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Posts Tagged ‘science’


Reporter: Gail S. Thornton

This article appeared on the web site of Harley Street Concierge, one of the U.K.’s leading independent providers of clinical, practical and emotion support for cancer patients. 

Cancer at Work: An Interview With Barbara Wilson

Whether you’re supporting an employee through cancer at work. Or you’re a cancer patient struggling to get the support you need. Either way, this Q and A with Barbara Wilson will help you out. Read on for a glimpse into Barbara’s personal experience with breast cancer. Find out where companies are falling short of supporting employees. Discover what you need to do if you’re feeling unsupported at work. And learn what’s unacceptable for Barbara in a modern and civilised society.

In a 2013 interview about cancer at work, you expressed amazement at “the lack of understanding there is about cancer. And what the impact is on individuals”. How would you say this has improved in the last 4 years? And what do you feel still needs to change?

There’s greater awareness and understanding about cancer at work. More organisations are aware of the difficulties people face. But many organisations don’t appreciate that recovery isn’t straightforward or quick. They also tend to rely on generic return to work policies. And these are inappropriate when it comes to supporting people recovering from cancer. A lot still depends on how far the local line manager is prepared to support an employee. And whether they’ll bend rules if need be about leave or sick pay.

You were diagnosed with breast cancer in 2005 and given the all clear in 2010. What did you learn about yourself through treatment and recovery?

 

I learned that I wasn’t immortal or superhuman! And also that life is precious and so it’s important to make the best of it. That doesn’t actually mean counting off things on your bucket list. Or living each day as if it’s your last. It’s about appreciating what you have, family, friends and the sheer joy of being alive.

“Life is precious. It’s about appreciating what you have, family, friends and the sheer joy of being alive.”

It’s a common misperception that people in remission want more family time or to travel the world. What reasons do your clients share with you for wanting to get back to work?

Yes. Before I had cancer, I remember asking a terminally ill employee why she still wanted to work. And she worked until a fortnight before her death. The simple answer is that it’s about feeling normal. Using your brain. Being with friends and colleagues rather than on your own. And losing yourself in your work. There are also financial reasons. But typically – and I can say this based on my own experience – it’s about being ‘you’ again rather than a cancer patient.

“I remember asking a terminally ill employee why she still wanted to work. And she worked until a fortnight before her death. Typically – and I can say this based on my own experience – it’s about being ‘you’ again rather than a cancer patient.”

You share tips for employers and HR professionals in this article for Macmillan. And you set out how to support a colleague during and after cancer treatment. What would you say to an employee who isn’t feeling supported by their employer or colleagues in this way?

In my experience there are two main reasons why people often aren’t supported.

1. Bosses and colleagues don’t understand the full impact of cancer treatment. They won’t understand what fatigue is or chemo brain or peripheral neuropathy. So they often expect people to get ‘back to normal’ work after 6 to 8 weeks. But recovery can take many months. This isn’t helped by the person often looking fit and well.

2. People don’t like talking about cancer at work. They feel awkward. And as a result often decide to say nothing. We advise people to be open from the outset. To understand their right to reasonable adjustments. And their responsibility to update their employer about their recovery and support needs. Employees recovering from cancer often have to take the lead. They have to guide their colleagues about the specific help they need. You can’t expect others to do it for you. It sounds wrong but that’s how it is.

“Bosses and colleagues often expect people to get ‘back to normal’ work after 6 to 8 weeks. But recovery can take many months. “

More than 100,000 people had to wait more than 2 weeks to see a cancer specialist in the UK last year. 25,153 had to wait more than 62 days to start treatment. What’s your reaction to these statistics?

It’s shocking. The worry for patients and their families during this period is totally debilitating. And on top of this it means that the cancer is growing unchecked. Where the cancer is aggressive, the delay may threaten lives. And it will certainly add to the overall costs of care. We really have to address this. It’s just not acceptable in a modern and civilised society.

“The worry for patients and their families during this period is totally debilitating. We really have to address this.”

Finally, can you tell us more about Working With Cancer?

Working With Cancer is a social enterprise and was established in June 2014. We support people affected by cancer to lead fulfilling and rewarding working lives. That means helping people to successfully return to work or remain in work. Or sometimes it’s about helping people to find work – depending on their personal needs. We work with corporate, charities and other third sector organisations to support people throughout the UK.

We coach people diagnosed with cancer to re-establish their working lives. And we train employers to understand how to manage work and cancer. We’ll advise teams about how to support a colleague affected by cancer. And we help carers juggle work whilst supporting their loved ones. Working With Cancer also helps organisations to update or improve their policies.

Barbara Wilson - Cancer at Work

About Barbara Wilson

Barbara Wilson is a senior HR professional with almost 40 years’ experience.  Roles include Group Head of Strategic HR at Catlin Group Ltd. Deputy Head of HR at Schroders Investment Management. And Chief of Staff to the Group HR Director at Barclays. After a breast cancer diagnosis, Barbara launched Working With Cancer. It’s a Social Enterprise providing coaching, training and consultancy to employers, employees, carers and health professionals.

 

For more information about Working With Cancer, click here to visit the websiteFollow this link to connect with Barbara on Twitter. Email admin@workingwithcancer.co.uk. Or call 07508 232257 or 07919 147784.

 

SOURCE

https://harleystreetconcierge.com/cancer-at-work/

Other posts on the JP Morgan 2019 Healthcare Conference on this Open Access Journal include:

2018

Top 10 Cancer Research Priorities

https://pharmaceuticalintelligence.com/2018/12/24/top-10-cancer-research-priorities/

Innovation + Technology = Good Patient Experience

https://pharmaceuticalintelligence.com/2018/12/24/innovation-technology-good-patient-experience/

2017

Inspiring Book for ALL Cancer Survivors, ALL Cancer Patients and ALL Cardiac Patients – The VOICES of Patients, Hospitals CEOs, Health Care Providers, Caregivers and Families: Personal Experience with Critical Care and Invasive Medical Procedures

https://pharmaceuticalintelligence.com/2017/10/24/inspiring-book-for-all-cancer-survivors-all-cancer-patients-and-all-cardiac-patients-the-voices-of-patients-hospitals-ceos-health-care-providers-caregivers-and-families-personal-experience-with/

2016

Funding Opportunities for Cancer Research

https://pharmaceuticalintelligence.com/2016/12/08/funding-opportunities-for-cancer-research/

2012

The Incentive for “Imaging based cancer patient’ management”

https://pharmaceuticalintelligence.com/2012/08/27/the-incentive-for-imaging-based-cancer-patient-management/

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#JPM19 Conference: Lilly Announces Agreement To Acquire Loxo Oncology

Reporter: Gail S. Thornton

 

News announced during the 37th J.P. Morgan Healthcare Conference (#JPM19): Drugmaker Eli Lilly and Company announced its plans to acquire Loxo for $8 billion, as part of its oncology strategy, which focuses  “opportunities for first-in-class and best-in-class therapies.”   

 

Please read their press release below.


INDIANAPOLIS and STAMFORD, Conn.Jan. 7, 2019 /PRNewswire/ —

  • Acquisition will broaden the scope of Lilly’s oncology portfolio into precision medicines through the addition of a marketed therapy and a pipeline of highly selective potential medicines for patients with genomically defined cancers.
  • Loxo Oncology’s pipeline includes LOXO-292, an oral RET inhibitor being studied across multiple tumor types, which recently was granted Breakthrough Therapy designation by the FDA and could launch in 2020.
  • Loxo Oncology’s Vitrakvi® (larotrectinib) is an oral TRK inhibitor developed and commercialized in collaboration with Bayer that was recently approved by the FDA.
  • Lilly will commence a tender offer to acquire all outstanding shares of Loxo Oncology for a purchase price of$235.00 per share in cash, or approximately $8.0 billion.
  • Lilly will conduct a conference call with the investment community and media today at 8:45 a.m. EST.

Eli Lilly and Company (NYSE: LLY) and Loxo Oncology, Inc. (NASDAQ: LOXO) today announced a definitive agreement for Lilly to acquire Loxo Oncology for $235.00 per share in cash, or approximately $8.0 billion. Loxo Oncology is a biopharmaceutical company focused on the development and commercialization of highly selective medicines for patients with genomically defined cancers.

The acquisition would be the largest and latest in a series of transactions Lilly has conducted to broaden its cancer treatment efforts with externally sourced opportunities for first-in-class and best-in-class therapies. Loxo Oncology is developing a pipeline of targeted medicines focused on cancers that are uniquely dependent on single gene abnormalities that can be detected by genomic testing.  For patients with cancers that harbor these genomic alterations, a targeted medicine could have the potential to treat the cancer with dramatic effect.

Loxo Oncology has a promising portfolio of approved and investigational medicines, including:

  • LOXO-292, a first-in-class oral RET inhibitor that has been granted Breakthrough Therapy designation by the FDA for three indications, with an initial potential launch in 2020.  LOXO-292 targets cancers with alterations to the rearranged during transfection (RET) kinase. RET fusions and mutations occur across multiple tumor types, including certain lung and thyroid cancers as well as a subset of other cancers.
  • LOXO-305, an oral BTK inhibitor currently in Phase 1/2. LOXO-305 targets cancers with alterations to the Bruton’s tyrosine kinase (BTK), and is designed to address acquired resistance to currently available BTK inhibitors. BTK is a validated molecular target found across numerous B-cell leukemias and lymphomas.
  • Vitrakvi, a first-in-class oral TRK inhibitor developed and commercialized in collaboration with Bayer that was recently approved by the U.S. Food and Drug Administration (FDA). Vitrakvi is the first treatment that targets a specific genetic abnormality to receive a tumor-agnostic indication at the time of initial FDA approval.
  • LOXO-195, a follow-on TRK inhibitor also being studied by Loxo Oncology and Bayer for acquired resistance to TRK inhibition, with a potential launch in 2022.

“Using tailored medicines to target key tumor dependencies offers an increasingly robust approach to cancer treatment,” said Daniel Skovronsky, M.D., Ph.D., Lilly’s chief scientific officer and president of Lilly Research Laboratories. “Loxo Oncology’s portfolio of RET, BTK and TRK inhibitors targeted specifically to patients with mutations or fusions in these genes, in combination with advanced diagnostics that allow us to know exactly which patients may benefit, creates new opportunities to improve the lives of people with advanced cancer.”

“We are gratified that Lilly has recognized our contributions to the field of precision medicine and are excited to see our pipeline benefit from the resources and global reach of the Lilly organization,” said Josh Bilenker, M.D., chief executive officer of Loxo Oncology. “Tumor genomic profiling is becoming standard-of-care, and it will be critical to continue innovating against new targets, while anticipating mechanisms of resistance to available therapies, so that patients with advanced cancer have the chance to live longer and better lives.”

“Lilly Oncology is committed to developing innovative, breakthrough medicines that will make a meaningful difference for people with cancer and help them live longer, healthier lives,” said Anne White, president of Lilly Oncology. “The acquisition of Loxo Oncology represents an exciting and immediate opportunity to expand the breadth of our portfolio into precision medicines and target cancers that are caused by specific gene abnormalities. The ability to target tumor dependencies in these populations is a key part of our Lilly Oncology strategy. We look forward to continuing to advance the pioneering scientific innovation begun by Loxo Oncology.”

“We are excited to have reached this agreement with a team that shares our commitment to ensuring that emerging translational science reaches patients in need,” said Jacob Van Naarden, chief operating officer of Loxo Oncology. “We are confident that the work we have started, which includes an FDA approved drug, and a pipeline spanning from Phase 2 to discovery, will continue to thrive in Lilly’s hands.”

Under the terms of the agreement, Lilly will commence a tender offer to acquire all outstanding shares of Loxo Oncology for a purchase price of $235.00 per share in cash, or approximately $8.0 billion. The transaction is not subject to any financing condition and is expected to close by the end of the first quarter of 2019, subject to customary closing conditions, including receipt of required regulatory approvals and the tender of a majority of the outstanding shares of Loxo Oncology’s common stock. Following the successful closing of the tender offer, Lilly will acquire any shares of Loxo Oncology that are not tendered into the tender offer through a second-step merger at the tender offer price.

The tender offer represents a premium of approximately 68 percent to Loxo Oncology’s closing stock price on January 4, 2019, the last trading day before the announcement of the transaction. Loxo Oncology’s board recommends that Loxo Oncology’s shareholders tender their shares in the tender offer.  Additionally, a Loxo Oncology shareholder, beneficially owning approximately 6.6 percent of Loxo Oncology’s outstanding common stock, has agreed to tender its shares in the tender offer.

This transaction will be reflected in Lilly’s financial results and financial guidance according to Generally Accepted Accounting Principles (GAAP). Lilly will provide an update to its 2019 financial guidance, including the expected impact from the acquisition of Loxo Oncology, as part of its fourth-quarter and full-year 2018 financial results announcement on February 13, 2019.

For Lilly, Deutsche Bank is acting as the exclusive financial advisor and Weil, Gotshal & Manges LLP is acting as legal advisor in this transaction. For Loxo Oncology, Goldman Sachs & Co. LLC is acting as exclusive financial advisor and Fenwick & West LLP is acting as legal advisor.

Conference Call and Webcast
Lilly will conduct a conference call with the investment community and media today at 8:45 a.m. EST to discuss the acquisition of Loxo Oncology.  Investors, media and the general public can access a live webcast of the conference call through the Webcasts & Presentations link that will be posted on Lilly’s website at www.lilly.com.  The webcast of the conference call will be available for replay through February 7, 2019.

About LOXO-292
LOXO-292 is an oral and selective investigational new drug in clinical development for the treatment of patients with cancers that harbor abnormalities in the rearranged during transfection (RET) kinase. RET fusions and mutations occur across multiple tumor types with varying frequency. LOXO-292 was designed to inhibit native RET signaling as well as anticipated acquired resistance mechanisms that could otherwise limit the activity of this therapeutic approach. LOXO-292 has been granted Breakthrough Therapy Designation by the U.S. FDA for three indications, and could launch as early as 2020.

About LOXO-305
LOXO-305 is an investigational, highly selective non-covalent Bruton’s tyrosine kinase (BTK) inhibitor. BTK plays a key role in the B-cell antigen receptor signaling pathway, which is required for the development, activation and survival of normal white blood cells, known as B-cells, and malignant B-cells. BTK is a validated molecular target found across numerous B-cell leukemias and lymphomas including chronic lymphocytic leukemia, Waldenstrom’s macroglobulinemia, mantle cell lymphoma and marginal zone lymphoma.

About Vitrakvi® (larotrectinib)
Vitrakvi is an oral TRK inhibitor for the treatment of adult and pediatric patients with solid tumors with a neurotrophic receptor tyrosine kinase (NTRK) gene fusion without a known acquired resistance mutation that are either metastatic or where surgical resection will likely result in severe morbidity, and have no satisfactory alternative treatments or have progressed following treatment. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

About LOXO-195
LOXO-195 is a selective TRK inhibitor that is being investigated to address potential mechanisms of acquired resistance that may emerge in patients receiving Vitrakvi® (larotrectinib) or other multikinase inhibitors with anti-TRK activity.

About Eli Lilly and Company
Lilly is a global healthcare leader that unites caring with discovery to create medicines that make life better for people around the world. We were founded more than a century ago by a man committed to creating high-quality medicines that meet real needs, and today we remain true to that mission in all our work. Across the globe, Lilly employees work to discover and bring life-changing medicines to those who need them, improve the understanding and management of disease, and give back to communities through philanthropy and volunteerism. To learn more about Lilly, please visit us at www.lilly.com and www.lilly.com/newsroom/social-channels. C-LLY

About Loxo Oncology
Loxo Oncology is a biopharmaceutical company focused on the development and commercialization of highly selective medicines for patients with genomically defined cancers. Our pipeline focuses on cancers that are uniquely dependent on single gene abnormalities, such that a single drug has the potential to treat the cancer with dramatic effect. We believe that the most selective, purpose-built medicines have the highest probability of maximally inhibiting the intended target, with the intention of delivering best-in-class disease control and safety. Our management team seeks out experienced industry partners, world-class scientific advisors and innovative clinical-regulatory approaches to deliver new cancer therapies to patients as quickly and efficiently as possible. For more information, please visit the company’s website at http://www.loxooncology.com.

Lilly Cautionary Statement Regarding Forward-Looking Statements

This press release contains forward-looking statements about the benefits of Lilly’s acquisition of Loxo Oncology, Inc. (“Loxo Oncology”). It reflects Lillys current beliefs; however, as with any such undertaking, there are substantial risks and uncertainties in implementing the transaction and in drug developmentAmong other things, there can be no guarantee that the transaction will be completed in the anticipated timeframe, or at all, or that the conditions required to complete the transaction will be met, that Lilly will realize the expected benefits of the transaction, that the molecules will be approved on the anticipated timeline or at all, or that the potential products will be commercially successful. For further discussion of these and other risks and uncertainties, see Lillys most recent Form 10-K and Form 10-Q filings with the United States Securities and Exchange Commission (“the SEC”). Lilly will provide an update to certain elements of its 2019 financial guidance as part of its fourth quarter and full-year 2018 financial results announcement. Except as required by law, Lilly undertakes no duty to update forward-looking statements to reflect events after the date of this release.

Loxo Oncology Cautionary Statement Regarding Forward-Looking Statements

This press release contains “forward-looking statements” relating to the acquisition of Loxo Oncology by Lilly. Such forward-looking statements include the ability of Loxo Oncology and Lilly to complete the transactions contemplated by the merger agreement, including the parties’ ability to satisfy the conditions to the consummation of the offer and the other conditions set forth in the merger agreement and the possibility of any termination of the merger agreement, as well as the role of targeted genomics and diagnostics in oncology treatment and acceleration of our work in developing medicines. Such forward-looking statements are based upon current expectations that involve risks, changes in circumstances, assumptions and uncertainties. Actual results may differ materially from current expectations because of risks associated with uncertainties as to the timing of the offer and the subsequent merger; uncertainties as to how many of Loxo Oncology’s stockholders will tender their shares in the offer; the risk that competing offers or acquisition proposals will be made; the possibility that various conditions to the consummation of the offer or the merger may not be satisfied or waived; the effects of disruption from the transactions contemplated by the merger agreement on Loxo Oncology’s business and the fact that the announcement and pendency of the transactions may make it more difficult to establish or maintain relationships with employees, suppliers and other business partners; the risk that stockholder litigation in connection with the offer or the merger may result in significant costs of defense, indemnification and liability; other uncertainties pertaining to the business of Loxo Oncology, including those set forth in the “Risk Factors” and “Management’s Discussion and Analysis of Financial Condition and Results of Operations” sections of Loxo Oncology’s Annual Report on Form 10-K for the year ended December 31, 2017, which is on file with the SEC and available on the SEC’s website at www.sec.gov. Additional factors may be set forth in those sections of Loxo Oncology’s Quarterly Report on Form 10-Q for the quarter endedSeptember 30, 2018, filed with the SEC in the fourth quarter of 2018.  In addition to the risks described above and in Loxo Oncology’s other filings with the SEC, other unknown or unpredictable factors could also affect Loxo Oncology’s results. No forward-looking statements can be guaranteed and actual results may differ materially from such statements. The information contained in this press release is provided only as of the date of this report, and Loxo Oncology undertakes no obligation to update any forward-looking statements either contained in or incorporated by reference into this report on account of new information, future events, or otherwise, except as required by law.

Additional Information about the Acquisition and Where to Find It

The tender offer for the outstanding shares of Loxo Oncology referenced in this communication has not yet commenced. This announcement is for informational purposes only and is neither an offer to purchase nor a solicitation of an offer to sell shares of Loxo Oncology, nor is it a substitute for the tender offer materials that Lilly and its acquisition subsidiary will file with the SEC upon commencement of the tender offer. At the time the tender offer is commenced, Lilly and its acquisition subsidiary will file tender offer materials on Schedule TO, and Loxo Oncology will file a Solicitation/Recommendation Statement on Schedule 14D-9 with the SEC with respect to the tender offer. THE TENDER OFFER MATERIALS (INCLUDING AN OFFER TO PURCHASE, A RELATED LETTER OF TRANSMITTAL AND CERTAIN OTHER TENDER OFFER DOCUMENTS) AND THE SOLICITATION/RECOMMENDATION STATEMENT WILL CONTAIN IMPORTANT INFORMATION. HOLDERS OF SHARES OF LOXO ONCOLOGY ARE URGED TO READ THESE DOCUMENTS CAREFULLY WHEN THEY BECOME AVAILABLE (AS EACH MAY BE AMENDED OR SUPPLEMENTED FROM TIME TO TIME) BECAUSE THEY WILL CONTAIN IMPORTANT INFORMATION THAT HOLDERS OF LOXO ONCOLOGY SECURITIES SHOULD CONSIDER BEFORE MAKING ANY DECISION REGARDING TENDERING THEIR SECURITIES. The Offer to Purchase, the related Letter of Transmittal and certain other tender offer documents, as well as the Solicitation/Recommendation Statement, will be made available to all holders of shares of Loxo Oncology at no expense to them. The tender offer materials and the Solicitation/Recommendation Statement will be made available for free at the SEC’s web site at www.sec.gov

In addition to the Offer to Purchase, the related Letter of Transmittal and certain other tender offer documents, as well as the Solicitation/Recommendation Statement, Lilly and Loxo Oncology file annual, quarterly and special reports and other information with the SEC.  You may read and copy any reports or other information filed by Lilly or Loxo Oncology at the SEC public reference room at 100 F Street, N.E., Washington, D.C. 20549. Please call the Commission at 1-800-SEC-0330 for further information on the public reference room.  Lilly’s and Loxo Oncology’s filings with the SEC are also available to the public from commercial document-retrieval services and at the website maintained by the SEC at www.sec.gov.

SOURCE

Eli Lilly and Company – https://www.lilly.com

Other related articles published in this Open Access Online Scientific Journal include the following:

2017

FDA has approved the world’s first CAR-T therapy, Novartis for Kymriah (tisagenlecleucel) and Gilead’s $12 billion buy of Kite Pharma, no approved drug and Canakinumab for Lung Cancer (may be?)

https://pharmaceuticalintelligence.com/2017/08/30/fda-has-approved-the-worlds-first-car-t-therapy-novartis-for-kymriah-tisagenlecleucel-and-gileads-12-billion-buy-of-kite-pharma-no-approved-drug-and-canakinumab-for-lung-cancer-may-be/

2016

Pioneers of Cancer Cell Therapy:  Turbocharging the Immune System to Battle Cancer Cells — Success in Hematological Cancers vs. Solid Tumors

https://pharmaceuticalintelligence.com/2016/08/19/pioneers-of-cancer-cell-therapy-turbocharging-the-immune-system-to-battle-cancer-cells-success-in-hematological-cancers-vs-solid-tumors/

2015

Personalized Medicine – The California Initiative

https://pharmaceuticalintelligence.com/2015/10/12/personalized-medicine/

2013

Volume One: Genomics Orientations for Personalized Medicine

https://pharmaceuticalintelligence.com/biomed-e-books/genomics-orientations-for-personalized-medicine/volume-one-genomics-orientations-for-personalized-medicine/

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The National Cancer Research Institute (NCRI) identified top 10 research priorities for people living with cancer to consider to improve treatment and quality of life. 

Reporter: Gail S. Thornton

By 2030 four million people in the UK will be living with the long-term consequences of cancer, but currently there is very little research on the problems they face and how these can be tackled. To help them live better lives, more focused research is needed.

To determine priorities for research that will help people live better with and beyond cancer, NCRI partnered with the James Lind Alliance on a Priority Setting Partnership. The two-year project involved two UK-wide surveys which attracted more than 3500 responses from patients, carers, and health and social care professionals. From these, we identified 26 key questions and distilled these down to 10 top research priorities.

This is the first time that clear research priorities have been identified in this area.

Questions 1 – 10 Questions 11 – 26

SOURCE

https://www.ncri.org.uk/lwbc/

 

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More than half of older Americans have “basic” or “below basic” health literacy. How do you make health care decisions when you don’t even understand what the doctor is saying?

From The New York Times

More than half of older Americans lack the skills to gather and understand medical information. Providers must simplify, researchers say.

Every time her parents pick up a new prescription at a Walgreens in Houston, they follow Duyen Pham-Madden’s standing instructions: Use the iPad she bought for them, log onto FaceTime, hold up the pill bottles for her examination.

Her mother, 79, and father, 77, need numerous medications, but have trouble grasping when and how to take them.

The label may say to take one pill three times a day, but “my dad might take one a day,” said Ms. Pham-Madden, 56, an insurance purchasing agent in Blue Springs, Mo. “Or take three at a time.”

So she interprets the directions for them, also reminding her mother to take the prescribed megadose of vitamin D, for osteoporosis, only weekly, not daily.

Part of their struggle, Ms. Pham-Madden believes, stems from language barriers. The family emigrated from Vietnam in 1975, and while her parents speak and read English, they lack the fluency of native speakers.

But recently, Ms. Pham-Madden said, her father posed a question that anyone grappling with Medicare drug coverage might ask: “What’s the doughnut hole?”

Researchers refer to this type of knowledge as “health literacy,” meaning a person’s ability to obtain and understand the basic information needed to make appropriate health decisions.

Can someone read a pamphlet and then determine how often to undergo a particular medical test? Look at a graph and recognize a normal weight range for her height? Ascertain whether her insurance will cover a certain procedure?

Most American adults — 53 percent — have intermediate health literacy, a national survey found in 2006; they can perform “moderately challenging” activities, like reading denser texts and handling unfamiliar arithmetic.

Just 12 percent rank as “proficient,” the highest category. About a fifth have “basic” health literacy that could cause problems, and 14 percent score “below basic.” Health literacy differs by education level, race, poverty and other factors.

And it varies dramatically by age. While the proportion of adults with intermediate literacy ranges from 53 to 58 percent in other age groups, it falls to 38 percent among those 65 and older. The percentage of older adults with basic or below basic literacy is higher than in any other age group; only 3 percent qualify as proficient.

Why is that? Compared to younger groups, the current generation of “older adults were less likely to go beyond a high school education,” said Jennifer Wolff, a health services researcher at Johns Hopkins University.

Moreover, “as adults age, they’re more likely to experience cognitive impairment,” she pointed out, as well as hearing and vision loss that can affect their comprehension.

Consider the recent experience of a retired 84-year-old teacher. All her life, “she was very detail-oriented” and competent, said her daughter, Deborah Johnson, who lives in Lansing, Mich.

But a neurologist diagnosed mild cognitive impairment last summer and prescribed a drug intended to ameliorate its symptoms. It caused a frightening reaction — personality changes, lethargy, dizziness, sky-high blood pressure.

Ms. Johnson thinks her mother might have overdosed. “She told me she thought, ‘This is going to fix me, and I’ll be O.K. So if I take more pills, I’ll be O.K. faster.’”

Yet health literacy can be particularly crucial for seniors. They’re usually coping with more complicated medical problems, including multiple chronic diseases, an array of drugs, a host of specialists. They have more instructions to decipher, more tests to schedule, more decisions to ponder.

Low health literacy makes those tasks more difficult, with troubling results. Studies indicate that people with low literacy have poorer health at higher cost. They’re less likely to take advantage of preventive tests and immunizations, and more apt to be hospitalized.

It may not help much that future cohorts of older adults will be better educated. “The demands of interacting with the health care system are increasing,” Dr. Wolff said. “Ask any adult child of a parent who’s been hospitalized. The system has gotten increasingly complex.”

That doesn’t mean patients deserve all the blame for misunderstandings and snafus. Rima Rudd, a longtime health literacy researcher at Harvard University, has persistently criticized the communications skills of health institutions and professionals.

“We give people findings and tell them about risk and expect people to make decisions based on those concepts, but we don’t explain them very well,” she said. “Are our forms readable? Are the directions after surgery written coherently? If it’s written in jargon, with confusing words and numbers, you won’t get the gist of it and you won’t get important information.”

A few years ago, Steven Rosen, 64, had spent more than two months at a Chicago hospital after several surgeries. Then a social worker came into his room and told his wife Dorothy, “You have to move him tomorrow to an L.T.A.C.”

“I don’t know what you’re talking about,” Ms. Rosen recalled saying. “What’s an L.T.A.C.?”

Question: Was she demonstrating inadequate health literacy, or should the social worker have clarified that L.T.A.C.s — long-term acute care hospitals — provide more care than nursing homes for very ill patients?

Aware of such issues, health care organizations are scrambling to try to make information more accessible and intelligible, and to help patients of all ages understand an often bewildering environment.

They’re hiring squadrons of care coordinators and navigators (sometimes too many), and redesigning and rewriting pamphlets and forms. They’re teaching medical students to communicate more clearly and to encourage patients’ questions.

They’re turning to technology, like secure websites where both patients and family members can see test results or ask questions.

“It’s not the silver bullet we hoped for,” said Amy Chesser, a health communications researcher at Wichita State University, pointing out that many patients are reluctant to turn to provider websites. But the potential remains.

For now, though, often the primary health literacy navigators for older people are their adult children, most commonly daughters and daughters-in-law.

“In the best of all worlds, she’d just be the daughter,” Dr. Chesser said. “But we need her to serve other roles — being an advocate, asking a lot of questions of the provider, asking where to go for information, talking about second opinions.”

The current cohort of people over 70 grew up in a more patriarchal medical system and asking fewer questions, Dr. Wolff pointed out. Her research shows that while most seniors manage their own health care, about a third prefer to co-manage with family or close friends, or to delegate health matters to family or doctors.

Duyen Pham-Madden plays the co-managerial role from hundreds of miles away, keeping spreadsheets of her parents’ drugs, compiling lists of questions for doctors’ appointments, texting photos to pharmacists when the pills in a refilled prescription look different from the last batch.

She’d probably score well in health literacy, but “sometimes even I get mixed up,” she said.

What’s the Medicare doughnut hole? “I had to look it up,” she said. Once she did, she wondered, “How do they expect seniors to understand this?”

SOURCE

 

 

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  • More than 77 percent of patients in the REMfresh® Patient Reported Outcomes DURation (REMDUR) study reported achieving 6 or more hours of sleep after taking REMfresh®, the first continuous release and absorption melatonin (CRA-melatonin)
  • More than 91 percent experienced improvements in sleep onset, sleep maintenance and total sleep quality, after taking REMfresh® (CRA-melatonin)
  • Post-marketing, patient-reported outcomes data reinforces clinical trial evidence demonstrating the potential of non-prescription REMfresh®, as a new, non-prescription, drug-free hypnotic (sleep) product designed to achieve 7-hour sleep
  • New data confirms previously presented SLEEP 2017 study showing the patented Ion Powered Pump (IPP) technology in REMfresh® helps extend melatonin-targeted sleep maintenance levels in the body from 3.7 hours (with marketed immediate-release melatonin) to 6.7 hours, while mimicking the pattern of the body’s natural melatonin blood levels during the nightly sleep cycle

Real Time Coverage at SLEEP 2018 meeting, Baltimore.

Reporters: Aviva Lev-Ari, PhD, RN, and Gail S. Thornton, MA

BALTIMORE – (June 6, 2018) – A patient-reported outcomes study presented at SLEEP 2018 provides confirmatory real-world evidence of the previously peer-reviewed and presented data showing the 7-hour action of REMfresh®, a new product for sleep. REMfresh® Ion-Powered Melatoninis the first and only, continuous release and absorption melatonin (CRA-melatonin) to mimic the body’s own 7-hour Mesa Wave, the natural pattern of melatonin blood levels during a normal night’s sleep cycle. This induces sleep onset and provides lasting and restorative sleep for up to 7 hours.

This new data shows a correlative relationship between a 7-hour Mesa Wave pharmacokinetic (PK) profile and real-world evidence of improvements in sleep duration, onset, maintenance and sleep quality after taking REMfresh® (CRA-melatonin).

The post-marketing REMfresh® Patient Reported Outcomes DURation (REMDUR) study was presented at SLEEP 2018, the 32nd Annual Meeting of the Associated Professional Sleep Societies (APSS), LLC, a joint partnership of the American Academy of Sleep Medicine (AASM) and the Sleep Research Society (SRS).

 

Brodner and Seiden

Pictured here is David C. Brodner, M.D., and David J. Seiden, M.D., FAASM, after presenting the latest study data which found REMfresh is the first and only continuous release and absorption melatonin™ to mimic the body’s own 7-hour Mesa Wave™.

 

In a sample of 500 patients on REMfresh® (CRA-melatonin) responding to an online survey, 77.6 percent achieved 6 or more hours of sleep compared to 23.6 percent who slept that duration prior to taking REMfresh® (p<.0001). A vast majority of respondents also reported a major or moderate improvement in sleep onset (91.6 percent, p<.0001), sleep maintenance (94.8 percent, p<.0001) and total sleep quality (97.2 percent, p<.0001). More than three-quarters (76.6 percent) of patients indicated they take REMfresh® (CRA-melatonin) nightly. The proportion of patients reporting nightly CRA-melatonin use was significantly greater than the proportion of patients with less than nightly use (p<.0001). Most importantly, over 98 percent of patients reported they were very likely or likely to continue taking REMfresh® (CRA-melatonin) to treat their sleep complaints.

“The real-world evidence reported today in REMDUR provides further confirmation that REMfresh® represents a significant advance in the use of melatonin as a baseline therapy for treating sleep complaints,” said David C. Brodner, M.D., a leading sleep specialist who is Double Board-Certified in Otolaryngology — Head and Neck Surgery and Sleep Medicine, founder and principle Physician at the Center for Sinus, Allergy, and Sleep Wellness, in Palm Beach County, Florida, and Senior Medical Advisor for Physician’s Seal, LLC®.

“REMfresh® Ion-Powered Melatoninhas been shown to be an effective drug-free solution that is now available to the millions of Americans in need of a good night’s sleep, many of whom seek new therapies that will induce sleep and keep them asleep until the morning, without causing residual effects they’ll feel the next day. With its unique delivery system that imitates the body’s own natural sleep pattern, REMfresh® has revolutionized the role of melatonin, when delivered in the CRA form. It is no longer just a treatment for jet lag, but the CRA-melatonin found in REMfresh® has been shown to provide substantial relief to individuals having nightly sleep challenges,” said Dr. Brodner.

The scientifically advanced, patented delivery system in REMfresh® (CRA-melatonin), called Ion Powered Pump (IPP™) technology, replicates the way in which the body naturally releases and absorbs melatonin, unlike conventional melatonin sleep products. Since REMfresh® is not a drug, there is no drug hangover.

Nearly one-third of U.S. adults sleep less than the recommended seven hours daily.[1],[2] Increasing evidence suggests an association between sub-optimal sleep duration and adverse health outcomes including a higher risk of diabetes, hypertension, heart attack, stroke, obesity and depression.[3] A pooled analysis of 16 studies and over one million patients found short sleep duration corresponded with greater risk of morbidity and mortality.[4]

 REMDUR Study Design

The post-marketing REMfresh® Patient Reported Outcomes DURation (REMDUR) study was designed to obtain real-world evidence about patients’ sleep patterns, duration of sleep before and after REMfresh® (CRA-melatonin), daily REMfresh® (CRA-melatonin) use, onset of action, sleep maintenance, quality of sleep, and overall satisfaction with REMfresh® (CRA-melatonin).

Patients with sleep disturbances in the general population who received a sample of CRA-melatonin (REMfresh®) from their physicians were invited to complete a 12-question survey. Survey responses were received from 500 patients.

Confirmation of the REMAKT Clinical Study

REMDUR confirmed clinical trial findings from REMAKT (REM Absorption Kinetics Trial), a U.S.-based randomized, crossover pharmacokinetic (PK) evaluation study in healthy, non-smoking adults that compared REMfresh® (CRA-melatonin) with a market-leading, immediate-release melatonin (IR-melatonin).[5]

The study results, peer-reviewed and presented last year at SLEEP 2017, showed that melatonin levels with REMfresh® (CRA-melatonin) exceeded the targeted sleep maintenance threshold for a median of 6.7 hours, compared with 3.7 hours with the leading IR-melatonin. Conversely, the levels of the market-leading IR-melatonin formulation dramatically increased 23 times greater than the targeted levels of exogenous melatonin for sleep maintenance and had a rapid decline in serum levels that did not allow melatonin levels to be maintained beyond 4 hours.

The REMfresh® (CRA-melatonin) studies build upon the body of evidence from prolonged-release melatonin (PR-M), marketed in Europe, which demonstrated in well-conducted, placebo-controlled studies, statistically significant improvement in sleep quality, morning alertness, sleep latency and quality of life in patients aged 55 years and older compared with placebo. REMfresh® (CRA-melatonin) was designed to overcome the challenges of absorption in the intestines, thereby extending the continual and gradual release pattern of melatonin through the night (known as the Mesa Wave, a flat-topped hill with steep sides). There was a fast time to Cmax, which is anticipated to result in improved sleep onset, while the extended median plateau time to 6.7 hours and rapid fall-off in plasma levels at the end of the Mesa Wave, may help to improve sleep maintenance and morning alertness.

Conventional melatonin products have had challenges at mimicking the profile of a Mesa Wave™. The scientific work behind REMfresh® (CRA-melatonin) sought to overcome these challenges by having the melatonin formulation in a matrix that maintains a patented, solubility-enhancing pH environment to help with the transport to the brush border of the gut and its subsequent absorption.

Designed as a hydrogel matrix tablet, REMfresh® (CRA-melatonin) provides rapid release of the melatonin from the surface of the tablet, as the hydrogel release-controlling matrix is setting up in the acidic environment (pH of 1 to 3.5) in the stomach. As the tablet moves into the higher pH (5.5 to 6.5) environment of the small-intestine, which is above the pKa of melatonin (~4.0), the acidic moiety in the tablet is designed to maintain the pH within the tablet below 4.0 for 7+ hours. The hydrogel matrix, after proper hydration, allows continuous release of the active melatonin and acidic moiety into the lumen of the intestines.

Melatonin: The Body’s Natural Sleep Ingredient

Melatonin is produced by the pineal gland in the brain and is the body’s natural sleep ingredient. Melatonin levels normally begin to rise in the mid-to late evening and remain high for the majority of the night. Levels begin to decline towards early morning, as the body’s wake cycle is triggered. As people age, melatonin levels can drop by as much as 70 percent[6] and their bodies may no longer produce enough melatonin to ensure adequate sleep.

Other available products, such as immediate-release melatonin, help initiate the onset of sleep but are usually unable to sustain prolonged sleep maintenance due to an immediate burst of melatonin, which is quickly degraded due to its relatively short half-life (60 minutes). Absorption in the lower digestive tract is limited by melatonin’s limited ability to be absorbed in a low acidity or neutral pH environment.

Importance of Sleep

Sleep is an essential part of every person’s life. The body requires a certain amount of sleep in order to properly rest, repair and renew itself. Sleep is customarily divided in four different stages, with each stage having a different effect. These four stages are:

N1, N2, deep sleep and REM sleep. The body moves among these four stages several times while asleep. If sleep is disrupted for any reason, a person’s body may not have a chance to properly restore itself, especially if it is struggling to get to the later stages, called deep sleep and REM sleep. Studies have shown that sound and sufficient sleep is important for learning, memory and a healthy immune system. A regular pattern of deep sleep and REM sleep will help a person begin the next day feeling refreshed and ready to go.

About Non-Prescription REMfresh®

REMfresh® (CRA-melatonin) is the first and only, continuous release and absorption formulation of UltraMel® melatonin (available as 2 mg and 5 mg and with a 0.5 mg anticipated in the second half of 2018). UltraMel® melatonin is a high-quality, 99 percent ultra-pure melatonin sourced from Western Europe exclusively for Physician’s Seal®.

REMfresh® (CRA-melatonin) is a dietary supplement and is regulated under the Federal Dietary Supplement Health and Education Act, which does not require pre-approval. Melatonin has been in common use for over two decades and has a well-established profile of safe use by millions of people around the world. As with all supplements, individual results may vary.

REMfresh® (CRA-melatonin) is non-habit forming and does not contain narcotics, hypnotics, barbiturates, sedatives, antihistamines, alcohol or other harsh or additive chemicals. The usual adult recommended dose is 1-2 tablets 30-60 minutes before bedtime. Follow specific dosing instructions found on the back of the box for proper use of supplements.

REMfresh® (CRA-melatonin) is available at Walmart, Rite Aid and CVS/pharmacy. In 2017 REMfresh® was ranked as  the #1 recommended brand for sleep management by sleep doctors[7].

About Physician’s Seal®

Physician’s Seal® is the innovator of REMfresh®, the first and only continuous release and absorption, 99 percent ultra-pure melatonin (CRA-melatonin) that mimics the way the body naturally releases and maintains melatonin over a 7-hour period. Physician’s Seal®, founded in 2015, is a privately held company based in Boca Raton, Florida. It is committed to bringing cutting-edge life science applications to doctors and their patients. For more information, visit www.remfresh.com and connect with us on Facebook and You Tube.

Its sister subsidiary, IM HealthScience® (IMH) is the innovator of IBgard® and FDgard® for the dietary management of Irritable Bowel Syndrome (IBS) and Functional Dyspepsia (FD), respectively. In 2017, IMH added Fiber Choice®, a line of prebiotic fibers, to its product line via an acquisition. IMH® is a privately held company based in Boca Raton, Florida. It was founded in 2010 by a team of highly experienced pharmaceutical research and development and management executives. The company is dedicated to developing products to address overall health and wellness, including conditions with a high unmet medical need, such as digestive health. The IM HealthScience® advantage comes from developing products based on its patented, targeted-delivery technologies called Site Specific Targeting® (SST®). For more information, visit www.imhealthscience.com to learn about the company, or www.IBgard.com,  www.FDgard.com,and www.FiberChoice.com.

This information is for educational purposes only and is not meant to be a substitute for the advice of a physician or other health care professional. You should not use this information for diagnosing a health problem or disease. The company will strive to keep information current and consistent but may not be able to do so at any specific time. Generally, the most current information can be found on www.remfresh.com. Individual results may vary.

Data Presented at SLEEP 2018 Poster Session on Sleep Maintenance/Sleep Quality

Tuesday, June 5, 2018, 5-7pm

  • (Abstract 0419, Poster Board #104) Improvement in Sleep Maintenance and Sleep Quality with Ion Powered Pump Continuous Release and Absorption Melatonin: Results from a Self-Reported Patient Outcomes Study
    • David J. Seiden, M.D., FAASM, David C. Brodner, M.D., Syed M. Shah, Ph.D.

Visit Physician’s Seal® at booth 220 to learn more about REMfresh®.

The abstract is published in an online supplement of the journal, Sleep, which is available at http://www.sleepmeeting.org/docs/default-source/default-document-library/abstractbook2018.pdf?sfvrsn=2

[1] Ford, E.S., Cunningham, T.J., & Croft, J.B. (2015, May 1). Trends in Self-Reported Sleep Duration among US Adults from 1985 to 2012. Sleep, 38(5):829-832. doi: 10.5665/sleep.4684.

[2] Watson, N.F., Badr, M.S., Belenky, G., Bliwise, D.L., Buxton, G.M., Buysse, D.,…Tasali, E. (2015). Joint Consensus Statement of the American Academy of Sleep Medicine and Sleep Research Society on the Recommended Amount of Sleep for a Healthy Adult: Methodology and Discussion. Journal of Clinical Sleep Medicine, 11(8):931-952. doi:10.1176/appi.ajp.158.11.1856.

[3] Colten, H.R., & Altevogt, B.M. (Eds). (2006). Sleep Disorders and Sleep Deprivation: An Unmet Public Health Problem.  Institute of Medicine (US) Committee on Sleep Medicine and Research. Washington, DC: National Academies Press (US). doi: https://doi.org/10.17226/11617.

[4] Cappuccio, F.P., D’Elia, L., Strazzullo, P.,&  Miller, M.A. (2010). Sleep duration and all-cause mortality: a systematic review and meta-analysis of prospective studies. Sleep, 33(5):585-592

[5] For this clinical trial, the head-to-head comparison was with the 5 mg form; a 2 mg form of the comparator was not available.

[6] Zisapel, N. (2010). Melatonin and sleep. The Open Neuroendocrinology Journal, 3: 85-95.

[7] Among primary care physicians with a certification in sleep disorders who recommended a brand of modified-release melatonin. Quintiles IMS ProVoice July-September 2017 survey.

REFERENCE/SOURCE

Physician’s Seal® and REMfresh® (www.remfresh.com)

Dr. David C. Brodner, Center for Sinus, Allergy, and Sleep Wellness (http://www.brodnermd.com/sleep-hygiene.html)

Other related articles published in this Open Access Online Scientific Journal include the following:

2017

Ultra-Pure Melatonin Product Helps Maintain Sleep for Up to 7 Hours

https://pharmaceuticalintelligence.com/2017/06/11/ultra-pure-melatonin-product-helps-maintain-sleep-for-up-to-7-hours/

2016

Sleep Science

Genetic link to sleep and mood disorders

https://pharmaceuticalintelligence.com/2016/02/27/genetic-link-to-sleep-and-mood-disorders/

2015

Sleep quality, amyloid and cognitive decline

https://pharmaceuticalintelligence.com/2015/10/31/sleep-quality-amyloid-and-cognitive-decline/

2013

Day and Night Variation in Melatonin Level affects Plasma Membrane Redox System in Red Blood Cells

https://pharmaceuticalintelligence.com/2013/02/23/httpwww-ncbi-nlm-nih-govpubmed22561555/

 

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Ultra-Pure Melatonin Product Helps Maintain Sleep for Up to 7 Hours

Curator: Gail S. Thornton, M.A.

Co-Editor: The VOICES of Patients, Hospital CEOs, HealthCare Providers, Caregivers and Families: Personal Experience with Critical Care and Invasive Medical Procedures

 

The role of melatonin is important in regulating natural sleep and wake cycles. Typically, melatonin levels decline with age, significantly decreasing after age 40. An estimated 50 to 70 million Americans are affected by sleep difficulties – a process regulated by melatonin — and long-term sleep deprivation has been associated with negative health consequences, including an increased risk of diabetes, hypertension, heart attack, stroke, obesity, and depression.

Clinical data from a new pharmacokinetic study suggests that REMfresh®, the first and only continuous release and absorption melatonin (CRA-melatonin), helps maintain sleep for up to 7 hours. REMfresh® contains 99 percent ultra-pure melatonin and is sourced in Western Europe, a factor that is significant and important to many sleep specialists.

Three research abstracts on the REMfresh® data were published in an online supplement in the journal, Sleep, and were presented recently at the 31st Annual Meeting of the Associated Professional Sleep Societies LLC (APSS).

REMfresh Photo

Image SOURCE: Photograph courtesy of Physician’s Seal®

How REMfresh® Works

REMfresh® (CRA-melatonin) mimics the body’s own 7-hour Mesa Wave™, a natural pattern of melatonin blood levels during a normal night’s sleep cycle.

The study demonstrated the continuous release and absorption of 99 percent ultra-pure melatonin in REMfresh® (CRA-melatonin) was designed to induce sleep onset and provide continuous, lasting restorative sleep over 7 hours.

The scientifically advanced, patented formulation, called Ion Powered Pump (IPP™) technology, replicates the way in which the body naturally releases and absorbs melatonin, unlike conventional melatonin sleep products.

Since REMfresh® (CRA-melatonin) is not a drug, there is no drug hangover.

REMfresh MesaCurveNew-1

Image SOURCE: Diagram courtesy of Physician’s Seal®

 

Data Based on Scientifically Advanced Delivery Technology

According to the primary study author, David C. Brodner, M.D., “These study results represent an unparalleled breakthrough in drug-free, sleep maintenance that physicians and patients have been waiting for in a sleep product.” Dr. Brodner is a sleep specialist who is double board-certified in Otolaryngology – Head and Neck Surgery and Sleep Medicine and is the founder and principle physician at the Center for Sinus, Allergy, and Sleep Wellness in Palm Beach County, Florida.

Dr. Brodner said, “Melatonin products have been used primarily as a chronobiotic to address sleep disorders, such as jet lag and shift work. The patented delivery system in REMfresh mimics the body’s own natural sleep pattern, so individuals may experience consistent, restorative sleep and have an improved quality of life with this drug-free product.”

Study Findings With REMAKT

The study findings are based on REMAKT™ (REM Absorption Kinetics Trial), a U.S.-based randomized, crossover pharmacokinetic (PK) evaluation study in healthy, non-smoking adults that compared REMfresh® (CRA-melatonin) with a market-leading, immediate-release melatonin (IR-melatonin).

The study found that melatonin levels with REMfresh® exceeded the targeted sleep maintenance threshold for a median of 6.7 hours, compared with 3.7 hours with the leading IR-melatonin. Conversely, the levels of the market-leading IR-melatonin formulation dramatically increased 23 times greater than the targeted levels of exogenous melatonin for sleep maintenance and had a rapid decline in serum levels that did not allow melatonin levels to be maintained beyond 4 hours.

Additional analysis presented showed that REMfresh® (CRA-melatonin) builds upon the body of evidence from prolonged-release melatonin (PR-M), which demonstrated in well-conducted, placebo-controlled studies, statistically significant improvement in sleep quality, morning alertness, sleep latency and quality of life in patients aged 55 years and older compared with placebo.

REMfresh® (CRA-melatonin) was designed to overcome the challenges of absorption in the intestines, thereby extending the continual and gradual release pattern of melatonin through the night (known as the Mesa Wave™, a flat-topped hill with steep sides). There was a faster time to Cmax, which is anticipated to result in improved sleep onset, while the extended median plateau time to 6.7 hours and rapid fall-off in plasma levels at the end of the Mesa Wave™ may help to improve sleep maintenance and morning alertness.

REFERENCE/SOURCE

Physician’s Seal® and REMfresh® (www.remfresh.com)

REMfresh® press release, June 5, 2017 (http://www.prnewswire.com/news-releases/scientifically-advanced-delivery-technology-in-sleep-management-debuts-at-sleep-2017-with-clinical-data-showing-remfresh-the-first-and-only-continuous-release-and-absorption-melatonin-helps-maintain-sleep-for-up-to-7-hours-300468218.html)

Dr. David C. Brodner, Center for Sinus, Allergy, and Sleep Wellness  (http://www.brodnermd.com/sleep-hygiene.html)

Other related articles published in this Open Access Online Scientific Journal include the following:

2017

Sleep Research Society announces 2017 award recipients including Thomas S. Kilduff, PhD, Director, Center for Neuroscience at SRI International in Menlo Park, California

https://pharmaceuticalintelligence.com/2017/04/28/sleep-research-society-announces-2017-award-recipients-including-thomas-s-kilduff-phd-director-center-for-neuroscience-at-sri-international-in-menlo-park-california/

2016

Sleep Science

Genetic link to sleep and mood disorders

https://pharmaceuticalintelligence.com/2016/02/27/genetic-link-to-sleep-and-mood-disorders/

2015

Sleep quality, amyloid and cognitive decline

https://pharmaceuticalintelligence.com/2015/10/31/sleep-quality-amyloid-and-cognitive-decline/

2013

Day and Night Variation in Melatonin Level affects Plasma Membrane Redox System in Red Blood Cells

https://pharmaceuticalintelligence.com/2013/02/23/httpwww-ncbi-nlm-nih-govpubmed22561555/

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A Revolutionary Approach in Brain Tumor Research

Author: Gail S. Thornton, M.A.

For the more than 680,000 Americans living with a brain tumor, there is a revolutionary research effort under way at the Cedars-Sinai Precision Medicine Initiative in Brain Cancer in Los Angeles to look at ways of using precision science to tailor personalized treatments for individuals with malignant brain tumors.

Brain Cancer Meets Precision Science

Brain cancer continues to be among the hardest of diseases to treat. Until now, most medical treatments for the most common, aggressive and lethal form of brain cancer, glioblastoma multiforme, which affects more than 138,000 Americans yearly, have been designed for the average patient. Given that every cancer is genetically unique, this “one-size-fits-all” drug treatment has not worked for brain cancer and for most solid cancers. Unfortunately, today’s standard-of-care, which includes surgical removal, radiation therapy, and chemotherapy, has only modest benefits with patients living on average 15 months after diagnosis.

“Precision Medicine, an innovative approach that takes into account individual differences in people’s genes, environments and lifestyles, only works when we apply ‘Precision Science’ to the effort,” notes Dr. Chirag Patil, M.D., Neurosurgeon & Program Director at Cedars-Sinai Medical Center. “If we want to treat cancer more effectively, we need a novel approach to cancer care. In our program, we use tumor genomics and precision science to build a holistic mathematical model of cancer that then can be used to develop new, personalized cancer treatments.  Right now, we’re focused on the most common type of brain cancer, but are developing a unique scientific process that could tackle ANY type of cancer.”

This past year, the White House launched the Precision Medicine Initiative to dramatically improve health and treatment through a $215 million investment in the President’s 2016 budget.  The Initiative will provide additional impetus to Precision Medicine’s approach to disease prevention and treatment that has already led to powerful new discoveries and several new treatment methods for critical diseases.

PMI photo.png

Caption: The Cedars-Sinai program uses precision science to build a mathematical virtual brain tumor for testing.

Image SOURCEhttp://www.drchiragpatil.com/main.html

Delivering Personalized Cancer Care Through Big Data And Virtual Simulations

Harnessing the power of big data, Dr. Patil’s program puts a patient’s brain tumor through next-generation genomic sequencing to establish a comprehensive profile of that specific brain cancer. Researchers, in collaboration with Cellworks Inc., a therapeutics design company, use this profile to build a mathematical “virtual“ tumor cell. The simulations are then compared to the real patient tumor cells that have been growing in Dr. Patil’s laboratory. The “real data” from experiments in the lab are used to confirm  the virtual tumor model – again, this is customized for each individual patient.

The next step is to run a virtual experiment where all FDA-approved targeted drug combinations are tried on the virtual tumor cell to identify the best drug combination that eradicates the cells for the specific brain tumor.  In the final step, researchers expose the patient’s real cancer cells to this unique and personalized drug combination to ensure that it effectively kills the patient’s cancer cells in the laboratory.

Spreading the Word

This effort is not someday in the future but is happening now, and has demonstrated remarkable progress in the last six months. Researchers expect to have data on 30 brain cancer patients from this precision medicine strategy by mid-2016. From this, they will develop an innovative randomized clinical trial, not simply to compare one drug to another, but rather compare this innovative Precision Medicine treatment algorithm to a current standard treatment regimen.

Learn More

For more information on this revolutionary approach, visit www.BrainTumorExpert.com, to learn more about Dr. Patil and his precision science approach to treating brain tumors.

REFERENCE

http://www.drchiragpatil.com/main.html

SOURCE

http://www.drchiragpatil.com/main.html

Other related articles:

http://www.rsc.org/chemistryworld/2016/02/junk-dna-genome-nessa-carey-book-review

http://www.genengnews.com/gen-news-highlights/advanced-immunotherapeutic-method-shows-promise-against-brain-cancer/81252433/

http://www.mdtmag.com/news/2015/11/blood-brain-barrier-opened-noninvasively-focused-ultrasound-first-time

http://www.biosciencetechnology.com/news/2015/11/protein-atlas-brain

 

Other related articles published in this Open Access Online Scientific Journal include the following:

2015

The 11th Annual Personalized Medicine Conference, November 18-19, 2015, Joseph B. Martin Conference Center of the Harvard New Research Building at Harvard Medical School

https://pharmaceuticalintelligence.com/2015/07/09/the-11th-annual-personalized-medicine-conference-november-18-19-2015-joseph-b-martin-conference-center-of-the-harvard-new-research-building-at-harvard-medical-school/

Silicon Valley 2015 Personalized Medicine World Conference, Mountain View, CA, January 26, 2015, 8:00AM to January 28, 2015, 3:30PM PST
https://pharmaceuticalintelligence.com/2015/01/08/silicon-valley-2015-personalized-medicine-world-conference-mountain-view-ca-january-26-2015-800am-to-january-28-2015-330pm-pst/

2014

10th Annual Personalized Medicine Conference at the Harvard Medical School, November 12-13, 2014, The Joseph B. Martin Conference Center at Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA
http://pharmaceuticalintelligence.com/2014/10/09/10th-annual-personalized-medicine-conference-at-the-harvard-medical-school-november-12-13-2014-hotel-commonwealth-boston-ma/

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Medical 3D Printing and Metals in use in Medical Devices,
Presentation by Danut Dragoi, PhD

The main objective of medical 3D printing (M3DP) is to build solid / semi-solid / scaffolds / or gel structures from bio-compatible materials that can be utilized in medicine in order to correct, alleviate, support certain surgeries, or even cure some diseases based on medical / biological principles applied to human body.

Materials that replace bones are metals like Ti, Ti alloys, Tantalum, Gold, Silver, Zr and other. For replacement of teeth is traditionally used a combination of Ti-pivots and ceramic / polymers / or in some cases Hydroxylapatite (HA) coated Ti.

In order to produce a metallic object implantable in the human body, most useful technology is 3D printing of metals, commonly known as AT (addition manufacturing) technology. A definition of 3D printing is a process for making a physical object from a three-dimensional digital model, typically by laying down many successive thin layers of a material. If a printer system uses metal powders and binder instead of normal ink the printed layer by layer will develop a 3D object.

The printed object may be an orthopedic bone replacement, a tooth pivot or an artificial tooth. The picture on Slide 4 shows a Laser Sintering System (SLM) for Medical 3D Printing for metals, find specs in here.

Slide 4

Slide4

The machine shown on Slide 5 is one of the three metal printers from SLM Solutions using the technology of Selective Laser Melting, find specs in here,
Slide 5

Slide5
Feature highlight: for aerospace and medical orthopedics. Large build volume.
Material: Stainless steel, tool steel, aluminium, titanium, cobalt-chrome, inconel
Build capacity: 19.68 x 11.02 x 12.80 in. / (500 x 280 x 325 mm)
Build rate: 70 cm³/h
Resolution/Layer thickness: 20 – 200µm
Machine dimensions: 118 x 98 x 43 in.

An important aspect of metal source for M3DP is the shape of the particles, uniform size distribution and chemical purity. Using a new manufacturing approach, Zecotek, a company in Germany, link in here, developed metallic powders that can be successfully used in M3DP. Next Slide 6 shows some characteristics of this breakthrough technology.

Slide6
Slide 7

Slide7

More information on Slide 7 can be found in here.

Slide 8

Slide8

Information on Slide 8 can be found in here .
Slide 9

Slide9

Information on Slide 9 can be found in here, which is a novelty in terms of materials, the fusion for the first time between a Ti alloy and a ceramic.
Slide 10

Slide10The schematic on Slide 10 can be found in here . SLS technology is in wide use around the world due to its ability to easily make very complex geometries directly from digital CAD data. While it began as a way to build prototype parts early in the design cycle, it is increasingly being used in limited-run manufacturing to produce end-use parts. Here is how it is working. The powders are in a compartment controlled by a piston going one small step up, the roller swipes to the right a thin layer of metallic powder on the second compartment controlled by a piston that goes only one small step down, due to the fact that the printed model starts to grow up. The tip of the laser beam melts the powder or fusion the particles according with a real drawing section of the model. The process is repeated until the model is done. The key element of this technology is the laser scan device that follows exactly the drawing section of the model.

Slide 12

Slide12

Slide 12 shows a 3D printed foot that is light and well manageable for the patient. The picture can be found at this link in here. This prosthetic introduces the traces concept on light-weighting of replaceable parts for human body.
Slide 13

Slide13

Slide 13 shows a 3D printed light orthopedic pieces that are using the concept of light-weighting using traces. Their picture can be found here.

Slide 14

Slide14

Slide 14 shows tiny parts obtained with 3D printing technology, details in here.

Slide 15

Slide15

A second way to obtain solid parts is using a 3D Bioplotter, link in here .

EnvisionTec’s 3D-Bioplotter builds its products in much the same way as a traditional 3D printer. However, instead of using plastics, metals or resins, the Bioplotter uses biologic materials to form a scaffold that will be used to grow more advanced cellular cultures.

Just like a traditional 3D printer, the 3D-Bioplotter can be fed a 3D model generated in a CAD program or from a CT scan. Users can slice and hatch a 3D model to define how it will be printed. That information is then translated to code and shipped off to the Bioplotter where the real work begins.

While prototype objects in the mechanical, architectural and civil worlds can be built from a single material, in the biological world it’s rare that the desired objects have a uniform material. To meet that reality, the Bioplotter can print a model in 5 different materials making it suitable for more complex cellular assemblies.

This ability to jet different materials during a single build requires the 3D-Bioplotter to change print heads. It comes equipped with a CNC-like tool holder that can be programmed to change “print-heads” based on the material being extruded. Most bio-engineering builds favor porosity. This machine’s ability to change print heads can also help alter the flow and spacing of successive print layers to give users greater control of their models.

Slide 16

Slide16

The scaffold on slide 16 obtained with a 3D Bioploter, is useful in dentistry to augment the base of the future implantable tooth. The fixation in the picture is made of Vivos Dental’s OsteoFlux product, link see in here.
Slide 17

Slide17

Slide 17 Metals in medical dental implants, Ti becomes fused with the bone, and the tooth attached to one end of the Ti pivot, see link in here.

Slide 18

Slide18

Slide 18, Hot plasma spray bio-ceramics is the solution that doctors used for biocompatibility of an artificial jaws, link in here.

Slide 20

Slide20On slide 20 the traditional Ti casting is compared with Ti 3D printing from the powders. The advantage of 3D method is low cost and high productivity. This link in here is for traditional method, and this link here for 3D printing method.
Slide 21

Slide21Slide 21 For 3D Bioploter made by EnvisionTec we notice the usage of materials such as metal followed by post-processing sintering, Hydroxylapatite, TCP, Titanium. Using a preciptation method the machine can handle Chitosan, Collagen, 2-component system of the two possible combination: Alginate, Fibrin, PU, and Silicone. More details in here.

Slide 26

Slide26

Slide 26 shows two ultra-miniature medical pressure sensors in the eye of a needle, for details see the link in here.

Slide 27

Slide27

Slide 27 The electrodes of the bio-mems implanted on the surface of the heart are made of Gold for the electrical contact and good bio-compatibility. Classes of materials and assembly approaches that enable electronic devices with features – area coverage, mechanical properties, or geometrical forms – that would be impossible to achieve using traditional, wafer-based technologies. Examples include ’tissue-like’ bio-integrated electronics for high resolution mapping of electrophysiology in the heart and brain. The research on bio-integrated electronics can be found here.

Slide 28

Slide28

Slide 28 shows a polymeric material for determining pressure inside the eye, which is useful to monitor patients at risk from glaucoma. Again the circular electrode is made of Gold and its role is that of an antena to transmit data to a iPhone / receiver about the intraocula pressure data.
Slide 29

Slide29

The device in slide 29 is a bio-MEMS implantable for drug dosage. It has multiple micro-needles that are equivalent to a needle of a normal syringe, but painless since theyr tips do not reach the pain receptors. This picture taken from here, shows a side size of the MEMS of about 25 mm.

Slide 30

Slide30

Slide 30 lists some effects of metals in human body. Traces of heavy metals are dangerous for human body. Human body is made of light elements C,H,N,O. Heavy metals: Pb, Hg, accumulate in the body, they disrupt the metabolic processes since they are very toxic to humans. Therefore, heavy metals don’t have “+” physiological effects and Al as element is known to produce Alzheimer’s which has been implicated as a factor. According to the Alzheimer’s Society, the medical and scientific opinion is that studies have not convincingly demonstrated a causal relationship between aluminium and Alzheimer’s disease. Nevertheless, some studies, cite aluminium exposure as a risk factor for Alzheimer’s disease. Some brain plaques have been found to contain increased levels of the metal. Research in this area has been inconclusive; aluminium accumulation may be a consequence of the disease rather than a causal agent, see link in here.
Slide 31

Slide31

Slide 31 shows percent distribution of elements in human bodies, It is interesting that Ti is not making the list, see link in here.

Slide 32

Slide32

Slide 32 has Ti element circled on the Table of the elements, we notice that Zr as element was found to be a bio-compatible element too just like Ti. It is very possible from chemical point of view that all elements in Ti group have same property. The only inconvenient of elements bellow Ti is that they are heavier and their density should be adapted closer to that of human body.
Slide 33

Slide33

Slide 33 is a plot of stress (MPa) of some human implantable materials as a function of Young modulus E (GPa), their principal mechanical characteristic. There are crystalline materials such as: MgZnCa, MgZr, etc.) as well as amorphous materials bio-compatible such as: MgZnCa BMG, Ca based BMG, Sr based BMG, etc.) that have important mechanical strength that can be used in various applications. The circle in green centered on the point (75GPa, 650 MPa) is that for HydroxylApatite, which is a component of teeth and bones. Further details on this plot can be found at this link here,  .

Magnesium and its alloys are suitable materials for biomedical applications due to their low weight, high specific strength, stiffness close to bone and good biocompatibility. Specifically, because magnesium exhibits a fast biodegradability, it has attracted an increasing interest over the last years for its potential use as “biodegradable implants”. However, the main limitation is that Mg degrades too fast and that the corrosion process is accompanied by hydrogen evolution. In these conditions, magnesium implants lose their mechanical integrity before the bone heals and hydrogen gas accumulates inside the body. To overcome these limitations different methods have been pursued to decrease the corrosion rate of magnesium to acceptable levels, including the growth of coatings (conversion and deposited coatings), surface modification treatments (ion implantation, plasma surface modification, etc) or via the control of the composition and microstructure of Mg alloys themselves.

Slide 34

Slide34

Slide 34 shows two types of three point bending tests, one in which the flexural stress is plotted against displacement and second in which the stress intensity factor is plotted against the length of the crack extended beyond the notch. It is interesting that both plots can differentiate between young and aged bones. The plots can be downloaded from here,  where more experimental details and explanation can be found.

Slide 35

Slide35

Slide 35 shows the geometry for 3 point bending for fracture toughness testing. in which the stress intensity factor can be considered as a function of delta a, the depth of the notch at various values of loads. The equation of stress intensity factor can be found here.

Slide 36

Slide36

Slide 36 describes a family of stress-strain curves as function of composition for four Ti alloys. As we can see the mechanical strength of Ti alloys is well above 400 MPa, which is more than enough for replacement of bones that have a lower mechanical strength of about 175 MPa. The plot in this slide can be reviewed at this site.
Slide 37

Slide37

Slide 37 Mechanical strength of cortical bone, see link in here,  and mechanical strength of Ti alloys, seen in here.

The comparison shows a limit of elasticity of 160 MPa which is well below 400 MPa of Ti alloys or even simply Ti element which has a yield strength of 434 MPa, see link video here.
Slide 38

Slide38

Slide 38 provides information about the oxide layer on Ti binding biological tissues. Rutile and Anatase, are the two crystalline species of TiO2 formation on Ti surface. Rutile is less bio-reactive than Anatase, info in here, http://cdn.intechopen.com/pdfs-wm/33623.pdf . The metal work function changes as a consequence of the formation of the passivisation layer (the oxide), but ΔΦ is positive for rutile and negative for anatase, info in here, http://pubs.acs.org/doi/abs/10.1021/jp309827u?journalCode=jpccck .

Slide 39

Slide39

Slide 39 provides information about the crystal structures of three species of Titanium oxide: Rutile, Anatase, and Brookite. As seen from the slide, the density varies with the crystal structure. The valence of Ti in these structures is 4+, same as Carbon in many organic molecules.
Slide 40

Slide40

Slide 40 provides information about the crystal structures of Titanium monoxide. As seen from the slide, the density is the highest among all Titanium oxides. The crystal structure of Titanium monoxide is shown in this slide. The valence of Ti in these structure is 2+, that makes this oxide special in applications.
Slide 41

Slide41

Slide 41 provides information about two metals, Ti and Zr that are used in human body implantable. An explanation of why these two metals are bio-compatible is given in this slide. As we know not all metals are inert/not reactive in human body environment. As a fact bulk cubic structures of metals is less preferred such as Al, Cu, Nb, Pb, etc.. Based on a symmetry remark for living structures (carbohydrates, nucleic acids, lipids and proteins), the lower implantable metals symmetry the better. As an example Lysozyme (S.G. P43212, space group number 96) as a possible interface material with an implantable metal such as Au, Ti, Zr, admits lower space groups such as Ti ( P63/mmc. Space group number: 194). Gold is not preferred for multiple reasons too: it has a high symmetry S.G. 225 (Fm-3m) 96<225, it has has a high density 19.32 g/cc, and it is expensive.

Many metals have a degree of leachability in human body fluids except the rare/precious metals Au, Pt, Ir that are expensive as implants. The coatings of Ti with a tiny thin layer of oxide or laser coated organic ceramics, makes Ti as the best choice as human body implantable with extremely low leachability in human body fluids.
Slide 42

Slide42

Slide 42 provides crystallographic information on Ti crystal structure, unit cell size and directions.
Slide 43

Slide43

Slide 43 provides information on Zr metal as the second choice on human body implantables. The crystal structure of Zr is same as Ti, with hexagonal close packed (HCP) unit cell. The HCP cell is shown together with a body center cubic (BCC) unit and face close cubic (FCC) unit for comparison reason.
Slide 44

Slide44

Slide 44 shows the Table of major biomedical metals and alloys and their applications. More details about materials in the Table can be found here.

Slide 45

Slide45

The Table on Slide 45 shows a comparison of mechanical properties for three metal alloys. Notice the the increase of the ultimate tensile strength of Ti 64, from 434 MPa for Titanium (see slide 37) to 900 MPa for Ti 64. More data about other materials can be found here.

Slide 46

Slide46

Slide 46 lists some medical devices as they were created by the inventor Alfred Mann’s companies. Such devices are:
-rechargeable pacemaker,
-an implant for deaf people,
-an insulin pump and a
-prosthetic retina. (Mel Melcon, Los Angeles Times)
Slide 47

Slide47

Slide 47 As we imagine, the implanted devices should be coated with one of these Ti, Zr, ceramic coated Ti and Stainless Steel. Three example are given as: Ti-plates and rods, 3D printed Jaws + plasma coated HAp, Gold nano-wires.
Slide 48

Slide48

In the example on slide Slide 48, the pacemaker casing is made of titanium or a titanium alloy, electrodes are made of metal alloy insulated with polyurethan polymers, more info in here.

Slide 49

Slide49

The second device shown in slide 49 is an implant for deaf people, whose surface in contact with human body fluids is coated with Ti. More info on how this implant works can be found in here.
Slide 50Slide50The insulin pump shown in slide 50 is a schematic of the pump controlled electronically by a control algorithm device, a sensor, an electronic receiver that connects with an iPhone through an wireless channel.
Slide 51Slide51

The prosthetic retina on slide 51 is an example of a bio-MEMS based optical sensor that takes the outside image through a tiny camera, the electrical signal of the camera is sent to a receiver and then to an array of micro-electrodes tacked to the retina which send electrical impulses to the brain through the optical nerve. More details can be found in here.

Slide 52Slide52Slide 52 describes how easily available bio-compatible metal powders
can revolutionize 3D printing for medical implants. The surgical implants need to generate expected responses from neighboring cells and tissues. Cell behavior (adhesion, functional alteration, morphological changes, and proliferation) is strongly affected by the surgical implants’ surface properties. Surface topography, surface chemistry, and surface energy influence decisively the biological response to an implanted device.
The well controlled 3D printing atmosphere (neutral gases and restricted oxygen) guarantees the high purity of the 3D printed parts and preserves the materials’ properties.
The advantages of 3D printing for medical applications is thoroughly discussed in here.

Slide 53Slide53

Slide 53 shows five conclusions of the presentation, in which 1) many engineered metals are mechanically resistant in human body, but prone to certain corrosion if not coated,
2) Ti, Zr coated bio-ceramics are bio-compatible materials in human body, 3) medical devices implants and MEMS are useful as heart stent, orthopedic prosthetic, prosthetic retina, 3) M3DP has low costs, high quality, long life cycle and 4) Metal/bio-ceramic and Vivos dental’s synthetic bone for oral augmentation is a solution for today’s dental health care.
Slide 54Slide54Slide 54 shows conclusions regarding the hardware of the presentation, in which: 6) there are two types of metal 3D printing hardware for medical applications: Selective Laser Melting / Selective Laser Sintering, and 3D Bioploter (metal powder mixed with binder and further thermal treatment to remove binder and sinter the metallic matrix in a solid object that can be used as a replacement. Thank you for your attention!

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Huge advance in burn surgery

Curator: Larry H. Bernstein, MD, FCAP

 

 

26-Hour Face Transplant Made Possible with 3D Printing

By On Thu, Nov 19, 2015

One fateful night back in 2001, a former volunteer firefighter from Mississippi named Patrick Hardison bravely entered a burning home seeking to rescue anyone who might be stuck inside. When the burning house collapsed upon Hardison, he was left with critical injuries that completely disfigured his facial features, leaving him complete unrecognizable even to his own wife and children. This horrific accident forced Hardison onto the operating table over 70 times, where traditional surgical operations were only adding to the mental and physical strain he had been undergoing since the fire had left him disfigured.

 

3dprint)nyu_rodriguez_patrick_smaller

It wasn’t until Dr. Eduardo D. Rodriguez, a plastic surgeon at NYU’s Langone Medical Center, came up with a plan to give Hardison a full face transplant. The plan involved finding a ‘donor’ who matched in hair color, skin color, blood type, and who also has a similar skeletal structure to Hardinson. Once the selected donor was found, Rodriguez and his staff utilized 3D Systems’ Virtual Surgical Planning (VSP) technology, which allows for adequate surgical preparation by offering cutting guides over an actual 3D scan of the bone structure of both the patient and the donor.

 

VSP Technology

 

VSP Technology

VSP technology is able to create these surgical templates by using medical scan data, which are transformed into 3D models and, in some cases, are even 3D printed for a visual aid. 3D Systems’ Medical Modeling team actually assisted in the printing of these templates, using a biocompatible 3D printing material that is easily sterilized, and can, therefore, be safely utilized within the confines of an operating room.

 

 

3dprint)nyu_before_after

 

Using the careful surgical plan the Rodriguez and his team prepared on 3D Systems’ VSP technology, Hardinson received an extremely successful surgery and suddenly had all of the features of a human face again for the first time in years. Although the intensive surgery took Rodriguez and over 100 other individuals who assisted in the operation a whopping 26 hours to complete, the surgery would have likely been impossible to even plan without the preparation help offered by 3D Systems and their Virtual Surgical Planning technology. Now, thanks to Dr. Rodriguez, 3D Systems’ Medical Modeling team, and the rest of the NYU’s Langone Medical Center staff, Patrick Hardison can finally smile at the world, once again.

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New Generation of Platinated Compounds to Circumvent Resistance

Curator/Writer: Stephen J. Williams, Ph.D.

Resistance to chemotherapeutic drugs continues to be a major hurdle in the treatment of neoplastic disorders, irregardless if the drug is a member of the cytotoxic “older” drugs or the cytostatic “newer” personalized therapies like the tyrosine kinase inhibitors.  For the platinatum compounds such as cisplatin and carboplatin, which are mainstays in therapeutic regimens for ovarian and certain head and neck cancers, development of resistance is often regarded as the final blow, as new options for these diseases have been limited.

Although there are many mechanisms by which resistance to platinated compounds may develop the purpose of this posting is not to do an in-depth review of this area except to refer the reader to the book   Ovarian Cancer and just to summarize the well accepted mechanisms of cisplatin resistance including:

  • Decreased cellular cisplatin influx
  • Increased cellular cisplatin efflux
  • Increased cellular glutathione and subsequent conjugation, inactivation
  • Increased glutathione-S-transferase activity (GST) and subsequent inactivation, conjugation
  • Increased γ-GGT
  • Increased metallothionenes with subsequent conjugation, inactivation
  • Increased DNA repair: increased excision repair
  • DNA damage tolerance: loss of mismatch repair (MMR)
  • altered cell signaling activities and cell cycle protein expression

Williams, S.J., and Hamilton, T.C. Chemotherapeutic resistance in ovarian cancer. In: S.C. Rubin, and G.P. Sutton (eds.), Ovarian Cancer, pp.34-44. Lippincott, Wilkins, and Williams, New York, 2000.

Also for a great review on clinical platinum resistance by Drs. Maritn, Hamilton and Schilder please see the following Clinical Cancer Research link here.

This curation represents the scientific rationale for the development of a new class of platinated compounds which are meant to circumvent mechanisms of resistance, in this case the loss of mismatch repair (MMR) and increased tolerance to DNA damage.

An early step in the production of cytotoxicity by the important anticancer drug cisplatin and its analog carboplatin is the formation of intra- and inter-strand adducts with tumor cell DNA 1-3. This damage triggers a cascade of events, best characterized by activation of damage-sensing kinases (reviewed in 4), p53 stabilization, and induction of p53-related genes involved in apoptosis and cell cycle arrest, such as bax and the cyclin-dependent kinase inhibitor p21waf1/cip1/sdi1 (p21), respectively 5,6. DNA damage significantly induces p21 in various p53 wild-type tumor cell lines, including ovarian carcinoma cells, and this induction is responsible for the cell cycle arrest at G1/S and G2/M borders, allowing time for repair 7,8.  DNA lesions have the ability of  to result in an opening of chromatin structure, allowing for transcription factors to enter 56-58.  Therefore the anti-tumoral ability of cisplatin and other DNA damaging agents is correlated to their ability to bind to DNA and elicit responses, such as DNA breaks or DNA damage responses which ultimately lead to cell cycle arrest and apoptosis.  Therefore either repair of such lesions, the lack of recognition of such lesions, or the cellular tolerance of such lesions can lead to resistance of these agents.

resistmech2

Mechanisms of Cisplatin Sensitivity and Resistance. Red arrows show how a DNA lesion results in chemo-sensitivity while the beige arrow show common mechanisms of resistance including increased repair of the lesion, effects on expression patterns, and increased inactivation of the DNA damaging agent by conjugation reactions

 

 

 

 

 

 

 

 

 

 

 

 

 

 

mechPtresistance

 

 

Increased DNA Repair Mechanisms of Platinated Lesion Lead to ChemoResistance

 

DNA_repair_pathways

Description of Different Types of Cellular DNA Repair Pathways. Nucleotide Excision Repair is commonly up-regulated in highly cisplatin resistant cells

 

 

 

 

 

 

 

 

 

 

 

Loss of Mismatch Repair Can Lead to DNA Damage Tolerance

dnadamage tolerance

 

 

 

 

 

 

 

 

In the following Cancer Research paper Dr. Vaisman in the lab of Dr. Steve Chaney at North Carolina (and in collaboration with Dr. Tom Hamilton) describe how cisplatin resistance may arise from loss of mismatch repair and how oxaliplatin lesions are not recognized by the mismatch repair system.
Cancer Res. 1998 Aug 15;58(16):3579-85.

The role of hMLH1, hMSH3, and hMSH6 defects in cisplatin and oxaliplatin resistance: correlation with replicative bypass of platinum-DNA adducts.

Abstract

Defects in mismatch repair are associated with cisplatin resistance, and several mechanisms have been proposed to explain this correlation. It is hypothesized that futile cycles of translesion synthesis past cisplatin-DNA adducts followed by removal of the newly synthesized DNA by an active mismatch repair system may lead to cell death. Thus, resistance to platinum-DNA adducts could arise through loss of the mismatch repair pathway. However, no direct link between mismatch repair status and replicative bypass ability has been reported. In this study, cytotoxicity and steady-state chain elongation assays indicate that hMLH1 or hMSH6 defects result in 1.5-4.8-fold increased cisplatin resistance and 2.5-6-fold increased replicative bypass of cisplatin adducts. Oxaliplatin adducts are not recognized by the mismatch repair complex, and no significant differences in bypass of oxaliplatin adducts in mismatch repair-proficient and -defective cells were found. Defects in hMSH3 did not alter sensitivity to, or replicative bypass of, either cisplatin or oxaliplatin adducts. These observations support the hypothesis that mismatch repair defects in hMutL alpha and hMutS alpha, but not in hMutS beta, contribute to increased net replicative bypass of cisplatin adducts and therefore to drug resistance by preventing futile cycles of translesion synthesis and mismatch correction.

 

 

The following are slides I had co-prepared with my mentor Dr. Thomas C. Hamilton, Ph.D. of Fox Chase Cancer Center on DNA Mismatch Repair, Oxaliplatin and Ovarina Cancer.

edinborough2mmrtranslesion1

 

 

 

 

 

 

Multiple Platinum Analogs of Cisplatin (like Oxaliplatin )Had Been Designed to be Sensitive in MMR Deficient Tumors

edinborough2diffptanalogs

 

 

 

 

 

 

mmroxaliplatin

 

 

 

 

 

 

edinborough2ptanalogsresist

 

 

 

 

 

 

edinborough2relresistptanalogsdifflines

 

 

 

 

 

 

edinborough2msimlmh2refract

 

 

 

 

 

 

edinborough2gogoxaliplatintrial

 

 

 

 

 

 

 

Please see below video on 2015 Nobel Laureates and their work to elucidate the celluar DNA repair mechanisms.

Clinical genetics expert Kenneth Offit gives an overview of Lynch syndrome, a genetic disorder that can cause colon (HNPCC) and other cancers by defects in the MSH2 DNA mismatch repair gene. (View Video)

 

 

References

  1. Johnson, S. W. et al. Relationship between platinum-DNA adduct formation, removal, and cytotoxicity in cisplatin sensitive and resistant human ovarian cancer cells. Cancer Res 54, 5911-5916 (1994).
  2. Eastman, A. The formation, isolation and characterization of DNA adducts produced by anticancer platinum complexes. Pharmacology and Therapeutics 34, 155-166 (1987).
  3. Zhen, W. et al. Increased gene-specific repair of cisplatin interstrand cross-links in cisplatin-resistant human ovarian cancer cell lines. Molecular and Cellular Biology 12, 3689-3698 (1992).
  4. Durocher, D. & Jackson, S. P. DNA-PK, ATM and ATR as sensors of DNA damage: variations on a theme? Curr Opin Cell Biol 13, 225-231 (2001).
  5. el-Deiry, W. S. p21/p53, cellular growth control and genomic integrity. Curr Top Microbiol Immunol 227, 121-37 (1998).
  6. Ewen, M. E. & Miller, S. J. p53 and translational control. Biochim Biophys Acta 1242, 181-4 (1996).
  7. Gartel, A. L., Serfas, M. S. & Tyner, A. L. p21–negative regulator of the cell cycle. Proc Soc Exp Biol Med 213, 138-49 (1996).
  8. Chang, B. D. et al. p21Waf1/Cip1/Sdi1-induced growth arrest is associated with depletion of mitosis-control proteins and leads to abnormal mitosis and endoreduplication in recovering cells. Oncogene 19, 2165-70 (2000).
  9. Davies, N. P., Hardman, L. C. & Murray, V. The effect of chromatin structure on cisplatin damage in intact human cells. Nucleic Acids Res 28, 2954-2958 (2000).
  10. Vichi, P. et al. Cisplatin- and UV-damaged DNA lure the basal transcription factor TFIID/TBP. Embo J 16, 7444-7456 (1997).
  11. Xiao, G. et al. A DNA damage signal is required for p53 to activate gadd45. Cancer Res 60, 1711-9 (2000).

Other articles in this Open Access Journal on ChemoResistance Include:

Cancer Stem Cells as a Mechanism of Resistance

An alternative approach to overcoming the apoptotic resistance of pancreatic cancer

Mutation D538G – a novel mechanism conferring acquired Endocrine Resistance causes a change in the Estrogen Receptor and Treatment of Breast Cancer with Tamoxifen

Can IntraTumoral Heterogeneity Be Thought of as a Mechanism of Resistance?

Nitric Oxide Mitigates Sensitivity of Melanoma Cells to Cisplatin

Heroes in Medical Research: Barnett Rosenberg and the Discovery of Cisplatin

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