‘Baron of Botox’ Dr Fredric Brandt Dead at Age 65


Fredric Brandt, MD, a world-renowned dermatologist, died at his home in Coconut Grove, Florida, on April 5. The 65-year-old hanged himself, according to the Miami, Florida, police.

His publicist, Jacquie Tractenberg, told the Washington Post he had been suffering from depression and was upset by a recent episode of Tina Fey’s Netflix comedy series, “Unbreakable Kimmy Schmidt,” in which Martin Short appeared to parody him. Short’s character had thinning blonde hair with a receding hairline, exaggerated cheekbones, and a face so frozen his speech was distorted.

“It definitely bothered him. It was a very mean portrayal,” she told the Post, but added, “He didn’t kill himself because of that one particular show.”
Dr Brandt was a pioneer in the use of onabotulinum toxin A (Botox Cosmetic, Allergan) and collagen fillers. He had dermatology practices in Manhattan, New York, and Coral Gables, Florida. “He was a giant in this field…he was recognized as a world leader in cosmetic medicine,” Roy G. Geronemus, MD, director, Laser and Skin Surgery Center of New York, told Medscape Medical News. “He really took the science and made it an art.”

“He was a brilliant and caring physician. He really helped transform the techniques for the approach towards the aging face and body,” he said.

Dubbed the “Baron of Botox” and the “King of Collagen,” Dr Brandt had reportedly used more Botox Cosmetic and collagen fillers than any other dermatologist in the world. His celebrity clients included the singer Madonna, television talk-show host Kelly Ripa, and comedian Joy Behar.


Dr Fredric Brandt.
Dr Geronemus said he has known Dr Brandt since 1978, when they were both at the University of Miami in Florida. Dr Brandt was a medical resident and Dr Geronemus was a medical student there. The two dermatologists had worked together for 20 years. Dr Brandt treated patients at the Laser and Skin Surgery Center of New York in Manhattan at the time of his death.

Loved by Patients and Colleagues.

“The staff that we shared absolutely loved him. He was very creative in making everyone feel like a part of his family. His staff were his family, his patients were his family. The response that we’re getting from his patients with his death is truly overwhelming. His patients are just devastated,” Dr Geronemus said.

Dr Brandt would often relax his patients by singing to them as he was treating them, Dr Geronemus said. “He was very, very knowledgeable about medicine; he was not just someone looking to put a few needles into someone’s face in exchange for a few dollars. He was very creative and really had a true vision for what a younger face should look like.”

“He was a good friend. Many of his patients became his personal friends,” Dr Geronemus added, noting that even colleagues who were considered competitors liked him.

Clinical Practices in Manhattan and Coral Gables

Dr Brandt was born on June 26, 1949, in Newark, New Jersey, to Irving and Esther Brandt and grew up there. He is survived by his brother, Paul.

He graduated with a Bachelor of Arts degree from Rutgers University in New Brunswick, New Jersey, in 1971 and earned a medical degree from Hahnemann Medical College (now known as Drexel University College of Medicine) in Philadelphia, Pennsylvania, in 1975.

Dr Brandt completed an internship at New York University in New York City from 1975 to 1976, a residency in internal medicine at New York University from 1976 to 1978, and a residency in dermatology at the University of Miami in Florida from 1978 to 1981, according to his curriculum vitae. The information in his curriculum vitae conflicts with media reports that say he completed medical residencies at New York University and Memorial Sloan Kettering Cancer Center in Manhattan, with residencies in nephrology and oncology.

Dr Brandt went into private practice in Coral Gables in 1982 and in New York City in 1996. He was the founder and chairman of the board for Cosmetic Dermatology Inc in Miami from 1990 until his death. It was there that he created the Dr Brandt skincare line, which has been sold in more than 40 countries. “He was very creative and thoughtful about what he was doing with [his product line],” Dr Geronemus noted.

He was a clinical voluntary associate professor in the Department of Dermatology at the University of Miami in Florida from 1999 until May 2001.

Esteemed Researcher, Author

He founded and was the principal investigator for the Dermatology Research Institute LLC in Coral Gables from 2006 until his death. “He had a clinical research program in Miami, [and] we did some drug studies in New York as well,” Dr Geronemus explained. “He was involved with the clinical development of many of the products that he used, so he understood them quite well. He understood their limitations, he understood their strengths, he understood which products should be used where, and would always look for any method possible for improving the outcome of his patients.”

“A lot of it was based on his own research, with the knowledge that he gained helping these companies develop their products or doing the phase 1, 2, and 3 clinical trials for the [US Food and Drug Administration],” he added.

Along with the multiple studies in which he was the principal investigator, Dr Brandt was also a sought-after presenter at scores of dermatology conferences around the world.

He was a board-certified member of the American Board of Internal Medicine and the American Board of Dermatology. He was a member of the International Society for Dermatologic Surgery, International Society of Cosmetic Laser Surgeons, American Medical Association, American Society for Dermatologic Surgery, Dermatology Foundation Leaders Society, and Florida Medical Association, among others.

Dr Brandt wrote two books about skin aging and maintaining a youthful appearance: 10 Minutes/10 Years: Your Definitive Guide to a Beautiful and Youthful Appearance and Age-less: The Definitive Guide to Botox, Collagen, Lasers, Peels, and Other Solutions for Flawless Skin.

“He had some novel ideas, concepts, and techniques in terms of the use of botulinum toxin and filler substances,” Dr Geronemus said. “[M]any physicians in the country and around the world have adopted them into their daily practice.”

Dr Brandt claimed he tested every product he used on himself before using them on his patients.

They see flow signals: Researchers identify nature of ‘sixth sense’ in fish


A team of scientists has identified how a “sixth sense” in fish allows them to detect flows of water, which helps resolve a long-standing mystery about how these aquatic creatures respond to their environment.
It is well known that fish respond to changes in their fluid environment. These include avoiding obstacles, reducing swimming effort by slaloming between vortices, or whirlpools, and tracking changes in water flow left by prey — even without the aid of vision.

A team of scientists has identified how a “sixth sense” in fish allows them to detect flows of water, which helps resolve a long-standing mystery about how these aquatic creatures respond to their environment. Their findings, which appear in the journal Physical Review Letters, illustrate how sensory systems evolve in accordance with physical principles while also offering a framework for understanding how sensory networks are structured.

“We identified a unique layout of flow sensors on the surface of fish that is nearly universal across species, and our research asks why this is so,” explains Leif Ristroph, an assistant professor at New York University’s Courant Institute of Mathematical Sciences and one of the study’s authors. “The network of these sensors is like a ‘hydrodynamic antenna’ that allows them to retrieve signals about the flow of water and use this information in different behaviors.”

The study’s other authors were James Liao, an assistant professor at the University of Florida’s Whitney Laboratory for Marine Bioscience, and Jun Zhang, a professor of physics and mathematics at NYU and NYU Shanghai.

It is well known that fish respond to changes in their fluid environment. These include avoiding obstacles, reducing swimming effort by slaloming between vortices, or whirlpools, and tracking changes in water flow left by prey — even without the aid of vision.

To explore how fish exploit flow information, the research team focused on a fish’s “lateral line” — a system of sensory organs known to detect both movement and vibration in the water that surrounds them — with particular consideration to the line’s sensory-laden canals that open to the environment through a series of pores. They specifically focused on the placement of these canals along the body, noting that their location can help explain how a fish’s sixth sense functions. For instance, the concentration of these canals at the heads of blind cave fish seems well-suited for detecting obstacles.

To test their theory, the researchers created a plastic model of a rainbow trout that replicated the location of the fish’s canals and included illuminated markers used to detect the speed of surrounding water.

In their experiments, the model fish was put through a series of tests the replicated real- life aquatic conditions — changes in water flow that altered water pressure or mimicked the presence of “prey” — and examined where the canals were located in relation to strongest changes in water pressure.

Their results showed that, as predicted, the canal system is concentrated at locations on the body wherever strong variations in pressure occur. Just as the shape of a TV or radio antenna is designed to detect electromagnetic signals, the fish’s canal system is like an antenna laid out on the body surface and configured to be sensitive to pressure changes. The team’s use of finely detailed models — developed with the help of a taxidermist who made custom molds from real trout — made it possible to record this data for the first time.

“You can’t put pressure sensors on a live fish and have it behave normally,” Liao says. “This was a creative way to use engineering and physics techniques to answer biological questions you can’t answer otherwise.”


Story Source:

The above story is based on materials provided by New York University. Note: Materials may be edited for content and length.


Journal Reference:

  1. Leif Ristroph, James C. Liao, Jun Zhang. Lateral Line Layout Correlates with the Differential Hydrodynamic Pressure on Swimming Fish. Physical Review Letters, 2015; 114 (1) DOI: 10.1103/PhysRevLett.114.018102

Worst Seizures Respond to Fycompa


AMPA antagonist drug shows mettle in generalized tonic-clonic seizures.

Most patients with generalized tonic-clonic seizures (GTCSs) despite conventional therapy showed major improvement when perampanel (Fycompa) was added to their regimens in a phase III trial, researchers reported here.

Some 31% of patients achieved complete freedom from these extremely debilitating seizures after 17 weeks of treatment and about an equal number had at least a 50% reduction in GTCS frequency in the randomized, placebo-controlled trial, said Jacqueline French, MD, of New York University’s Comprehensive Epilepsy Center in New York City.

The overall responder rate (seizure freedom or 50% or greater reduction in seizure frequency) with perampanel was 64.2%, versus 39.5% in the placebo group (P<0.01), French reported at the American Epilepsy Society’s (AES) annual meeting.

At a press briefing, French said the results were important because many drugs approved for less severe seizures are ineffective for GTCSs and may even worsen them. Perampanel, an antagonist of excitatory glutamate activity through so-called AMPA receptors, is currently approved for treating partial onset seizures.

For the current trial, French and colleagues enrolled 163 patients with idiopathic generalized epilepsy marked by GTCSs that did not respond to currently approved therapies. One patient in the placebo group was excluded from the efficacy analysis.

To be enrolled, patients had to have at least three GTCSs during an 8-week baseline observation period while taking from one to three approved therapies. Patients with vagal nerve stimulator implants were allowed into the study if the device had been used for at least 5 months prior to enrollment.

Individuals with progressive neurological disease, Lennox-Gastaut syndrome, history of recent status epilepticus, or use of rescue benzodiazepines more than twice in the 30 days prior to enrollment were excluded.

Perampanel was started at 2 mg/day and then increased in 2-mg increments to a target of 8 mg/day during a 4-week titration period. The drug was then continued for 13 weeks at either 8 mg/day or at the maximally tolerated dose if lower.

Primary endpoints were the responder rate and the reduction in seizure frequency from the level recorded during the initial 8-week baseline period.

As already noted, the responder analysis clearly favored perampanel. So did the other primary outcome: patients in the perampanel group showed a mean 76.5% reduction in GTCS frequency, compared with 38.4% with placebo (P<0.0001).

Complete seizure freedom was achieved by 30.9% of the perampanel group versus 12.3% of the placebo group (not significant).

A total of 23 patients did not complete the study, including 13 assigned to perampanel and 10 to placebo. Of these, 9 in the perampanel group and five of the placebo group stopped the assigned medication because of treatment-emergent adverse effects. There was no clear difference between treatment assignments in the types of adverse events leading to withdrawal, and rates of serious, severe, and fatal adverse effects were the same in the two arms.

Nonserious adverse events were somewhat more common with perampanel, particularly somnolence, dizziness, fatigue, and irritability.

Overall, French and colleagues indicated that perampanel’s side effect profile was similar to that seen in patients with partial-onset seizures.

Although the current trial tested the drug as an add-on, French said she expected that it would also be effective as monotherapy. However, the FDA is currently not approving drugs as monotherapies without trials specifically testing that use.

She said many in the epilepsy community believe that this policy is wasteful and unnecessary, because there is no reason to believe that, if a drug that reduces seizures in patients not responding to another approved therapy, it wouldn’t be effective as monotherapy.

She pointed out that taking patients off their current therapies — as could be required in a monotherapy trial — can be “catastrophic” for an epilepsy patient.

But without an approved monotherapy indication, neurologists and their patients face a dilemma when it is necessary to replace one drug with another. This situation commonly arises when a young epileptic woman becomes pregnant while taking a known teratogenic drug such as valproate. Switching this patient to a drug that is approved only as an add-on is thus, technically, off-label.

Consequently, she said, the field’s major professional societies — the AES and theInternational League Against Epilepsy — are currently drafting a white paper calling on the FDA to approve drugs as monotherapies on the basis of add-on studies.

In the meantime, perampanel’s manufacturer, Eisai, asked the FDA in August to approve an expanded indication covering adjunctive treatment of GTCSs, mainly on the basis of the current study.

Domestic Violence Hurts Kids’ Ability To Read Emotions And Regulate Their Own


Kids who witness their parents fighting have trouble recognizing other people’s emotions and regulating their own, finds a newstudy from New York University on the collateral damage of domestic violence.

The study also suggests household chaos and chronic poverty take a similar toll on young minds. Not only are the financial and health-related concerns an issue for children, but their emotional intelligence and psychological well-being is at stake. Instability at home translates into poor performance, academically and socially, in school. Helping to reduce kids’ suffering could go a long way toward fixing other ailments that may be branching off.

fighting

“This study shines a bright light on the importance of supporting parents as they navigate the ups and downs of partnership or marriage,” said C. Cybele Raver, professor of applied psychology at NYU, in a statement.

When parents encounter financial hardship and personal turmoil, that’s when anger management strategies are needed the most, Raver added, because the net effect is a budding generation taking its cues from them. In their study, the team looked at several forms of adversity, tracking behavior outcomes among 1,025 children from the time they were 2 months old until they were just under 5.

They made house visits, issued parent questionnaires, administered tasks to both parents and children, and measured the level of household chaos — defined as the number of times families moved, changes in caregiver, noise levels, and the number people compared to the number of rooms. At 4 years and 10 months, they evaluated kids’ abilities to spot specific emotions.

Verbal and physical aggression were two of the greatest predictors of emotional recognition skills. Interestingly, while physical aggression predicted poorer skills, verbal aggression actually predicted kids would have better abilities at recognizing particular emotions — perhaps because the emotions found in a person’s words are more easily deduced than the emotion behind a slap or punch.

As expected, both forms of aggression predicted kids’ poorer ability to regulate their own emotions. When sad, they were less able to develop coping strategies on their own. The same played out when they were fearful and withdrawn. The researchers found this finding of particular concern because it could lay a dangerous foundation for depression and anxiety later in life.

Among the other influencers in the study, kids were most likely to suffer emotional deficits when they spent a greater number of years in poverty and when their homes were disorganized. According to Raver, the findings put the onus on parents in poverty, or approaching poverty. Too often, she said, they “need help regulating their own feelings of anger, frustration, and worry when balancing the demands of work, family, and romantic partnership, especially when money is tight.”

Prior research has found these cycles of poverty not only to be near-impossible to break, but actually affect the future generation’s DNA. In April, researchersdiscovered kids in poverty had older genes than kids of wealthier families. Coupled with the latest findings, the body of research paints poverty as far more than a socioeconomic bracket. It’s an entirely different world, filled with unique challenges and an overwhelming number of risks.

“Arguing and fighting is psychologically stressful for the adults caught in conflict,” Raver said. “This study demonstrates the costs of that conflict for children in the household as well.”

Source: Raver C, Blair C, Garrett-Peters P, et al. Poverty, household chaos, and interparental aggression predict children’s ability to recognize and modulate negative emotions. Development and Psychopathology. 2014.

Video Analytics Could Flag Crimes Before They Happen.


Boston-Video-AnalyticsSoon after the investigation into Monday’s Boston Marathon bombings began, law enforcement urged the public to e-mail any video, images or other information that might lead them to the guilty party. “No piece of information or detail is too small,” states the F.B.I.’s Web site. Picking through all of this footage in search of clues has been no small task for investigators, given the size of the camera-carrying crowd that had assembled to watch the race, not to mention the video surveillance already put in place by the city and local merchants.

Law enforcement now say they have found video images of two separate suspects carrying black bags at each explosion site and are planning to release the images Thursday so that the public can help identify the men, the Boston Globe reports.

Whereas software for analyzing such video can identify and flag objects, colors and even patterns of behavior after the fact, the hope is that someday soon intelligent video camera setups will be able to detect suspicious activity and issue immediate warnings in time to prevent future tragedies.

A team of New York University researchers is working toward that goal, having developed software they say can measure the “sentiment” of people in a crowd. So far, the technology has primarily been tested as a marketing tool at sporting events (gauging what advertisements capture an audience’s attention, for example), but the researchers are eyeing homeland security applications as well. The U.S. military, which is funding much of the N.Y.U. research, is interested in knowing whether this software could detect when someone is approaching a checkpoint or base with a weapon or explosives concealed under their clothing.

“So far, we can detect if they’re eating or using their cell phones or clapping,” says N.Y.U. computer science professor Chris Bregler. It’s not an exact science, but monitoring crowd behavior helps marketers understand what creates a positive crowd response—whether they are high-fiving action on the field, responding to a call for “the wave” or laughing at an advertisement on the scoreboard. The software is programmed to detect only positive sentiment at this time. Negative sentiments—booing and impolite gestures–are next on the researchers’ agenda.

The key to analyzing video in real time is programming the accompanying analytical software to look for certain cues–a rigid object under soft, flowing clothing, for example–and issue immediate alerts. First, the software must be “trained,” Bregler says. This is done with the help of Internet services such as Amazon’s Mechanical Turk digital labor marketplace, where participants are paid to analyze and tag video footage based on what’s on the screen. Bregler and his team load these results into a computer neural network—a cluster of microprocessors that essentially analyzes relationships among data—so that the software can eventually identify this activity on its own.

One challenge for the researchers is developing its analytical software so that it can examine a variety of different types of video footage, whether it’s professional-quality camerawork on the nightly news or someone recording an event with a shaky cell phone camera. “The U.S. military wants us to look at, say, Arab Spring footage and large demonstrations for early signs that they will turn violent,” Bregler says.

Bregler’s earlier research to identify specific movement signatures (see video below) used the same motion-capture technology used for special effects in the Lord of the Rings and Harry Potter movies. Bregler’s motion-analysis research attracted the attention of the Pentagon’s Defense Advanced Research Projects Agency (DARPA) in 2000 as a possible means of identifying security threats. Following 9/11 his researched ramped up thanks to funding from the National Science Foundation and the U.S. Office of Naval Research. Law enforcement and counterterrorism organizations already had facial-recognition technology but were looking for additional ways to better make sense of countless hours of surveillance footage.

Given that people don’t normally walk around in tight-fitting motion-capture suits laden with reflective markers, the N.Y.U. team developed their technology to focus more on scanning a camera’s surroundings and identifying spots that are unique, such as the way light reflects off a shirt’s button differently than it does off the shirt’s fabric. The researchers’ goal is for their software to be able to identify a person’s emotional state and other attributes based on movement.

Without such advanced video analytics, investigators must essentially reverse-engineer the action depicted in the video they receive, Bregler says. In the case of the Boston Marathon, the researchers have been analyzing video of the explosions and then working backward to see who was in the area prior to the bombing. “Most likely the data needed to figure out what happened exists,” he adds. “Investigators just need to find it, which is difficult given the volume of the video coming in.”

Source: Scientific American

Targeting Invasive Glioma Cells.


Name of the Trial
Phase I Trial of AZD7451, a Tropomyosin-Receptor Kinase (TRK) Inhibitor, for Adults with Recurrent Gliomas (NCI-12-C-0005). See the protocol summary.

Principal Investigators
Dr. Katharine McNeill, NCI Center for Cancer Research, and Dr. Howard Fine, New York University Cancer Institute

Why This Trial Is Important

Glioblastoma is the most common malignant brain tumor in adults, with about 12,000 new cases diagnosed each year in the United States. It is also one of the deadliest, with a median survival following diagnosis of about 14 months.

Surgery to remove as much of the tumor as possible is the standard primary treatment for glioblastoma. After surgery, doctors use radiation therapy and treatment with the chemotherapy drug temozolomide to try to delay the growth of the remaining cancer. Although these measures may delay disease progression for a while, they cannot prevent it, and death usually occurs within a few months. Currently, the only therapy that has proven effective in delaying death in patients with progressive glioblastoma is bevacizumab, which helps block the tumor’s ability to induce the formation of new blood vessels.

Glioblastoma is particularly difficult to treat because of its highly invasive nature. Although the bulk of the tumor may be well defined, malignant cells have usually migrated away from the tumor by the time it is discovered. Some of these cells inevitably remain behind after surgery and, if left unchecked, will eventually kill the patient.

Progress in the treatment of glioblastoma has been hampered by the absence of preclinical tumor models that mimic the invasiveness of the cancer. However, NCI researchers recently developed new cell lines from a subset of glioblastoma tumor-initiating cells that more accurately replicate the invasiveness of human glioblastoma in animal models. Using the new models, they were able to determine that cells near the edge of glioblastoma tumors express a set of proteins that help make them highly invasive. Subsequently, they identified a compound that may be effective in blocking the function of one of these key proteins.

A protein called tropomyosin-receptor kinase, or Trk, is commonly found on brain cells and helps regulate the development, function, and survival of nerve cells. In glioblastoma, Trk is highly expressed on the cells around the edges of the tumor and on the infiltrative cells that have migrated away from the tumor mass, whereas those cells in the bulk of the tumor show lower levels of Trk expression. Doctors want to see if inhibiting the function of Trk will help block the invasiveness of glioblastoma cells and reduce the likelihood that the tumor will progress.

In this first-in-class phase I trial, patients with glioblastoma that has not responded to standard postoperative therapy or that has progressed will be treated with varying amounts of a Trk inhibitor called AZD7451 to determine the maximum tolerated dose and the side effects of this drug. Doctors will also look for signs of clinical activity.

“Regardless of the extent of tumor resection, there are always residual tumor cells because these cells are highly invasive and infiltrate normal brain tissue,” said Dr. Fine, former chief of NCI’s Neuro-Oncology Branch. “So surgery is never curative in this disease; some type of postoperative therapy is always required to try to address these remaining infiltrative tumor cells.

“We became interested in trying to study this invasive process in the laboratory in hopes of identifying new molecular targets for therapy,” he continued. “We were able to find that this molecule called Trk was expressed specifically on glioblastoma cells that were invading and [that] Trk was signaling to these tumor cells in a way that was important for the cells to move within the brain. Further, by inhibiting Trk we were able to shut off the invasive process in these models.”

The trial is taking place at the NIH Clinical Center in Bethesda, MD, and at the New York University Cancer Institute in New York City.

STUDY PROTOCOL

AZD7451 for Recurrent Gliomas

Basic Trial Information

Phase

Type

Status

Age

Sponsor

Protocol IDs

Phase I Biomarker/Laboratory analysis, Treatment Active 18 and over NCI 120005
12-C-0005, NCT01468324

Trial Description

Summary

Background:

  • AZD7451 is a drug that may help interfere with brain tumor cell growth. It can prevent glioma cells from entering into normal brain tissue, and slow or stop the growth of additional tumors. Researchers want to see if AZD7451 is effective against gliomas that have not responded to surgery, radiation, or chemotherapy.

Objectives:

  • To see if AZD7451 is a safe and effective treatment for gliomas that have not responded to standard treatments.

Eligibility:

  • Individuals at least 18 years of age who have gliomas that have not responded to standard treatments.

Design:

  • Participants will be screened with a physical exam, medical history, blood and urine tests, heart function tests, an eye exam, and imaging studies.
  • Participants will take AZD7451 daily by mouth for 28-day cycles of treatment.
  • Participants will keep a medication diary and record any side effects. Treatment will be monitored with frequent blood tests and imaging studies.
  • Treatment will continue as long as there are no serious side effects and the tumor does not start growing again….

Further Study Information

BACKGROUND:

Recurrent glioma patients have very limited treatment options. A major cause of gliomarelated morbidity and mortality is the extensive infiltrative and invasive nature of glioma cells. Thus, inhibition of glioma invasion is a potentially promising strategy.

Work in the laboratory of Dr. Howard Fine has identified TrkA as an important signaling receptor for mediating glioma cell invasion. Both genetic and pharmacological inhibition of Trk potently inhibits glioma invasion and tumor progression in vitro and in vivo.

AZD7451 is a first in-class inhibitor of Trk.

OBJECTIVES:

To establish the maximally tolerated dose (MTD) of continuous once daily AZD7451 in patients with recurrent malignant gliomas not on enzyme-inducing anti-epileptic drugs (EIAED).

To generate pharmacokinetic data on continuous twice a daily AZD7451 dosing.

ELIGIBILITY:

Patients with histologically proven glioblastoma are eligible for this study. Patients should have failed prior standard treatment with radiotherapy.

DESIGN:

This study will accrue up to 60 evaluable patients. Cohorts of 3 to 6 patients will receive continuous AZD7451 twice a day orally for 28 days. The MTD will be based on the tolerability observed during the first 4 weeks of treatment only. Up to three patients may be enrolled simultaneously at each dose level. The dose of AZD7451 can be progressively escalated if only 0/3 or 1/6 patients experience a dose limiting toxicity at the prior dose level.

At the end of Cycle 1, patients may choose to continue to receive AZD7451 until disease progression or until they experience unmanageable drug related toxicity, as long as they are continuing to derive clinical benefit and do not fulfill any of the criteria for removal from protocol therapy. Each cycle during this extension period will last 28 days.

Eligibility Criteria

  • INCLUSION CRITERIA:
  • Patients with histologically proven malignant primary gliomas who have progressive disease after radiotherapy will be eligible for this protocol.
  • Patients must have an MRI scan performed within 14 days prior to registration and on a fixed dose of steroids for at least 5 days. If the steroid dose is increased between the date of imaging and registration a new baseline MRI is required.
  • Patients having undergone recent resection of recurrent or progressive tumor will be eligible as long as all of the following conditions apply:

1. Patients will be eligible four weeks after surgery if they have recovered from the effects of surgery.

2. Residual disease following resection of recurrent tumor is not mandated for eligibility into the study. To best assess the extent of residual disease postoperatively, an MRI should be done:

  • no later than 96 hours in the immediate post-operative period or
  • at least 4 weeks post-operatively, and
  • within 14 days of registration, and
  • on a stable steroid dosage for at least 5 days.

If the 96 hour scan is more than 14 days before registration, the scan needs to be repeated. If the steroid dose is increased between the date of imaging and registration, a new baseline MRI is required on a stable steroid dosage for at least 5 days.

  • Patients must have failed prior radiation therapy.
  • Ability of subject or Legally Authorized Representative (LAR) (if the patient is deemed by the treating physician to be cognitively impaired or questionably impaired in such a way that the ability of the patient to give informed consent is questionable) to understand and the willingness to sign a written informed consent document indicating that they are aware of the investigational nature of this study.
  • Patients must be greater than or equal to18 years old, and must have a life expectancy > 8 weeks. Because no dosing or adverse event data are currently available on the use of AZD7451 in patients < 18 years of age, children are excluded from this study, but may be eligible for future pediatric trials.
  • Patients must have a Karnofsky performance status of greater than or equal to 60
  • Patients must be at least 4 weeks from radiation therapy. Additionally, patients must be at least 6 weeks from nitrosoureas, 4 weeks from temozolomide, 3 weeks from procarbazine, 2 weeks from vincristine and 2 weeks from last bevacizumab administration. Patients must be at least 4 weeks from other cytotoxic therapies not listed above and 2 weeks for non-cytotoxic agents (e.g., interferon, tamoxifen) including investigative agents. With the exception of alopecia, all toxicities from prior therapies should be resolved to CTCAE less than or equal to grade 1.
  • Patients must have adequate bone marrow function (WBC less than or equal to 3,000/microl, ANC > 1,500/mm(3), platelet count of > 100,000/mm(3), and hemoglobin greater than or equal to 9 gm/dl), adequate liver function (AST, ALT and alkaline phosphatase less than or equal to 2.5 times ULN and bilirubin less than or equal to 1.5 times ULN), and adequate renal function (creatinine less than or equal to 1.5 times ULN and/or creatinine clearance less than or equal to 50 cc/min calculated by Cockcroft-Gault) before starting therapy. Patients must also have serum potassium greater than or equal to 3.5 mmol/L, magnesium greater than or equal to 0.75 mmol/L, phosphate and calcium levels within normal levels; supplementation is allowed. In cases where the serum calcium is below the normal range, 2 options would be available: 1) the calcium adjusted for albumin is to be obtained and substituted for the measured serum value. Exclusion is to then be based on the adjusted for albumin values falling below the normal limit. 2) Determine the ionized calcium levels. Exclusion is then to be based on whether these ionized calcium levels are out of normal range despite supplementation. These tests must be performed within 14 days prior to registration. Eligibility level for hemoglobin may be reached by transfusion.
  • Patients must either not be receiving steroids, or be on a stable dose of steroids for at least five days prior to registration.
  • The effects of AZD7451 on the developing human fetus are unknown. For this reason and because AZD7451 is known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or herpartner is participating in this study, the treating physician should be informed immediately.
  • A 12 lead electrocardiogram (ECG) to be performed within 2 weeks of trial entry with QTc less than or equal to 470 msec.
  • Patients must have normal left ventricular ejection fraction (LVEF greater than or equal to 55% or normal by NIH Clinical Center criteria).

EXCLUSION CRITERIA:

  • Patients who, in the view of the treating physician, have significant active hepatic, renal, pulmonary or psychiatric diseases are ineligible.
  • 2 Prior treatment with AZD7451.
  • History of hypersensitivity to active metabolites or excipients of AZD7451.
  • Clinically significant cardiovascular event (e.g. myocardial infarction, angina pectoris, coronary artery bypass graft, angioplasty, vascular stent, superior vena cava syndrome (SVC), New York Heart Association (NYHA, Appendix I) classification of heart disease > 2 within 6 months before entry; or presence of cardiac disease that, in the opinion of the investigator, increases the risk of ventricular arrhythmia.
  • Hemorrhagic or ischemic stroke, including transient ischemic attacks and other central nervous system bleeding in the preceding 6 months that were not related to glioma surgery. History of prior intratumoral bleeding is not an exclusion criterion; patients with history of prior intratumoral bleeding, however, need to undergo a non-contrast head CT to exclude acute blood.
  • Ventricular arrhythmias requiring continuous therapy or asymptomatic sustained ventricular tachycardia within 12 months before study entry. Continuous or intermittent atrial fibrillation requiring treatment. Patients with significant ECG abnormalities such as complete left bundle block and third degree heart block are not eligible.
  • QTc prolongation with other medications that required discontinuation of that medication.
  • Congenital long QT syndrome or 1st degree relative with unexplained sudden death under 40 years of age. QTc with Bazett’s correction that is unmeasurable, or > 470 msec on screening ECG. (Note: If a subject has a QTc interval > 470 msec on screening ECG, the screen ECG may be repeated twice (at least 24 hours apart). The average QTc from the three screening ECGs must be less than or equal to 470 msec in order for the subject to be eligible for the study. Patients who are receiving a drug that has a risk of QTc prolongation are excluded if QTc is greater than or equal to 460 msec.
  • Any concurrent medication that may cause QTc prolongation or induce

Torsades de Pointes 1) Drugs listed in Appendix H, Table 2, that in the investigator’s opinion cannot be discontinued are allowed; however, must be monitored closely.

  • Concomitant medications that are moderate or potent inducers or inhibitors of CYP3A4 are not permitted within the specified wash-out periods prior to or during treatment with AZD7451
  • Patients with a history of corneal disease such as corneal ulcers, corneal dystrophies, keratoconus.
  • Refractory nausea and vomiting or significant gastrointestinal impairment, as judged by the investigator, that would significantly affect the absorption of AZD7451, including the ability to swallow the oral solution.
  • Patients known to have active hepatitis B or C (testing not required for entry on study).
  • Other concomitant anti-cancer therapy except corticosteroids.
  • Patients with a peripheral neuropathy CTCAE > 1 in the prior 4 weeks or active muscle diseases (including dermatomyositis, polymyositis, inclusion body myositis, muscular dystrophy and metabolic myopathy) or family history of myopathy. Patients with pre-existing renal disease including glomerulonephritis, nephritic syndrome, Fanconi syndrome or renal tubular acidosis.
  • Evidence of active infection or active bleeding diatheses.
  • Pregnant women are excluded from this study because AZD7451 is an agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with AZD7451, breastfeeding should be discontinued if the mother is treated with AZD7451. Female patients must have a negative pregnancy test prior to start of dosing if of child-bearing potential or must have evidence of non-childbearing potential by fulfilling one of the following criteria at screening:
  • Post-menopausal defined as aged more than 50 years and amenorrheic for at least 12 months following cessation of all exogenous hormonal treatments.
  • Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation.
  • Patients known to have a malignancy (other than their malignant glioblastoma) that has required treatment in the last 12 months and/or is expected to require treatment in the next 12 months (except for non-melanoma skin cancer, carcinoma in situ in the cervix or ductal carcinoma in situ).
  • Major surgery within 4 weeks or incompletely healed surgical incision before starting therapy.
  • Patients known to be HIV-positive (testing is not required for entry on study) and on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD7451. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated.

Trial Contact Information

Trial Lead Organizations/Sponsors

National Cancer Institute

Howard A Fine, M.D. Principal Investigator

 

Tracy Cropper, R.N. Ph: (301) 402-6298
  Email: tcropper@cc.nih.gov

 

Howard A Fine, M.D. Ph: (301) 402-6298
  Email: hfine@mail.nih.gov

 

Source: NCI

 

 

 

Gut microflora and probiotics.


There are 100 trillion cells in your body, but 90% of the genetic material is not yours. It is from the bacteria, fungi, viruses and other microorganisms, i.e. your microflora. Gut microbes are big in the news lately, as researchers continue to discover the important roles these tiny organisms play in your overall health and well-being. We now know that your microflora influence your:

  • Genetic expression
  • Immune system
  • Weight, and
  • Risk of numerous chronic and acute diseases, from diabetes to cancer

Most recently, research has shown that a certain set of these microbes may actually influence the activity of genes in your brain – and the parts they play are not small parts. They may work to manipulate your behavior, and your memory as well.

Microbes Manipulate Your Mind

According to a recent article in The Guardian1, certain species of gut bacteria have been found to influence gene activity in your brain. Some of this research was published in 2011.2 Mice lacking gut bacteria were found to engage in “high-risk behavior,” and this altered behavior was accompanied by neurochemical changes in the mouse brain.

According to the authors, microbiota (your gut flora) may play a role in the communication between your gut and your brain, and:

“Acquisition of intestinal microbiota in the immediate postnatal period has a defining impact on the development and function of the gastrointestinal, immune, neuroendocrine and metabolic systems. For example, the presence of gut microbiota regulates the set point for hypothalamic-pituitary-adrenal (HPA) axis activity.”

But they also discovered other differences between the mice with normal gut flora and those lacking gut bacteria. When examining the animals’ brains, they discovered a number of genetic alterations in the germ-free mice. According to The Guardian:

Brain-derived neurotrophic factor (BDNF) was significantly up-regulated, and the 5HT1A serotonin receptor sub-type down-regulated, in the dentate gyrus of the hippocampus. The gene encoding the NR2B subunit of the NMDA receptor was also down-regulated in the amygdala.

All three genes have previously been implicated in emotion and anxiety-like behaviors.

BDNF is a growth factor that is essential for proper brain development, and a recent study showed that deleting the BDNF receptor TrkB alters the way in which newborn neurons integrate into hippocampal circuitry and increases anxiety-like behaviors in mice. Serotonin receptors, which are distributed widely throughout the brain, are well known to be involved in mood, and compounds that activate the 5HT1A subtype also produce anxiety-like behaviors.

The finding that the NR2B subunit of the NMDA receptor down-regulated in the amygdala is particularly interesting. NMDA receptors are composed of multiple subunits, but those made up of only NR2B subunits are known to be critical for the development and function of the amygdala, which has a well established role in fear and other emotions, and in learning and memory. Drugs that block these receptors have been shown to block the formation of fearful memories and to reduce the anxiety associated with alcohol withdrawal in rodents.”

Your Gut Bacteria Are Under Constant Assault

Your lifestyle can and does influence your gut flora on a daily basis. For example, your gut bacteria are extremely sensitive to:

All of these common exposures can wreak havoc on the makeup of bacteria in your gut, but researchers are now increasingly looking at the cascading ill effects of antibiotics in particular.

Not only are antibiotics overused in medicine, the vast majority of these drugs enter you via livestock – you consume antibiotics every time you eat meat from an animal raised in a confined animal feeding operation (CAFO). In fact, about 80 percent of all the antibiotics produced are used in agriculture3 – not only to fight infection, but to promote unhealthy (though profitable) weight gain in the animals.

Early Use of Antibiotics Also Linked to Obesity

With that in mind, is it any wonder that researchers are now finding that antibiotics are associated with weight gain in humans as well?

“For many years now, farmers have known that antibiotics are great at producing heavier cows for market,” Dr. Jan Blustein, MD, PhD, professor of population health and medicine told PreventDisease.com in a recent article.4 “While we need more research to confirm our findings, this carefully conducted study suggests that antibiotics influence weight gain in humans, and especially children…”

According to The Washington Post:5

“The use of antibiotics in young children might lead to a higher risk of obesity, and two new studies, one on mice and one on humans, conclude that changes of the intestinal bacteria caused by antibiotics could be responsible. Taken together, the New York University researchers conclude that it might be necessary to broaden our concept of the causes of obesity and urge more caution in using antibiotics.”

The first study, published in the journal Nature6, found that young mice treated with low doses of common antibiotics gained 10-15 percent more fat than the untreated controls. After surveying the gut bacteria in the mice, they found that mice treated with antibiotics had a different composition of gut bacteria compared to the untreated mice. Specifically, certain species of bacteria previously shown to be associated with obesity were found in higher concentrations in the treated mice. Furthermore, after genetic analysis of the bacteria’s metabolism, they discovered that genes responsible for fat synthesis had greater levels of activity in the treated mice.

According to lead author Martin Blaser:7

“The rise of obesity around the world is coincident with widespread antibiotic use, and our studies provide an experimental linkage. It is possible that early exposure to antibiotics primes children for obesity later in life.”

The co-author Dr Ilseung Cho added:8

“By using antibiotics, we found we can actually manipulate the population of bacteria and alter how they metabolize certain nutrients. Ultimately, we were able to affect body composition and development in young mice by changing their gut microbiome through this exposure.”

The second study, published in the International Journal of Obesity9, aimed to corroborate these findings in human subjects. The study, which included more than 10,000 children, found that treating babies with antibiotics before the age of six months old appears to predispose them to being overweight in childhood. Children exposed to antibiotics between the ages of six to 14 months did not have significantly higher body mass than unexposed children.

While this study does not prove causation between antibiotic use in infancy and later obesity, it does show a correlation, and the mechanism appears to be related to the way antibiotics alter your child’s gut flora. However, excess weight is not the only, or the worst problem that such imbalance can create. As previously explained by Dr. Natasha Campbell-McBride, children with imbalanced gut flora are more prone to develop neurological disorders, such as ADD/ADHD and various learning disorders. These children are also more prone to vaccine damage.

Prebiotics Research Highlighted at American Chemical Society Meeting

Increasingly, researchers are finding that proper nutrition is not just about getting the right kind and amount of nutrients needed for biological processes. You also need to nourish these non-human cells in your body, i.e. your gut microflora. This issue was recently raised at the 244th National Meeting & Exposition of the American Chemical Society. According to a recent article in NewHope360:10

“‘Just as people need food to thrive, so do the billions of healthful bacteria that live in our guts, our gastrointestinal tract,’ [Robert] Rastall [Phd] explained. ‘There’s a large and expanding body of scientific evidence that bacteria in the gut play a role in health and disease. Prebiotics are foods that contain nutrients that support the growth and activity of these friendly bacteria.’

Rastall contrasted prebiotics to the more familiar probiotics, already being promoted on the labels of food like yogurt and some dietary supplements.

Probiotic foods actually contain friendly bacteria like Lactobacillus acidophilus believed to release healthful substances as they grow in the GI tract. Prebiotics are indigestible food ingredients that provide no nutrition to people. Their purpose is to nourish the friendly bacteria among the estimated 100 trillion microbes living inside the human GI tract.”

While raised awareness about the importance of prebiotics and probiotics is good news, it comes with the territory that researchers are also working on ways to produce prebiotics that can easily be added to processed foods. Pre- and probiotics are very sensitive to heat, and excessive heat-treatment is a hallmark of most processed foods. It therefore stands to reason that any prebiotic inventions they come up with for the processed foods market will inevitably be of inferior quality, and I strongly recommend avoiding any and all processed foods that proclaim to contain prebiotics or probiotics, and stick with the real thing, i.e. traditionally fermented foods for healthful probiotics, and unprocessed whole foods for prebiotics, such as onions and garlic.

Study Finds “Clear Link” Between Inflammation, Bacterial Communities and Cancer

Demonstrating just how far-reaching the health impact of the bacterial balance in your gut can be, another recent study claims the key factor behind cancer appears to be ecological rather than genetic.11

Published in the journal Science12, the study suggests cancer may be due to a chain reaction that starts with inflammation that disrupts your gut ecosystems, allowing pathogens, such as E.coli, to invade your gut and cause cellular damage. The presence of E.coli was increased by a factor of 100 by inflammation, and 80 percent of germ-free mice infected with E.coli developed colorectal cancer, while germ-free mice inoculated with another common gut bacterium remained cancer-free, although these mice, like the others, did develop severe colitis (gut inflammation).

According to a press release by the University of North Carolina:13

“In a series of experiments conducted with mice prone to intestinal inflammation, the researchers found that inflammation itself causes significant simplification in diverse communities of gut microbes and allows new bacterial populations to establish major footholds. Among the bacterial taxa invading the disturbed intestinal ecosystem, the research team found a greatly increased presence of E. coli and related bacteria.

By putting E. coli bacteria into mice that were raised under sterile conditions, the team also found that the presence of E. coli promoted tumor formation. When regions of the E. coli genome known to be involved in DNA damage were removed, the ability of the E. coli to cause tumors was substantially decreased.

The researchers noted that the mouse results may have implications for human health as well, as they also found an E. coli variant with the suspect genes in high percentages of human patients with colorectal cancer and irritable bowel disease.

…’As is usual in human studies, we didn’t have cause and effect,’ Fodor noted. ‘We don’t know if microbes are somehow causing conditions to shift in the gut that would cause cancer or if there are conditions that are associated with cancer that would increase the openness of the gut to particular microbes. A shift in the microbial community is associated with inflammation… It is interesting that the microbial community is actually changing with the disease state, which indicates that it is either responding to or contributing to the disease state.'”

Like Bacteria, Cancer Cells Rely on Communication and Cooperation

In related news, an article published in Trends in Microbiology14 examines the shared traits of cancer cells and bacteria. Bacteria and cancer cells both use sophisticated communication to gain supremacy within the host. As reported by Medical News Today:15

“Inspired by the social and survival tactics of bacteria, the team presents a new picture of cancer as a meta-community of smart communicating cells possessing special traits for cooperative behavior. Using intricate communication, cancer cells can distribute tasks, share resources, differentiate, and make decisions. Before sending cells to colonize organs and tissues throughout the body (metastasis), ‘spying cells’ explore the body and return the cancer’s origin. Only then do metastatic cells leave the primary tumor and navigate to new posts.

Also like bacteria, cancer cells change their own environment. They induce genetic changes and enslave surrounding normal cells, forcing them to do the disease’s bidding – providing physical support, protecting them from the immune system, and more.”

Three years ago, I posted a TED video featuring Bonnie Bassler, in which she discusses how bacteria “talk” to each other using a chemical language that lets them coordinate defense and mount attacks. Cancer cells, as it turns out, employ similar forms of communication, and as discussed by Bassler, these discoveries pave the way for the development of drugs aimed at shutting down or altering cell-to-cell communication.

According to Medical News Today:

“The team also suggests further research into cancer ‘cannibalism,’ when cancer cells may consume their peers when they run out of resources. The idea is to send signals which trigger cancer cells to kill each other, which can be done with bacteria. Other researchers have demonstrated that injected bacteria can ‘outsmart cancer.’ Bacteria can be used to induce gap junctions between the cancer cells and immune cells, ‘teaching’ the immune system to recognize and kill the tumor cells.”

The Phenomenal Health Benefits of Fermented Vegetables

Cultured or fermented foods have a very long history in virtually all native diets, and have always been highly prized for their health benefits. The advent of processed foods dramatically altered the human diet, and we’re now reaping the results in the form of rapidly rising chronic health problems. I believe the shunning of traditionally fermented foods has a lot to do with this.

The culturing process produces beneficial microbes that are extremely important for your health as they help balance your intestinal flora. If you do not regularly consume the traditionally fermented foods below, a high-quality probiotic supplement will provide similar benefits:

  • Fermented vegetables
  • Lassi (an Indian yoghurt drink, traditionally enjoyed before dinner)
  • Fermented milk, such as kefir (a quart of unpasteurized kefir has far more active bacteria than you can possibly purchase in any probiotics supplement)
  • Natto (fermented soy)

When choosing fermented foods, steer clear of pasteurized versions, as pasteurization will destroy many of the naturally occurring probiotics. This includes most of the “probiotic” yogurts you find in every grocery store these days; since they’re pasteurized, they will be associated with all of the problems of pasteurized milk products and they typically contain added sugars, high fructose corn syrup, artificial coloring, or artificial sweeteners, all of which will only worsen your health.

Fermented foods are also some of the best chelators and detox agents available, meaning they can help rid your body of a wide variety of toxins, including heavy metals.

When you first start out, you’ll want to start small, adding as little as half a tablespoon of fermented vegetables to each meal, and gradually working your way up to about a quarter to half a cup (2 oz to 4 oz) of fermented vegetables or other cultured food with one to three meals per day. Since cultured foods are efficient detoxifiers, you may experience detox symptoms, or a “healing crisis,” if you introduce too many at once.

Learn to Make Your Own Fermented Vegetables

Fermented vegetables are easy to make on your own. It’s also the most cost-effective way to get high amounts of healthful probiotics in your diet. To learn how, review the following interview with Caroline Barringer, a Nutritional Therapy Practitioner (NTP) and an expert in the preparation of the foods prescribed in Dr. Natasha Campbell-McBride’s Gut and Psychology Syndrome (GAPS) Nutritional Program. In addition to the wealth of information shared in this interview, I highly recommend getting the book Gut and Psychology Syndrome, which provides all the necessary details for Dr. McBride’s GAPS protocol.

Although you can use the native bacteria on cabbage and other vegetables, it is typically easier to get consistent results by using a starter culture. Caroline prepares hundreds of quarts of fermented vegetables a week and has found that she gets great results by using three to four high quality probiotic capsules to jump start the fermentation process.

Caroline prepares the vegetables commercially and I used hers for a month before I started making my own. So, if you just want to put your toe in the water and see if you like them, you can order a jar or two and try them out. You can find her products on www.CulturedVegetables.net or www.CulturedNutrition.com.

AVOID This to Optimize Your Gut Flora!

Along with eating naturally fermented foods and/or taking a high-quality supplement, it’s essential that you avoid sugar, including fructose. Sugar nourishes pathogenic bacteria, yeast, and fungi in your gut, which may actually harm you more than its impact on insulin resistance. One of the major results of eating a healthy diet like the one described in my nutrition plan is that you cause your beneficial gut bacteria to flourish, and they secondarily perform the real “magic” of restoring your health.

Remember, an estimated 80 percent of your immune system is located in your gut, which is just one more reason why “tending to” your gut microflora is an essential element of good health. A robust immune system, supported by your flourishing inner ecosystem, is your number one defense against ALL disease, from the common cold to cancer.

I feel very strongly that if we can catalyze a movement to get more people to implement this ancient dietary wisdom to their normal eating patterns, then we’ll start seeing a radical change in health.

Sources and References

Source: Dr. Mercola