pathologist examines a piece of cancerous tissue.

EU regulators back AstraZeneca thyroid cancer drug - Yahoo!

EU regulators back AstraZeneca thyroid cancer drug

Reuters – 6 hours ago

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LONDON (Reuters) - European drug regulators have recommended AstraZeneca's new thyroid cancer pill Caprelsa, or vandetanib, for approval, giving a boost to a drug which has suffered past setbacks.
The Anglo-Swedish drugmaker said in a statement on Friday its application for a marketing authorisation for Caprelsa received a positive opinion from the European Medicines Agency for the treatment of advanced and non-operable medullary thyroid cancer.
Vandetanib was once seen as a potential $1 billion (631 million pounds)-plus blockbuster for AstraZeneca, but suffered a major setback after failing to extend survival in patients with lung cancer.
The drug is now targeted at the niche market of treating patients with non-operable advanced medullary thyroid cancer (MTC), which accounts for about 4 percent of thyroid cancers.
U.S. drug regulators approved it for MTC in April.
Analysts on average now expect sales of Caprelsa to reach $112 million by 2016, according to consensus forecasts on Thomson Reuters Pharma.
AstraZeneca said the European agency came to its decision after reviewing data from Phase III clinical trials of the drug, which included a double-blind trial of 331 patients with advanced MTC that had spread to other parts of the body, and showed a 54 percent reduction in risk for disease progression with Caprelsa compared to placebo.
Thyroid cancer affects around 48,000 people a year in Europe and kills around 6,300, of which between 5 to 10 percent have MTC.
Advanced MTC has a poor prognosis and clinical outcomes for patients with this disease have not changed substantially in the past 20 years. Currently there are no approved therapies in Europe for this advanced stage of the disease.
(Editing by Mike Nesbit and Ben Hirschler)

Mortality Greatest With Recurrence of Papillary Type Thyroid Cancer : IMNG Oncology Report

Mortality Greatest With Recurrence of Papillary Type Thyroid Cancer

By: CAROLINE HELWICK, Oncology Report Digital Network

SAN FRANCISCO – Thyroid cancer recurs in almost 40% of elderly patients, and while recurrence is accompanied by an increased mortality risk, this seems to be confined to the subset of patients with papillary thyroid cancer, according to researchers from Penn State Milton S. Hershey Medical Center in Hershey, Pa.

"Elderly patients with follicular disease and recurrence did not have a significantly different risk of death compared to patients without recurrences," said lead author Melissa M. Boltz, D.O., who presented the findings at the annual clinical congress of the American College of Surgeons.

About half of patients who develop recurrent disease will die from this, but little is known about the risk of recurrence. "We questioned whether the implications could be different for the elderly population," she said.

The researchers focused on recurrent well-differentiated thyroid cancer (WDTC) in patients aged 65 years or older and assessed its impact on 1-year and 5-year survival, controlling for patient-, disease-, and treatment-related variables.

From the SEER (Surveillance Epidemiology and End Results), Medicare-linked database, they identified 2,883 patients with primary WDTC treated between 1995 and 2007. They documented recurrence through billing codes, evidence of I-131 treatment, thyroid imaging, or the performance of additional thyroid procedures beyond 6 months of diagnosis.

Of these, 1,126 patients (39%) developed recurrent disease, and the recurrent group was not demographically different from the group of patients without recurrence. The majority recurred within the first 2 years of initial treatment, after which the probability of developing recurrence was never more than 45% over 10 years, Dr. Boltz said.

Risk factors associated with recurrence included older age, advanced stage, lack of surgical treatment, and regional disease, she reported.

Regional disease was present in 44% of the recurrent group, vs. only 24% of the nonrecurrent group, and thyroidectomy was performed on 33% vs. 60%, respectively.

At 10 years, of the total thyroid cancer population, 662 (23%) died of some form of cancer with thyroid cancer as the cause of death in 273 (41%).

"In the 1-year landmark analysis, patients with recurrence had a higher risk for cancer-specific mortality within 10 years, versus those without recurrence, and the trend was similar at the 5-year landmark," Dr. Boltz noted.

By histology, patients who recurred with papillary thyroid cancer were significantly more likely to die of thyroid cancer as compared to papillary thyroid cancer patients not experiencing recurrence. Papillary patients who were older, had regional or distant disease, and who did not undergo surgery were also at increased risk for cancer-specific death.

The hazard ratios for thyroid cancer death for papillary thyroid cancer patients were as follows:

• Recurrence: HR, 1.96 (P less than .001).

• Age, 5-year increases: HR, 1.46 (P less than .001).

• Regional disease: HR, 4.90 (P less than .001).

• Distant disease: HR, 16.97 (P less than .001).

• No surgery: HR, 7.98 (P less than .001).

• Treatment other than surgery: HR, 3.47 (P less than 0.001).

In contrast, patients with follicular thyroid cancer had an increase in cancer-specific mortality only in relation to the presence of distant disease (HR, 17.78; P less than 0.001). Older age was also associated with an increase in cancer-specific mortality (HR, 1.24; P = 0.04), but disease recurrence was not (HR 0.58; P = 0.16).

"Unlike papillary cancer, follicular cancer recurrence did not contribute to cancer-specific mortality. The only risks were related to older age and advanced stage," Dr. Boltz reported.

Dr. Boltz cautioned that this study pertained to elderly Medicare patients, and the results should not be generalized to a younger population, in which thyroid cancer is more prevalent.

Dr. Boltz reported no relevant conflicts of interest.

MedWire News - Oncology - Polymorphisms may identify sunitinib poor responders

By Laura Dean

24 October 2011

Lancet Oncol 2011; Advance online publication

MedWire News: Polymorphisms in the genes encoding vascular endothelial growth factor receptor 3 (VEGFR3) and cytochrome P450 3A5 (CYP3A5) may partially account for the absence of response and low tolerability to sunitinib observed in some patients with renal-cell carcinoma (RCC), researchers report.

"These data suggest that alternative treatment approaches for patients with these genetic variants should be promoted," write Cristina Rodríguez-Antona (Spanish National Cancer Center, Madrid) and colleagues in The Lancet Oncology.

The researchers explain that sunitinib is a tyrosine kinase inhibitor with proven efficacy in RCC, but around 20% of patients do not respond, while around 32% need dose reductions due to toxicity.

In the present study, Rodríguez-Antona and team aimed to identify polymorphisms as potential markers of sunitinib outcome, focusing on genetic variants that could alter the pharmacokinetics and pharmacodynamics of this drug.

They genotyped 101 RCC patients for 16 single nucleotide polymorphisms (SNPs) in nine genes: VEGFR2, VEGFR3, platelet-derived growth factor receptor α (PDGFR-α), VEGF-A, interleukin 8 (IL-8), CYP3A4, CYP3A5, ATP-binding cassette B1 (ABCB1), and ABCB2.

The researchers then assessed associations between each SNP and efficacy and toxicity of sunitinib using multivariable analyses adjusted for clinical factors associated with survival or toxicity.

After a median follow-up period of 21.2 months, the median progression-free survival (PFS) among 89 patients included the efficacy analysis was 12.3 months.

Objective response was assessed in 78 patients with measurable disease; one (1%) patient had a complete response, 36 (46%) had a partial response, 26 (33%) had stable disease, and 15 (19%) had progressive disease.

The analysis showed that two VEGFR3 missense SNPs, rs307826 and rs307821, were significantly associated with reduced PFS with sunitinib. Indeed, median PFS for people with the wild-type (AA) allele at rs307826 was 13.7 months, compared with 3.6 months for heterozygous (AG) individuals. The corresponding values for the rs307821 wild-type (GG) and heterozygous (GT) alleles were 13.7 months and 6.7 months, respectively.

Although not statistically significant, SNPs in ABCB1, ABCG2, and VEGFR2(rs1128503, rs2231142, and rs1870377) also showed a tendency to have worse response to sunitinib in terms of PFS or overall survival.

In terms of toxicity, the CYP3A5*1 (rs776746) high-metabolizing genotype (AG) was significantly associated with a 3.75-fold increased risk for dose reductions due to toxicity.

The researchers conclude that if their findings are independently validated in further studies, "these genetic variants could provide the basis for individualized renal cancer treatment."

In a related commentary, Brian Rini (Cleveland Clinic Taussig Cancer Institute, Ohio, USA) said: "An ideal predictive biomarker is one that is easily and unambiguously measured and reliably separates patients who will benefit from a specific approach from patients who will benefit from an alternative approach. [The present data] thus represent a small but important step toward truly targeted therapy for patients with renal-cell carcinoma."

MedWire (www.medwire-news.md) is an independent clinical news service provided by Current Medicine Group, a trading division of Springer Healthcare Limited. © Springer Healthcare Ltd; 2010

Using Gene Therapy to Make Thyroid Tumors More Susceptible to Radioiodine Therapy

Newswise — Falls Church, Virginia. Oct. 27, 2011 – Some forms of differentiated thyroid cancer (DTC) respond to treatment with radioactive iodine, which is taken up by the thyroid gland, destroying the cancerous cells. However patients with two forms of thyroid cancer, radioiodine-refractory DTC and anaplastic thyroid cancer (ATC), do not benefit from radioiodine therapy, and other treatment options are limited.

Christine Spitzweg, MD, and colleagues from Ludwig-Maximilians-University, Munich, Germany, are exploring a novel therapeutic approach intended to modify the genetic make-up of radioiodine-refractory forms of thyroid cancer to make them more susceptible to the anti-cancer effects of radioiodine therapy. Using a non-viral gene delivery system based on nanoparticle vectors, the researchers are able to introduce the gene for the sodium iodide symporter (NIS) into radioiodine-refractory tumor cells, enhancing their uptake of therapeutic radioiodine.

The vectors contain the NIS gene, a protective polymer, and a synthetic peptide that targets the particle to an epidermal growth factor receptor (EGFR) present at varying levels on the surface of thyroid tumor cells. The researchers mixed the thyroid tumor cells with the nanoparticles. In a parallel experiment, the researchers created a similar nanoparticle complex that lacked the EGFR-specific targeting peptide.

According to data presented today at the 81st Annual Meeting of the American Thyroid Association, tumor cell lines containing higher levels of EGFR incorporated more of the nanoparticle complexes. The tumor cell lines that exhibited the most efficient nanoparticle transduction had a 7-10 fold increase in iodide uptake when the nanoparticles contained the EGFR targeting peptide compared to experiments using the complexes lacking the EGFR targeting peptide.

Preliminary tests of this therapeutic approach in mice indicate that a tumor-selective gene delivery strategy can enhance radioiodine uptake by refractory DTC and ATC tumors.

About the ATA Annual Meeting
The 81st Annual Meeting of the American Thyroid Association will be held October 26-30, 2011 at the Renaissance Esmeralda Resort & Spa in Indian Wells (near Palm Springs), California. This four day creative and innovative scientific program, chaired by Drs. Anthony Hollenberg and Martha Zeiger, has carefully balanced clinical and basic science sessions on the latest advances in thyroidology. The ATA meeting is designed to offer continuing education for endocrinologists, internists, surgeons, basic scientists, nuclear medicine scientists, pathologists, endocrine fellows and nurses, physician assistants and other health care professionals. Visit www.thyroid.org for more information.

About the ATA
The American Thyroid Association (ATA) is the leading worldwide organization dedicated to the advancement, understanding, prevention, diagnosis and treatment of thyroid disorders and thyroid cancer. ATA is an international individual membership organization with over 1,400 members from 43 countries around the world. Celebrating its 88th anniversary, ATA delivers its mission through several key endeavors: the publication of highly regarded monthly journals, THYROID, Clinical Thyroidology and Clinical Thyroidology for Patients; annual scientific meetings; biennial clinical and research symposia; research grant programs for young investigators, support of online professional, public and patient educational programs; and the development of guidelines for clinical management of thyroid disease. Visitwww.thyroid.org for more information.

Researchers explore novel therapeutic approach for thyroid cancer

Some forms of differentiated thyroid cancer (DTC) respond to treatment with radioactive iodine, which is taken up by the thyroid gland, destroying the cancerous cells. However patients with two forms of thyroid cancer, radioiodine-refractory DTC and anaplastic thyroid cancer (ATC), do not benefit from radioiodine therapy, and other treatment options are limited.
Christine Spitzweg, MD, and colleagues from Ludwig-Maximilians-University, Munich, Germany, are exploring a novel therapeutic approach intended to modify the genetic make-up of radioiodine-refractory forms of thyroid cancer to make them more susceptible to the anti-cancer effects of radioiodine therapy. Using a non-viral genedelivery system based on nanoparticle vectors, the researchers are able to introduce the gene for the sodium iodide symporter (NIS) into radioiodine-refractory tumor cells, enhancing their uptake of therapeutic radioiodine.
The vectors contain the NIS gene, a protective polymer, and a synthetic peptide that targets the particle to an epidermal growth factor receptor (EGFR) present at varying levels on the surface of thyroid tumor cells. The researchers mixed the thyroid tumor cells with the nanoparticles. In a parallel experiment, the researchers created a similar nanoparticle complex that lacked the EGFR-specific targeting peptide.
According to data presented today at the 81st Annual Meeting of the American Thyroid Association, tumor cell lines containing higher levels of EGFR incorporated more of the nanoparticle complexes. The tumor cell lines that exhibited the most efficient nanoparticle transduction had a 7-10 fold increase in iodide uptake when the nanoparticles contained the EGFR targeting peptide compared to experiments using the complexes lacking the EGFR targeting peptide.
Preliminary tests of this therapeutic approach in mice indicate that a tumor-selective gene delivery strategy can enhance radioiodine uptake by refractory DTC and ATC tumors.
Source: American Thyroid Association

Advanced papillary thyroid cancer patients with BRAFV600E gene mutation at higher risk

Individuals with advanced papillary thyroid cancer (PTC) that are associated with the BRAFV600E gene mutation have a higher risk of recurrent disease and progression to more advanced, poorly differentiated thyroid cancer, according to data presented today at the 81st Annual Meeting of the American Thyroid Association (ATA). An understanding of the biological processes that underlie this progression could lead to the development of more effective therapies.
One approach to studying the role of BRAFV600E in PTC initiation and progression is to create mice in which the gene mutation (BRAFV600E) has been introduced and activated in the thyroid. These transgenic mice develop advanced PTCs that closely resemble human poorly differentiated PTCs. Mabel Ryder, MD, and colleagues from Memorial Sloan-Kettering Cancer Center and the Sloan-Kettering Institute (New York, NY) used BRAFV600E transgenic mice to study the effects of tumor-associatedmacrophages (TAMs), a type of white blood cell, on PTC initiation and progression. In cancers, TAMs are versatile and can either support or inhibit cancer progression. In PTCs, BRAF activation in the thyroid is accompanied by increased levels of colony stimulating factor 1, which stimulates the recruitment of TAMs to the thyroid. Once in the thyroid, TAMs accumulate alongside cancer-associated myofibroblasts (CAMs) to form a dense layer within and around the thyroid. The researchers used genetic techniques to kill the TAMs in PTCs. The result was a significant reduction in PTC size, total tumor cell volume and a more well-differentiated, less advanced PTC. The authors also demonstrated a functional link between TAMs, the recruitment of CAMs and PTC initiation. The researchers observed that when TAMs are depleted during PTC initiation, the density of CAMs is significantly diminished along with an impairment of PTC initiation.
"Many of the new treatments for thyroid cancer, such as kinase inhibitors, aim to block the activity of oncoproteins present within tumor cells. Our data suggests that immune cells in the tumor microenvironment play an important role in the biology of these cancers. This may be clinically relevant since there are new agents in development that can target TAMs, and we believe these should be explored, particularly in patients with advanced forms of the disease," said Dr. Ryder.
Based on these findings, the researchers concluded that TAMs have an important role in the initiation and progression of PTC and may represent a potent therapeutic target for combating advanced thyroid cancers that do not respond to conventional therapies.
Source American Thyroid Association (ATA)

New rapid method for detection of BRAF V600E gene in thyroid tissue

During surgical removal of thyroid tissue suspicious for cancer, fast, reliable, and cost-effective techniques are needed to analyze the resected tissue for biomarkers—including BRAF V600E, is a molecular biomarker for papillary thyroid cancer (PTC)—that can confirm the presence and type of cancer cells. Researchers have developed a new, rapid method for direct detection of the BRAF V600E gene in thyroid tissue without the need to purify DNA from tumor cells—high resolution melting analysis (HRM).
In HRM analysis, a sample of the resected thyroid tissue is homogenized and the DNA-containing portion is collected and washed. Polymerase chain reaction (PCR), a targeted gene detection technique, is then used to identify the presence of the BRAF V600E gene in the tissue sample. This is achieved without having to purify or sequence the DNA.
Jun Hee Park and G. Park from Chosun University Hospital, Republic of Korea, have demonstrated that HRM is at least as effective as alternative methods that rely on purified DNA for intra-operative detection of the BRAF V600E biomarker, according to data presented today at the 81st Annual Meeting of the American Thyroid Association (ATA). Using HRM to analyze cancerous tissue from 96 patients, Park and Park obtained a positive result for BRAF V600E in 58 of 96 samples (60.4%). The same 96 samples were subjected to two other testing methods that both required DNA purification—DNAsequencing and restriction fragment length polymorphism (RFLP) analysis. These analytical methods yielded a positive BRAF V600E result in 46.8% and 61.5% of samples, respectively. In comparison to these two techniques, direct HRM produced comparable results, was economical, and was suitable for intra-operative use with results available within 50 minutes.
Source: American Thyroid Association

Exelixis' thyroid cancer drug may get early approval - Yahoo! News

(Reuters) - Exelixis Inc's drug to treat a rare form of thyroid cancermet the main goal of a late-stage study, prompting the company to look to an accelerated approval process that could bring the drug to market within a year.

Shares of San Francisco-based Exelixis were up 18 percent at $7.09 in heavy trading on Monday on Nasdaq. They had touched a high of $7.53 earlier in the day.

Exelixis said based on the study it was requesting permission to begin a rolling submission of data toward the marketing application of the drug cabozantinib in advanced medullary thyroid cancer(MTC).

"With the positive data, we expect cabozantinib's filing to be completed in first quarter of 2012, with potential approval in the third quarter," Lazard Capital Markets analysts said in a note.

The drug significantly improved median progression-free survival (PFS) in patients suffering from MTC to 11.2 months versus 4 months for those on placebo in a trial called EXAM.

While that was lower than the numbers returned by AstraZeneca Plc's competing Caprelsa, Jefferies analysts said the drugs appeared comparable given that the EXAM trial appears to have enrolled more severe patients.

About 44,600 new thyroid cancer cases were diagnosed in the United States during 2010, and about 1,690 people died from the disease, according to the National Cancer Institute.

Cabozantinib, which is also being tested for metastatic ovarian cancer and castration-resistant prostate cancer (CRPC), is an oral drug designed to limit blood supply to tumors and block two segments of a pathway used by cancer cells to grow and spread.

In June, Exelixis reported data from a clinical trial showing cabozantinib led to significant tumor shrinkage in several different types of solid tumors, including 24 percent of patients with metastatic ovarian cancer, but also caused the deaths of six patients.

The EXAM trial is being conducted under a special protocol assessment (SPA) agreement, which guarantees that the design and analysis of the trial are adequate to support a marketing application submission to the U.S. Food and Drug Administration.

(Reporting by Esha Dey and Kavyanjali Kaushik in Bangalore; Editing by Roshni Menon and Supriya Kurane)

Many cancer survivors struggle with PTSD symptoms - Yahoo! News

NEW YORK (Reuters Health) - A cancer diagnosis can leave lasting psychological scars akin to those inflicted by war, according to a new survey.

More than decade after being told they had the disease, nearly four out of 10 cancer survivors said they were still plagued by symptoms of post-traumatic stress disorder, or PTSD.

Those symptoms include being extra jumpy, having disturbing thoughts about the cancer and its treatment, or feeling emotionally numb toward friends and family.

One in 10 patients also said they avoided thinking about their cancer and one in 20 said they steered clear of situations or activities that reminded them of the disease.

That could amount to a medical problem, in addition to the psychological toll, said lead researcher Sophia Smith from the Duke Cancer Institute in Durham, North Carolina.

"You worry if the patient is avoiding medical care, you worry they might not be getting follow-ups," she told Reuters Health. "We don't have data to support that, but we worry about it."

The survey is based on 566 patients with non-Hodgkin's lymphoma, a relatively common kind of cancer that strikes about 66,000 Americans every year.

Smith's team had surveyed these patients for PTSD symptoms once before, estimating that about one in 12 had full-blown PTSD. The diagnosis involved a trio of symptoms, including avoidance, arousal and flashbacks.

Many more had one or more PTSD symptoms, however. And the new survey, published in the Journal of Clinical Oncology, shows they often persist.

Overall, half of the patients had no PTSD symptoms 13 years after their diagnosis. The problems had disappeared in 12 percent, but had remained or worsened in 37 percent.

"This study found that people seemed to have worse PTSD later on," said Bonnie L. Green, a trauma expert who pioneered the study of PTSD in breast cancer survivors, but was not linked to the new work.

"It's just very stressful for people to be told that they have cancer," Green, of Georgetown University in Washington, D.C., told Reuters Health. "You can't just assume that they feel bad now, but it will go away."

She stressed that it's only a minority of patients who develop full-blown PTSD, but added that depression is common after a cancer diagnosis.

The new survey shows that low-income people are extra vulnerable to the psychological impact of living with cancer.

"I am particularly concerned about the patients who are poor or have less resources," said Smith.

She said doctors have to be better at recognizing distress in patients and improving patients' experience when they get the diagnosis.

"Each time they come in you are asking not only if they're having pain, but also if they are having stress," Smith said. "There are wonderful therapies out there."

Those treatments include trauma counseling and talk therapy, which have been proved effective in several studies. Smith recommended the website http://www.ptsd.va.gov/ for people interested in more information about PTSD.

SOURCE: http://bit.ly/n1pJMg Journal of Clinical Oncology, online October 11, 2011.

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How do people cope emotionally if the cancer recurs?

How do people cope emotionally if the cancer recurs?

Ongoing Cancer: Understanding Cancer that Doesn't Go Away

For some people, cancer is a one-time event. They go through treatment and recovery, and the disease does not return. For others, cancer may not ever fully disappear. Their cancer may respond to treatment and then come back, or treatment may simply keep it from growing and spreading. For people living with cancer, it's important to understand what it means when cancer doesn't go away – and how remission and recurrence may be part of your cancer journey.

Facing the same cancer more than once can be a frustrating and exhausting experience. Learn how you can better cope with the effects of recurring cancer here.

When cancer is not growing or changing but is still present in your body, over time, it is sometimes referred to as a "chronic" (meaning ongoing) disease. The cancer may be responding to treatment well enough that it is not growing, spreading, or causing new issues, but the signs and symptoms of the cancer remain. In cases like these, cancer can sometimes be managed with ongoing care, much like other chronic diseases such as heart disease or diabetes. In other cases, the cancer may mean that signs and symptoms of the cancer go away partially or completely thanks to treatment, but the cancer is still in the body. When the signs and symptoms of cancer aren't present for at least a month, doctors refer to this period as remission. Some remissions can last months or years, but since the cancer may not be totally gone, a remission is not considered a "cure." The cancer could come back, and you may need additional treatments to try to control it once more.

When a cancer comes back after treatment, it is known as cancer recurrence. The cancer sometimes returns at the same spot (known as local recurrence) or it may show up in parts of the body that were not previously affected. Some types of cancers, such as ovarian cancer, are more likely to return than others. People with recurring cancer may need multiple rounds of treatment or they may need to change the type of treatment they receive.

Remember that even when a cure is not possible, treatment may help keep cancer at bay. If you have cancer that does not go away, talk to your doctor about what options may be right for you.

Fatty Acids in Humans, Fish May Induce Chemo Resistance

Fatty Acids in Humans, Fish May Induce Chemo Resistance:

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CureToday.com: News Archives - 'Abysmal' participation in cancer trials

'Abysmal' participation in cancer trials

AUGUST 25, 2011

NEW YORK (Reuters Health) - Very few patients who've had cancer surgery end up participating in clinical trials to test new treatments, researchers have found.

And those who do participate are younger and usually white, fueling concerns that new drugs may not fare as well once they hit the market because trial subjects don't match real-world users.

"Are you going to see the same benefits in the average patient?" mused Dr. Monika Krzyzanowska, a cancer researcher at Princess Margaret Hospital in Toronto, Canada.

"Are the risks in the clinical trial truly reflective of the risk in the general population if the enrolled patients are younger and healthier?" added Krzyzanowska, who wasn't involved in the new work.

To get a sense of how often cancer patients enroll in clinical trials, Dr. Waddah Al-Refaie of the University of Minnesota in Minneapolis and colleagues tapped into a California cancer registry.

Only 1,566 of nearly 245,000 patients -- or about six of every 1,000 -- had participated in a trial, according to the report in the Annals of Surgery.

"The rate is abysmally low," Krzyzanowska told Reuters Health. Whether that's because few trials were available, or because patients are reluctant to join them, or something else isn't clear.

It's nothing new that clinical trials don't represent the average patients who may eventually end up using new drugs. For instance, fewer than one in 10 people with hay fever would be eligible to take part in the drug trials that end up dictating their care, French researchers said earlier this year (see Reuters Health story of Feb 17, 2011).

The new findings are another illustration of the gap between real-world patients and those who participate in trials.

"Should we fix it? I think the answer is yes," said Krzyzanowska. "What the solution is is a much harder question to answer."

While there is no universal answer as to whether it would make sense for a particular cancer patient to enroll in a trial, she added, "patients should inquire about what clinical trials are available and figure out if there is something available for them."

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