Πέμπτη, 18 Απριλίου 2019

White spots on tongue


A tongue is often called "the strongest muscle of the body". It is made up of a group of muscles which allow us to taste the food, swallow, and talk. A healthy tongue is of pink color and covered with small nodules called papillae.

There are lots of small spots on the tongue for taste and sensation. Usually, they are not very noticeable. But if spots are of an unusual color, cause irritation, or other symptoms accompany them, they can be the sign of a health problem.

Tongue spots can be uncomfortable and painful, but they are usually not so serious. Often, they resolve without any treatment. But, some spots on the tongue, might signal a severe underlying problem which needs quick medical attention. You may identify the cause of some spots easily, but others require further examination.

Healthy tongue spots
There are four kinds of healthy spots which naturally appear on your tongue. The medical term used for these spots is papillae.

• Fungiform papillae; these are the small spots which appear all over the tongue. A person has 200 to 400 of these. Mostly, they are present at the tip and edges of your tongue. Each of these papillae contains 3 to 5 taste buds.
• Circumvallate papillae; are bigger spots which appear at the back of the tongue. They are slightly raised and are arranged in a 'v' shape. Usually, an individual has 7 to 12 spots, with each comprising thousands of taste buds.
• Foliate papillae; appear on the back and at the edges of the tongue. A person usually has around 20, each one containing hundreds of taste buds.
• Filiform papillae; are found at the front of the tongue. There are more of this type of papillae than any other and they do not contain taste buds.

The basic purpose of papillae is to help people to sense and taste with the tongue. However, nerves which send messages about flavor to the brain are connected to these taste buds. Papillae also play an important role in giving information about temperature, chewing food, and speaking.

Unusual white spots on the tongue
White spots on the tongue may be a harmless sign of adequate dehydration which needs no interference or it may appear as a disturbing feature of a primary organic condition. Most of the time, white spots are due to the gathering of bacteria, cellular debris, and dead cells which gives the tongue a white appearance.

Serious conditions which may present with white spots on the tongue comprise various fungal or bacterial infections or in some cases pre-cancerous disorders of the tongue or oral cavity. There are several infectious conditions which may present with different changes in tongue appearance. Leukoplakia is one of such conditions.

What is leukoplakia?
Leukoplakia is a Greek word which means 'white patch'. These white patches develop on the tongue, the inside of the cheek, or on the floor of the mouth. Basically, it is the mouth's reaction to continuing irritation of the mouth's mucous membranes. But its actual cause is unknown. Furthermore, these patches can occur at any stage of your life. But they are most common in senior adults.

"Hairy" leukoplakia is an uncommon form of leukoplakia. It is caused by the Epstein-Barr virus. However,this uncommon form is seen only in people infected with HIV, have AIDS, or AIDS-related complex.

It consists of uncertain, white patches on the tongue and less frequently, somewhere else in the mouth. Leukoplakia also has some resemblance with thrush which is an infection caused by the fungus Candida. It is common in adults, usually occurs if the immune system is not working suitably.

Causes of leukoplakia
As you use your tongue continually, it can be uncomfortable when you experience tongue problems, counting soreness and discoloration. Therefore, there are many causes for a number of common tongue signs. Causes of leukoplakia can include;

Irritation from rough teeth, fillings, or crowns, or ill-fitting dentures which rubs against cheek or gum
Sun exposure to the lips
Oral cancer (though rare)
Tobacco use, chronic smoking, or other pipe smoking
Symptoms of leukoplakia
The white or gray colored patches commonly develop on your tongue in leukoplakia. But their occurrences in gums, a roof of the mouth, or the inside of the cheeks of mouth may also be a sign of leukoplakia.

These patches may develop slowly over weeks to months. They can be thick, slightly raised, and may ultimately take on a tough and rough texture. Usually, it is painless, but may be sensitive to heat, touch, spicy foods, or other irritation.

Diagnosis of leukoplakia
Your dentist may diagnose leukoplakia upon proper inspection; however, a biopsy will possibly be taken to rule out other causes, like oral cancer. For proper examination in the lab, a small piece of tissue from the lesion will be removed during biopsy. Moreover, a distressing agent will be used so that you will not feel any pain.

Treatment for Leukoplakia
Treatment for leukoplakia involves the removal of the source of irritation. For instance, if leukoplakia is caused by an irregular tooth or a rough surface on a denture or a filling, the tooth will be leveled and dental appliances fixed. If smoking is the cause of leukoplakia, you will be asked to reduce or stop smoking or using other tobacco products.

Usually, leukoplakia is harmless, and lesions clear in a few weeks or months after the removal of a source of irritation. If elimination of the source of irritation is ineffective and it does not reduce leukoplakia, the lesion may need to be removed surgically.

For that, the lesion can be removed either by your dentist or by an oral surgeon. However, hairy leukoplakia needs treatment with antiviral medication.

Here are some tips which can aid you to steer away from white spots on your tongue;

To reduce the chance or the recurrence of white spots on the tongue, try to maintain high dental care standards. Properly brushing your teeth and staying hydrated makes the environment inappropriate for bacterial growth. Antibacterial mouthwash can also be used for better results.
Avoid over spiced and acidic foods. Furthermore, try to avoid food that increases the chances of getting damaged. Spicy foods aggravate the lining of the tongue and mouth.
Avoid excessive alcohol intake and smoking as these could increase chances of oral cancers.
Limit sugar intake as sugar is a breeding place for oral bacteria.
Try to use home remedies such as salt water and baking soda to get rid of bacteria.
You can prevent or get rid of tongue problems by practicing some good dental hygiene. Brush and floss regularly. Moreover, regularly see your dentist for checkups and cleanings.

Ilene Johnstone
Ilene Johnstone is an author at Top Health Journal. Currently, she is working as a biochemist and researcher. She is keen on emerging research, diet, new treatments, diseases and other trending topics in health. She delivers best regarding health to viewers in the form of interesting writings.
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Sinus congestion: natural home remedies

How can you clear up sinus congestion?
By Timothy Huzar Reviewed by J. Keith Fisher, M.D.
Home remedies Over-the-counter medication When to see a doctor Summary
Sinus congestion occurs when a condition causes fluid to become trapped in the sinuses, making them feel blocked and painful. Many natural home remedies can help a person feel better, including hydration, steam inhalation, and applying a warm, wet towel to the face.
A virus or cold is the most common cause of sinus congestion, but a bacterial infection can also occasionally cause it. According to the Centers for Disease Control and Prevention (CDC), a person with sinus congestion may experience:

a blocked or runny nose
a sore throat
This article looks at six simple, natural home remedies for sinus congestion, as well as when to see a doctor.

Home remedies
There are many home remedies that a person can try to help relieve sinus congestion. These include:

1. Staying hydrated
The mucous membranes can become inflamed during sinus congestion. However, staying hydrated can help the membrane function correctly.

Drinking plenty of water and other fluids may help relieve the symptoms of sinus congestion. A person may find that keeping a water bottle close to them throughout the day can encourage them to drink more.

2. Breathing in steam
Inhaling steam which can help with sinus congestion
Inhaling steam can help with sinus congestion.
Breathing in steam can help keep the mucous membranes moist.

This is particularly important during winter or in colder climates.

This may help relieve the symptoms of sinus congestion and encourage the sinuses to unblock.

Running very hot water from a shower and breathing in the vapor may help unblock the sinuses and relieve symptoms.

It is also possible to use a humidifier for the same purpose.

3. Raising the head during sleep
To help encourage sinus blockages to clear, a person may consider raising their head during sleep. A person can use extra pillows to prop their head up.

Conversely, keeping the head level may result in a greater buildup of congestion overnight.

4. Using eucalyptus oil
Eucalyptus oil relieves the symptoms of sinus congestion. It may also help kill germs in and around the nasal passage that contribute to a sinus infection.

A person can use eucalyptus oil by applying it to tissue paper and sleeping next to it, or by adding it to hot water and inhaling the steam. However, if a person applies the hot water and eucalyptus oil mixture directly to the skin, it may cause burns.

Menthol-based oils are also popular, but they work by making a person feel as though they can breathe more easily. They do not unblock the congested sinuses.

5. Applying warm, wet towels
A warm, wet towel held against the face may help relieve the swelling and inflammation of sinus congestion.

It may also help keep the mucous membranes moist by breathing in moist air, which can help it function properly.

People can also soak a towel in warm water, wring it out, and drape it over their face in a way that is still comfortable for them to breathe through their mouth.

6. Trying a neti pot
oman using a neti pot to clear her nose of congestion
A neti pot can help to relieve the symptoms of sinus congestion.
Neti pots are small teapot-shaped devices that help a person pour a salt water solution into their nasal cavity.

This may help relieve the symptoms of sinus congestion by keeping the mucous membranes moist and functioning properly.

Neti pots may also help treat congestion by flushing out the sinuses and the buildup of any material causing a blockage. It is vital to follow instructions carefully.

The United States Food and Drug Administration (FDA) note that if a person has not properly cleaned the neti pot before using it, it might actually cause a sinus infection. People should clean neti pots using distilled, sterile, or previously boiled water that is free of harmful germs.

Over-the-counter medication
Nasal sprays that include a decongestant may be helpful in relieving congested sinuses.

However, Harvard Medical School point out that decongestants can also cause problems. For example, sometimes, congestion can become worse after a person stops using decongestants.

Taking painkillers may also help relieve pain due to sinus congestion.

If a person experiences side effects or the medication is not working, they should speak to a medical professional.

What is the best remedy for sinus drainage?
What is the best remedy for sinus drainage?
Draining the sinuses can help relieve congestion. Learn about the best ways to drain the sinuses here.
When to see a doctor
Though a person can usually resolve sinus congestion using home remedies, complications can arise. In these cases, seeing a medical professional is important.

The CDC recommend seeing a medical professional if a person has:

a temperature above 100.4F (38C)
symptoms that are worsening
symptoms that have not gone away after 10 days
frequent sinus issues
symptoms that over-the-counter (OTC) medication does not resolve
Sinus congestion most commonly occurs as a result of a cold, virus, or bacterial infection. Symptoms include a sore throat, a runny nose, and coughing, among others.

There are a number of simple home remedies that a person can try to help relieve these symptoms. These include inhaling steam, using eucalyptus oil, and staying hydrated. A person can also use OTC medications such as nasal sprays.

They should consider seeing a doctor when their symptoms do not go away or become worse, and the doctor will be able to work out what is causing a person's infection and prescribe appropriate medication if necessary.


What is frontal sinusitis and what causes it?
The sinuses are cavities that produce mucus. If a person has frontal sinusitis, the cavities just behind the eyes become inflamed, and the mucus cannot drain correctly. Infections, allergies, or long-term health issues may be responsible. Here, we examine the causes of frontal sinusitis and how treatments vary.

How do I know if I have a cold or sinusitis?
The symptoms of a sinus infection are very similar to those caused by a cold, but if symptoms continue for some time, medical help may be needed. Learn how to spot symptoms caused by sinus infection. Get some tips for home remedies and other treatments, and find out when to see a doctor.

Common symptoms of a sinus infection
Sinus infections, or sinusitis, occur when a virus of bacteria enters the sinuses. The symptoms of sinusitis are similar to a cold, but it also involves a feeling of pressure and congestion in the sinuses. Read on for a list of common symptoms and treatments for sinus infections.

How can you unblock your ear?
A clogged ear can happen for a variety of reasons. It can be a buildup of wax or caused by a cold or sinus infection. Thankfully, many cases of a clogged ear can be treated with some simple home remedies. These include ear irrigation, steam inhalation, or simply ear drops. Learn about home remedies plus what not to do.

Everything you need to know about sinus infection
The sinuses behind the nose can become inflamed for a variety of reasons. This MNT Knowledge Center article explains the symptoms of sinus infection, also known as sinusitis. Sinus infection is one of the most commonly diagnosed infections in the U.S. This article shows how it can complicate and what types there are.
Additional information
Article last reviewed by Wed 28 November 2018.

Visit our Flu / Cold / SARS category page for the latest news on this subject, or sign up to our newsletter to receive the latest updates on Flu / Cold / SARS.

All references are available in the References tab.

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Nasal mucus transplant

Believe it or snot: St. Paul's nasal mucus transplant study targets inflamed sinuses
In the first study of its kind, patients with chronic sinus conditions will get transplanted nasal mucus from close relatives with healthy snot.

Dr. Amin Javer, with study subject Maggie Bernet, shows how photodynamic therapy — a blue-light treatment that sterilizes the nasal cavity as it kills bacterial and viruses — works as part of the broader nasal mucous transplant study at St. Paul's Hospital.
Dr. Amin Javer, with study subject Maggie Bernet, shows how photodynamic therapy — a blue-light treatment that sterilizes the nasal cavity as it kills bacterial and viruses — works as part of the broader nasal mucous transplant study at St. Paul's Hospital. NICK PROCAYLO / PNG

There's healthy snot, then there's the other kind. And now those with good nasal mucus will be donating their slimy stuff to relatives suffering from chronically inflamed sinuses in a novel transplantation study at St. Paul's Hospital.

Study leader Dr. Amin Javer said in an interview the inspiration for the chronic rhinosinusitis (CRS) study is the success of fecal transplants for inflammatory bowel diseases and colitis caused by Clostridium difficile (C-diff). A member of his research team — epidemiologist Amee Manges — has been involved in several human microbiome studies related to the higher risk of hospitalized patients getting potentially deadly C-diff infections.

Just as in bowel disorders, good microorganisms — known as microbiome — in the sinus are disrupted and outnumbered by slimy groups of damaging bacterial and/or viral micro-organisms. Antibiotic therapy is not only often useless but often more damaging since antibiotics cut a wide swath, taking down good bacteria along with the bad.

The chronic sinus condition is common; it is said to affect up to 12 per cent of the North American population. Indeed, the hospital clinic gets 6,000 outpatient visits a year, many of them patients with the chronic sinus condition.

Ethics approval for the St. Paul's Hospital sino nasal microbiota transplant study, as it is called, has been granted by the hospital and the University of B.C. But Javer is waiting for final approval from Health Canada, which he expects to get next month.

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The study aims to answer whether transplants are both beneficial and safe in patients with the chronic condition. The working hypothesis is that inflammation, mucous discharge and recurring infections will indeed be improved by renewing and replenishing the sinus microbiome with healthy snot from donors.

What would recovery look like? No more constant coughing, no more blocked nasal passages, no more dripping from their noses, no more headaches, sinus infections, fatigue and poor sleep, among many other symptoms.

A patient getting photodynamic therapy with a blue light that sterilizes sinuses by killing bacterial and viral germs. (Photo: Handout)
A patient getting photodynamic therapy with a blue light that sterilizes sinuses by killing bacterial and viral germs. HANDOUT

Potential donors are now being screened and patients enrolled in the non-transplant arm of the study. Those patients will receive only photodynamic therapy — a blue-light treatment that sterilizes the nasal cavity as it kills all bacteria and viruses. While two-thirds of patients who get such treatment reportedly improve, the effect is short term. Just like antibiotics, it doesn't distinguish between beneficial germs and bad ones, so a small number of patients actually get worse.

A second group in the study will be randomized to phototherapy plus the transplant while a third will get only the transplant. About 200 participants will be enrolled in the study.

Former nurse Pat Taylor is one of the participants in the trial. She's been randomized to the branch of patients receiving only blue-light therapy. The Victoria resident said most people have no idea how life-altering and disabling chronic sinusitis is.

"It is financially, physically and emotionally debilitating with a poor quality of life. Many health professionals know little or nothing about CRS, so many people go undiagnosed," she said, adding that patients often bounce around between specialists like respirologists and allergists, often to no avail.

Javer echoes her sentiments. "Chronic sinusitis has been shown by research to totally ruin the quality of life of patients. It's a disease that creates so much emotional distress for people. I've got patients who tell me they'd rather be dead than endure all these symptoms. One patient from Prince George recently said to me that if I couldn't fix him, he'd rather I killed him."

Javer said he's convinced a "sinus probiotic" is needed to repopulate unhealthy sinus cavities with healthy microbes. Without a beneficial probiotic, harmful pathogens find a way to return and multiply in the nasal cavity, ensuring the recurrence of the sinus disorder.

'We think the transplants using healthy donor microbiome could drastically improve the long-term health of those with diseased sinuses," he said, adding that a recently started study in Sweden is also exploring the use of sinus microbiome transplants. In that study, phototherapy is not being used and no results have yet been reported.

Javer said research has not yet pointed to the cause of the sinus disorder but it starts when something alters the environment in the nasal/sinus cavity.

"It can be a virus or a cold that starts this cascade of symptoms, and what's worse is patients get antibiotics from their family doctors and the vast majority of them don't need them," said Javer. "Prescribing oral antibiotics when you aren't sure they are needed can be the worst thing you can do because they can alter the microbiome."

The $300,000 study is funded through private donations to a charitable foundation that Javer established at St. Paul's Hospital. The funds are earmarked for sinus disorders.

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Watch out for the symptoms of head and neck cancer - Make Sense Campaign



Be head and neck cancer aware
« HOME PAGE Dr. Vinayak Munirathnam
Watch out for the symptoms of head and neck cancer
According to oncologist, a lump in the neck can be the first sign.

By Dr. Vinayak MunirathnamApr 19,2019 8:30 IST
Head and neck cancers are curable if detected on time. Fortunately, these cancers produce symptoms early. Here are some of them.

A lump in the neck that lasts for more than two weeks. Not all lumps are cancerous. But a lump in the neck can be the first sign of cancer of the mouth, throat, voice box (larynx), or salivary glands.
Such lumps are generally painless. Commonly, antibiotics are prescribed as an initial mode of treatment under the assumption that the lumps have been caused due to an infection. If the lump persists or continues to grow despite the use of antibiotics, further investigation is essential.

Most cancers in the voice box cause a change in voice. If you find your voice becoming hoarse or if the change lasts for more than two weeks, you must visit an ENT.
Cancers of the mouth or tongue cause a sore or swelling that doesn't go away or may or may not be painless.
Bleeding may occur, but often not until late. If an ulcer or swelling is accompanied by lumps in the neck, you should seek medical advice.
Tumors in the nose, mouth, or throat can lead to blood in your saliva or phlegm. If this continues for more than a few days, you should consult a doctor.
Cancer of the throat may make swallowing solid foods (and sometimes liquids) difficult. You may also end up throwing up the food.
Most squamous cell cancers occur in the lower lip and ear. They might present as a sore which does not heal.
Constant pain in or around the ear when you swallow can be a sign of infection or tumor growth in the throat.

Nearly 90% of head and neck cancers are caused due to tobacco and alcohol consumption. Therefore, you must quit their usage immediately. In adults who do not smoke or drink, cancer of the mouth and throat can occur as a result of HPV infection. Prolonged exposure to sunlight is linked to lip cancer.

This article has been written by Dr. Vinayak Munirathnam, MBBS,MD,DM,Consultant Medical Oncologist, HCG Hospitals, Bangalore.



The above content has not been created by any HT Journalist or editorial team.
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Clinical Trials

Incentivizing healthy lifestyle behaviors to reduce cardiovascular risk in people with serious mental illness: An equipoise randomized controlled trial of the wellness incentives program

Publication date: June 2019

Source: Contemporary Clinical Trials, Volume 81

Author(s): Sarah I. Pratt, Mary F. Brunette, Rosemarie Wolfe, Emily A. Scherer, Haiyi Xie, Stephen Bartels, Joelle C. Ferron, Kelley Capuchino


Medicaid recipients with serious mental illness die 25–30 years earlier than people in the general population due to health conditions that are modifiable through lifestyle changes. Cardiovascular diseases from excess weight, smoking, and sedentary lifestyle contribute substantially to this life expectancy disparity. The current study evaluated the impact of incentives on participation in weight management programming (for overweight and obese adults) and smoking cessation treatment (for regular smokers).


Participants were Medicaid recipients with disabling mental illness receiving services at any one of 10 community mental health centers across New Hampshire. Using an equipoise stratified randomized design, n = 1348 were enrolled and assigned to one of four weight management programs (Healthy Choices Healthy Changes: HCHC) and n = 661 were enrolled and assigned to one of three smoking cessation interventions (Breathe Well Live Well: BWLW). Following assignment to an intervention, participants were randomized to receive financial incentives (to attend weight management programs, or to achieve abstinence from smoking) or not. Data were collected at baseline and every 3 months for 12 months.


New Hampshire's HCHC and BWLW programs were designed to address serious and preventable health disparities by providing incentivized health promotion programs to overweight/obese and/or tobacco-smoking Medicaid beneficiaries with mental illness. This study was an unprecedented opportunity to evaluate an innovative statewide implementation of incentivized health promotion targeting the most at-risk and costly beneficiaries. If proven effective, this program has the potential to serve as a national model for widespread implementation.

Proactive text messaging (GetReady2Quit) and nicotine replacement therapy to promote smoking cessation among smokers in primary care: A pilot randomized trial protocol

Publication date: May 2019

Source: Contemporary Clinical Trials, Volume 80

Author(s): G.R. Kruse, E. Park, J.E. Haberer, L. Abroms, N.N. Shahid, S.E. Howard, Y. Chang, J.S. Haas, N.A. Rigotti


Most smokers see a physician each year, but few use any assistance when they try to quit. Text messaging programs improve smoking cessation in community and school settings; however, their efficacy in a primary care setting is unclear. The current trial assesses the feasibility and preliminary clinical outcomes of text messaging and mailed nicotine replacement therapy (NRT) among smokers in primary care.


In this single-center pilot randomized trial, eligible smokers in primary care are offered brief advice by phone and randomly assigned to one of four interventions: (1) Brief advice only, (2) text messages targeted to primary care patients and tailored to quit readiness, (3) a 2-week supply of nicotine patches and/or lozenges (NRT), and (4) both text messaging and NRT. Randomization is stratified by practice and intention to quit. The text messages (up to 5/day) encourage those not ready to quit to practice a quit attempt, assist those with a quit date through a quit attempt, and promote NRT use. The 2-week supply of NRT is mailed to patients' homes.


Feasibility outcomes include recruitment rates, study retention, and treatment adherence. Clinical outcomes are assessed at 1, 2, 6, and 12-weeks post-enrollment. The primary outcome is ≥1self-reported quit attempt(s). Secondary clinical outcomes include self-reported past 7- and 30-day abstinence, days not smoked, NRT adherence, and exhaled carbon monoxide.


This pilot assesses text messaging plus NRT, as a proactively offered intervention for smoking cessation support in smokers receiving primary care and will inform full-scale randomized trial planning.

Specialized tobacco quitline and basic needs navigation interventions to increase cessation among low income smokers: Study protocol for a randomized controlled trial

Publication date: May 2019

Source: Contemporary Clinical Trials, Volume 80

Author(s): Amy McQueen, Christina Roberts, Rachel Garg, Charlene Caburnay, Qiang Fu, Jacob Gordon, Terry Bush, Robin Pokojski, Tess Thompson, Matthew Kreuter


Smoking in the United States follows a clear socioeconomic gradient: low-income Americans smoke more and quit less than those with more education and income. Evidence-based interventions like tobacco quitlines are designed to make effective cessation services available on a population basis to all smokers. However, these interventions do not address many of the unique challenges faced by low-income smokers, including unmet basic needs like food, housing, personal safety and money for necessities that often supersede health needs. Research is needed to maximize the use and effectiveness of tobacco quitlines in low-income populations. This paper details the rationale, design and methods for a 2 × 2 randomized controlled trial currently underway comparing the effects of Standard and Specialized Tobacco Quitlines with and without Basic Needs Navigation on intervention engagement and smoking cessation among low-income smokers. Smokers are recruited from United Way 2-1-1 in Missouri and all participants receive tobacco quitline services from Optum. Quitline and navigation services are provided for 3 months. Participants complete telephone surveys at baseline, 3- and 6-month follow up. The primary study outcome is self-reported 7-day point prevalence abstinence at 6-month follow up. Embedding the study in practice agencies will accelerate dissemination and scalability should our findings demonstrate intervention effectiveness.

Dose-response analysis of ranibizumab as-needed regimens for visual improvement in patients with diabetic macular edema using a modelling approach

Publication date: May 2019

Source: Contemporary Clinical Trials, Volume 80

Author(s): Yuan Xiong, Etienne Pigeolet, Zufar Mulyukov, Philippe Margaron, Amy Racine, Andreas Clemens


Ranibizumab and aflibercept are anti-vascular endothelial growth factor therapies for diabetic macular edema (DME) but have only been directly compared in one study: the Protocol T study, a 24-month randomized controlled trial which compared the safety and efficacy of three anti-VEGF agents (ranibizumab 0.3 mg, aflibercept 2.0 mg and bevacizumab 1.25 mg). The ranibizumab dose used in Protocol T is not licensed for use outside of the US, where a higher ranibizumab dose of 0.5 mg is approved. Therefore, the relevance of the head-to-head Protocol T study findings to healthcare providers in Europe is limited. The purpose of this research was to predict the visual outcomes that may have been achieved in Protocol T with ranibizumab 0.5 mg.


A simplified dose-response model was constructed to describe the relationship between average monthly dose and one-year best corrected visual acuity (BCVA) change from baseline. A linear mixed effects model was evaluated and Bayesian Monte-Carlo Markov chains method was used to estimate the model parameters.


If ranibizumab 0.5 mg PRN had been studied in Protocol T, it would have resulted in a BCVA gain of 14–15 early treatment diabetic retinopathy study (ETDRS) letters; 3–4 letters more than the actual BCVA gain reported with ranibizumab 0.3 mg PRN. In Protocol T patients with poor baseline BCVA (<69 letters), a similar additional letter gain would have been achieved.


The relevance of the Protocol T study findings are limited due to the use of ranibizumab 0.3 mg PRN which, based on the modelling approach reported herein, resulted in sub-optimal visual gains.

Design and recruitment of the randomized order safety trial evaluating resident-physician schedules (ROSTERS) study

Publication date: May 2019

Source: Contemporary Clinical Trials, Volume 80

Author(s): Terri Blackwell, Dana R. Kriesel, Eric Vittinghoff, Conor S. O'Brien, Jason P. Sullivan, Natalie C. Viyaran, Shadab A. Rahman, Steven W. Lockley, Laura K. Barger, Ann C. Halbower, Sue E. Poynter, Kenneth P. Wright, Pearl L. Yu, Phyllis C. Zee, Christopher P. Landrigan, Charles A. Czeisler, Katie L. Stone, for the ROSTERS Study Group


While the Accreditation Council for Graduate Medical Education limited first year resident-physicians to 16 consecutive work hours from 2011 to 2017, resident-physicians in their second year or higher were permitted to work up to 28 h consecutively. This paper describes the Randomized Order Safety Trial Evaluating Resident-physician Schedules (ROSTERS) study, a clustered-randomized crossover clinical trial designed to evaluate the effectiveness of eliminating traditional shifts of 24 h or longer for second year or higher resident-physicians in pediatric intensive care units (PICUs).


ROSTERS was a multi-center non-blinded trial in 6 PICUs at US academic medical centers. The primary aim was to compare patient safety between the extended duration work roster (EDWR), which included shifts ≥24 h, and a rapidly cycling work roster (RCWR), where shifts were limited to a maximum of 16 h. Information on potential medical errors was gathered and used for classification by centrally trained physician reviewers who were blinded to the study arm. Secondary aims were to assess the relationship of the study arm to resident-physician sleep duration, work hours and neurobehavioral performance.


The study involved 6577 patients with a total of 38,821 patient days (n = 18,749 EDWR, n = 20,072 RCWR). There were 413 resident-physician rotations included in the study (n = 203 EDWR, n = 210 RCWR). Resident-physician questionnaire data were over 95% complete.


Results from data collected in the ROSTERS study will be evaluated for the impact of resident-physician schedule roster on patient safety outcomes in PICUs, and will allow for examination of a number of secondary outcome measures.

ClinicalTrials.gov Identifier: NCT02134847

Evaluation of worldwide clinical trials by gender: An FDA perspective

Publication date: May 2019

Source: Contemporary Clinical Trials, Volume 80

Author(s): Emily Ayuso, Ruth J. Geller, Junyang Wang, John Whyte, Marjorie Jenkins


The US Food and Drug Administration (FDA) has undertaken efforts to promote representation of women in clinical trials. The objectives of this research are to assess women's participation in clinical trials from a global perspective and to analyze the demographic characteristics of clinical trial participants.


FDA's Center for Drug Evaluation and Research-Professional Affairs and Stakeholder Engagement (CDER/PASE) and Office of Women's Health (OWH) collaborated to evaluate demographic data (race, ethnicity, gender, and age) of pivotal trials of New Molecular Entities (NMEs) approved in 2015–2016 by geographic location. One hundred fifty-four pivotal clinical trials supporting 66 NMEs were identified, and the research team analyzed demographic characteristics of 131,749 participants from 70 countries.


U.S. sites contributed 31% of the 131,749 study participants. On the country level, the United States contributed the largest number of participants and other individual countries contributed 5% or less of the total trial population. Overall, 43% (n = 56,272) of the 131,747 clinical trial participants were women. Of the 40,833 U.S. participants, 49% were women as compared to 40% of the 90,914 non-U.S. participants. Similar levels of participation were seen after the exclusion of sex-specific drug indications, and by therapeutic area for U.S. and non-U.S. sites.


Clinical trials are becoming increasingly multi-national, and the increasing representation of women across countries is promising. FDA approval processes ensure that global data used in the drug approval process meets regulatory standards and that data can be generalized to the U.S. population.

Care partner problem solving training (CP-PST) for care partners of adults with traumatic brain injury during inpatient rehabilitation: Study protocol for a multisite, randomized, single-blind clinical feasibility trial

Publication date: May 2019

Source: Contemporary Clinical Trials, Volume 80

Author(s): Shannon B. Juengst, Valeria Silva, Yelena Goldin, Keith Cicerone, Jean Lengenfelder, Nancy Chiaravalloti, Simon Driver, David Mellick, Georgianna Dart, Chung Lin Kew, Andrew Nabasny, Kathleen R. Bell


Traumatic brain injury (TBI) often leads to immediate and chronic functional impairments that affect care partners, or those providing physical and/or emotional support to individuals with TBI. The many challenges associated with being a care partner often lead to caregiver burden and can compromise the well-being and quality of life of care partners and individuals with TBI under their care. Equipping care partners with problem-solving skills could facilitate and sustain their transition into this supportive role. Problem-solving training (PST) has demonstrated efficacy for providing such skills to care partners of individuals with TBI after discharge from inpatient rehabilitation. We propose that PST delivered to care partners during inpatient rehabilitation of individuals with TBI will provide care partners with the skills to manage their caregiving roles across the transition from hospital to home. Herein, we describe the methodology of a current randomized controlled trial that examines the feasibility and efficacy of PST plus TBI education compared to TBI education alone to improve care partner burden, emotional distress, and adaptive coping when delivered during the inpatient rehabilitation stay of individuals with moderate-severe TBI.

Design and patient characteristics of the randomized controlled trial TExT-MED + FANS A test of mHealth augmented social support added to a patient-focused text-messaging intervention for emergency department patients with poorly controlled diabetes

Publication date: May 2019

Source: Contemporary Clinical Trials, Volume 80

Author(s): Elizabeth Burner, Janisse Mercado, Antonio Hernandez-Saenz, Anne Peters, Lourdes Baezconde-Garbanati, Sanjay Arora, Shinyi Wu


Although diabetes is a nationwide epidemic, US Latinos are a particularly vulnerable population. Culturally appropriate interventions can combat this disparity, especially those that increase social support. However, these interventions face significant cost and time barriers, which mHealth (mobile health) may overcome. This trial examines the benefit of adding social support to an existing text-message based, patient-focused mHealth intervention for emergency department patients with poorly controlled diabetes. Family members and friends of patients were randomized to mHealth augmented social support training (daily text-messages that synchronize with the patient messages) or a pamphlet based training (the same content mailed to their house.) We hypothesize that patients who received mHealth augmented social support will have a larger improvement in diabetes management (glycosylated hemoglobin or A1C) than those receiving standard support at six-months, and that improvement will be sustained at twelve-months. Secondary patient outcomes are clinical (weight, blood pressure), behavioral (medication adherence, self-care activities) and psychosocial (general and diabetes-specific social support, self-efficacy, diabetes-related distress, depression, fatalism and quality of life). We screened 2004 patients and enrolled 166 patient/supporter dyads. 70% of patients are Spanish-speaking, 51% female, with a mean A1C of 10.8. We employed innovative measures to remotely enroll family members and support a bilingual population, which will assist other investigators in design of similar trials. The findings of our trial will have real-world applicability for clinicians, health system administrators, health educators and mHealth developers who aim to improve the health of this vulnerable population.

Social incentives to encourage physical activity and understand predictors (STEP UP): Design and rationale of a randomized trial among overweight and obese adults across the United States

Publication date: May 2019

Source: Contemporary Clinical Trials, Volume 80

Author(s): Joseph D. Harrison, Jeremy M. Jones, Dylan S. Small, Charles A.L. Rareshide, Gregory Szwartz, David Steier, James Guszcza, Pameljit Kalra, Brian Torio, Gregory Reh, Victoria Hilbert, Mitesh S. Patel


Less than half of adults in the United States (US) obtain the recommended level of physical activity. Social incentives, the influences that impact individuals to adjust their behaviors based on social ties or connections, are ubiquitous and could be leveraged within gamification interventions to provide a scalable, low-cost approach to increase engagement. Gamification, or the use of game design in non-game situations, is commonly used in the real world, but in most cases has not appropriately leveraged principles from theories of health behavior.


We are conducting a four-arm, randomized, controlled trial of 602 overweight and obese adults to evaluate the effectiveness of gamification interventions that leverage insights from behavioral economics to enhance either supportive, competitive, or collaborative social incentives. Daily step counts are monitored using wearable devices that transmit data to the study platform. Participants established a baseline step count, selected a step goal increase, and then were randomly assigned to control or one of three interventions for a 24-week intervention and 12-week follow-up period. To understand predictors of strong or poor performance, we had participants complete validated questionnaires on a range of areas including their personality, risk preferences, social network, and habits relating to physical activity, eating, and sleep. Trial enrollment was conducted in partnership with Deloitte Consulting and included employees from 40 states across the US.


The STEP UP Trial represents a scalable model and interventions found to be effective could be deployed more broadly to increase physical activity.

Trial registration

Clinicaltrials.gov Identifier: NCT03311230

Effectiveness of shortened time interval to postpartum visit in improving postpartum attendance: Design and rationale for a randomized controlled trial

Publication date: Available online 18 April 2019

Source: Contemporary Clinical Trials

Author(s): Saba W. Masho, Timothy O. Ihongbe, Wen Wan, Whitney C. Graves, Nicole Karjane, Pamela Dillon, Gloria Bazzoli, Elizabeth McGee


Recent evidence suggests that there are numerous benefits to scheduling postpartum visits as early as 3 weeks post-delivery. However, findings are not conclusive due to methodological limitations. This report discusses the unique aspects of a randomized controlled trial's (RCT) design, intervention, and strategies to maintain participant retention.


This study was a four-year, prospective, open-label RCT conducted at the Virginia Commonwealth University Medical Center. Women who recently delivered a healthy, full-term baby vaginally, were randomized to receive a 3–4 or 6–8 weeks postpartum appointment and were followed for 18 months.


A total of 364 women participated in this study. A large proportion of women were retained in the study as demonstrated by the high completion rates at the 18-month follow-up interview (Total sample: 87.6%; 3–4 weeks group: 88.0%; 6–8 weeks group: 87.3%). Similarly, high adherence to the protocol-directed postpartum visit schedule was reported in the overall study sample (79.7%), as well as in the 3–4 (70.5%) and 6–8 (90.0%) week postpartum groups.


The study design offered unique features which ensured excellent participant completion and adherence rates, despite the presence of hard-to-track women who typically do not return for their postpartum visits.

Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00306932607174,00302841026182,alsfakia@gmail.com


Anterior ischemic stroke: Comparison of two clinical outcome prediction scores through the investigation of cerebral collaterals using multiphase CT angiography

Publication date: Available online 12 April 2019

Source: Journal of Neuroradiology

Author(s): A. Nigron, N. Bourgois, S. Dao, C. Lambert, M. Perrier, S. Akono, R. Moreno, E. Chabert, B. Jean, B. Claise, L. Gerbaud, L. Boyer, A. Zerroug


Purpose: To compare the evaluation of collaterals on multiphase computed tomography (CT) angiography using the score proposed by the reference study by Menon BK et al. and the Alberta Stroke Program Early CT (ASPECT) score for the prediction of favorable clinical outcome in patients with anterior ischemic stroke (IS).

Materials and Methods: Retrospective single center study including 199 patients with anterior ischemic stroke and evaluated using multiphase CT angiography. Collaterals were assessed using the reference score and ASPECT score. The early clinical outcome (National Institute of Health Stroke Score (NIHSS) over day 1) and later clinical outcome (90-day modified Rankin Scale (mRS)) were collected. The primary analysis related to the association between collateral scores and clinical outcome.

Results: Collaterals are an independent predictive factor of favorable clinical outcome with the two scores, ranging from an odds ratio (OR) [95% confidence interval (CI)] = 1.84 [1.23; 2.76], p = 0.003 for the reference score to an OR [95% CI] = 2.63 [1.21; 5.73], p = 0.015 for the phase 3 ASPECT score. The phase 3 ASPECT score offers better sensitivity (Se) for the prediction of a favorable clinical outcome (Se = 95%, specificity (Sp) = 37% for a threshold of 7/7) than the reference score (Se = 83%, Sp = 47% for a threshold of 4/5).

Conclusion: This study demonstrates the value of the ASPECT score in analyzing collaterals using multiphase CT angiography for the prediction of clinical outcome.

Fusion Imaging of Time Resolved Imaging of Contrast KineticS (TRICKS) and High Resolution Volumetric T2 MR Sequences in the Evaluation of Spinal Vascular Malformations

Publication date: Available online 11 April 2019

Source: Journal of Neuroradiology

Author(s): Satyanaryana Mandalapu, Santhosh Kannath, Chandrasekharan Kesavadas

Number of Stentriever Passes and Outcome after Thrombectomy in Stroke

Publication date: Available online 11 April 2019

Source: Journal of Neuroradiology

Author(s): Rawan Kharouba, Pavel Gavriliuc, Nour Eddine Yaghmour, John M. Gomori, Jose E. Cohen, Ronen R. Leker


Background and Purposes: Stroke secondary to emergent large vessel occlusions (ELVO) involving the anterior circulation can be treated with intravenous tissue plasminogen activator (IV-tPA) or thrombectomy. Data regarding the influence of the number of stentriever passes needed for vessel recanalization on outcome is lacking.

Patients and Methods: We prospectively accrued data on consecutive patients with ELVO that were treated with thrombectomy. Procedural details including the number of stentriever passes needed to achieve vessel recanalization and clot length were collected. Functional outcome was determined with the modified Rankin Scale (mRS) at 90 days post stroke with mRS≤2 considered favorable outcome. Data on demographics, risk factors, stroke severity, survival, and occurrence of symptomatic intracranial hemorrhage (sICH) was also collected.

Results:On univariate analysis more than one pass needed to achieve recanalization impacted survival and functional outcome after 90 days as did age, stroke severity and collateral and reperfusion status. On multivariate logistic regression the number of passes needed to achieve revascularization (OR 10.0, 95%CI 2.28–43.94, p = 0.002), age (OR 0.90, 95%CI 0.84–0.96, p = 0.001) and collateral status (OR 7.90, 95%CI 1.87–33.35, p = 0.005) remained significant modifiers for favorable outcome. On logistic regression the only variable associated with the need to perform more than a single stentriever pass was time from symptom onset to target vessel recanalization (OR 1.007 955 CI 1.002-1.012).

Conclusions:The number of passes needed to achieve target vessel recanalization modifies outcome after thrombectomy and successful recanalization after a single pass is associated with favorable outcome.

Force and Aspiration on Catheters Utilized in the ADAPT Technique in Acute Ischemic Stroke: A Bench Top Analysis

Publication date: Available online 11 April 2019

Source: Journal of Neuroradiology

Author(s): Mickey Smith, Jonathan Pace, Connie Ju, Yin C. Hu


INTRODUCTION: Given the high morbidity and mortality of stroke, there remains a demand for techniques that provide rapid and safe intervention while improving time to recanalization. The direct aspiration first-pass technique (ADAPT) uses force and aspiration for clot removal without the aid of separators or retrievers. In this study, we compare the force and aspiration qualities of commercially available catheters.

METHODS: Four different catheters with varying inner diameters were set up in a bench top model to test catheter tip pressure and flow rate. Catheter tip pressure was measured by attaching the catheter to a vacuum pressure gauge and an aspiration pump. The flow rate was calculated by measuring the volume of room temperature water aspirated through each catheter over a given time.

RESULTS: The Microvention Sofia catheter generated the greatest tip force (21.32 g), and the Stryker AXS Catalyst 6 catheter generated the smallest tip force (15.88 g). The Penumbra ACE 068 catheter and Medtronic ARC catheter measured 20.87 g and 16.78 g respectively. The ACE 068 had highest rate of aspiration at 289 mL/min, and the Catalyst 6 catheter had the lowest rate at 214. The Microvention Sofia catheter had the second highest rate while the ARC had the third highest rate, measuring 285 ml/min and 256 mL/min, respectively.

CONCLUSIONS: When using the ADAPT technique, knowledge of the tip force and catheter flow rate of newer catheters with larger distal inner diameters may guide selection of aspiration catheters. While this study demonstrates differences in tip force and flow rate of different commercially available catheters, clinical translation will require further testing and evaluation.

Aquaporin 4 distribution in the brain and its relevance for the radiological appearance of neuromyelitis optica spectrum disease

Publication date: Available online 11 April 2019

Source: Journal of Neuroradiology

Author(s): Roxana Ameli, Charles R.G.Guttmann, Juan Carlos Prieto, Fabien Rollot, Miklos Palotai, Sandra Vukusic, Romain Marignier, François Cotton, Group Members for OFSEP Imaging Working, COPIL of OFSEP, the NOMADMUS study group.


Background and Purpose: To determine the precise incidence of lesions at sites of high Aquaporin-4 expression (hAQP4) and their possible association with known neuromyelitis optica spectrum disease (NMOSD) lesions patterns.

Materials and methods: A retrospective analysis of brain and, when available, spinal cord MRI scans of 54 NMOSD patients recruited among the French NMOSD cohort was performed. Brain lesions were annotated as MS-like, non-specific, or evocative of NMOSD. The topography of hAQP4 was reassessed by human brain atlas. The incidence of lesions in hAQP4 and their association with lesions evocative of NMOSD was estimated.

Results:Among those included (41/54 female, mean age:45 years) 47/54(87%) presented brain lesions. Twenty-six/47(55%) had lesions in hAQP4. Thirty-two/54 patients(60%) had lesions considered evocative of NMOSD. The majority of them also presented lesions in hAQP4 (65%, 21/32). Patients with lesions in hAQP4 and lesions evocative of NMOSD demonstrated more extensive myelitis compared to the other patients (7[6–10] versus 4[3–5] vertebral segments, P = 0.009).

Conclusion:The coexistence of lesions evocative of NMOSD and in hAQP4 is associated with significantly more extensive myelitis, and might have pathophysiological and clinical significance.

Differences in cortical perfusion detected by arterial spin labeling in nonamnestic and amnestic subtypes of early-onset Alzheimer's disease

Publication date: Available online 11 April 2019

Source: Journal of Neuroradiology

Author(s): Verclytte Sebastien, Lopes Renaud, Viard Romain, Rollin Adeline, Vanhoutte Matthieu, Pasquier Florence, Pruvo Jean-Pierre, Leclerc Xavier


Objectives: Early-onset Alzheimer's disease (EOAD) begins before the age of 65 and is characterized by a faster clinical course and the frequency of nonamnestic symptoms compared to late onset Alzheimer disease (LOAD). However, the pathophysiological process of EOAD remains unclear. We expected that ASL may show widespread cortical hypoperfusion in EOAD compared to LOAD and in nonamnestic EOAD compared to amnestic EOAD.

Methods: In this study, 26 EOAD patients (16 amnestic and 10 nonamnestic patients), 29 LOAD patients and 12 healthy controls underwent pseudo-continuous ASL and 3D FFE T1 sequences. Statistical comparisons between EOAD, LOAD and control groups were made after surface-based analysis of CBF maps in regressing out the cortical thickness.

Results: ASL showed a more severe hypoperfusion in nonamnestic EOAD patients compared to amnestic EOAD ones, with mean CBF values (±std) of 26.9 (±3.8) and 46.6 (±24.1) ml/100 g/min respectively (p = 0.014), located in the bilateral temporo-parietal neocortex, the precuneus, the posterior cingulate cortices (PCC) and frontal lobes. Comparison between EOAD and LOAD patients showed a trend to hypoperfusion in the left parietal lobe, PCC and precuneus in EOAD (p < 0.001 uncorrected).

Conclusions: Different patterns of hypoperfusion between nonamnestic and amnestic EOAD subtypes were identified, with a more severe and extensive hypoperfusion in nonamnestic patients. A trend towards more severe hypoperfusion was detected in EOAD compared to LOAD. Further studies are needed to validate ASL as a potential tool for the distinction of EOAD subtypes and the prediction of the time course of the disease.

WEB-assisted microwire navigation for the treatment of complex wide-neck intracranial aneurysms: Technical note

Publication date: Available online 5 April 2019

Source: Journal of Neuroradiology

Author(s): Federico Cagnazzo, Cyril Dargazanli, Pierre-Henri Lefevre, Gregory Gascou, Imad Derraz, Carlos Riquelme, Alain Bonafe, Vincent Costalat


Unfavorable aneurysm anatomy can make microwire navigation challenging, increasing the risk of complications. We present our experience of WEB-assisted microcatheterization in complex aneurysms.

Clinical presentation

Flow diversion was performed for three wide-neck large/giant intracranial aneurysms. A WEB was placed inside the sac, blocking the aneurysm neck and providing a contact surface to redirect the microwire across the aneurysm.


WEB-assisted microcatheterization appears an alternative strategy for the treatment of complex aneurysms.

Carotid artery imaging: the study of intra-plaque vascularization and hemorrhage in the era of the "vulnerable" plaque

Publication date: Available online 4 April 2019

Source: Journal of Neuroradiology

Author(s): Michele Porcu, Michele Anzidei, Jasjit S. Suri, Bruce A Wasserman, Nicoletta Anzalone, Pierleone Lucatelli, Federico Loi, Roberto Montisci, Roberto Sanfilippo, Vasileios Rafailidis, Luca Saba


Intraplaque hemorrhage (IPH) is one of the main factors involved in atherosclerotic plaque (AP) instability. Its recognition is crucial for the correct staging and management of patients with carotid artery plaques to limit ischemic stroke. Imaging plays a crucial role in identifying IPH, even if the great variability of intraplaque vascularization and the limitations of our current imaging technologies make it difficult. The intent of this review is to give a general overview of the main features of intraplaque vascularization and IPH on Ultrasound (US), Computed Tomography (CT), Magnetic Resonance (MR) and Nuclear Medicine, and a brief description on the future prospectives.

Comparison between postmortem computed tomography and autopsy in the detection of traumatic head injuries

Publication date: Available online 4 April 2019

Source: Journal of Neuroradiology

Author(s): L. Legrand, T. Delabarde, R. Souillard-Scemama, I. Sec, I. Plu, J-M. Laborie, Y. Delannoy, L. Hamza, M. Taccoen, L. De Jong, J. Benzakoun, M. Edjlali, J-F. Méder, C. Oppenheim, B. Ludes


Introduction. – The aim of this study was to assess the agreement between postmortem computed tomography (PMCT) and autopsy in detecting traumatic head injuries.

Materials and Methods. – Consecutive cases of death that underwent both unenhanced PMCT and conventional autopsy were collected from our institution database during a period of 3 years and reviewed retrospectively. PMCT images were reviewed for the presence of fractures (cranial vault, skull base, facial bones and atlas/axis) and intracranial hemorrhage. Kappa values were calculated to determine the agreement between PMCT and autopsy reports.

Results. – 73 cases were included, of which 44 (60%) had head trauma. Agreement between PMCT and autopsy was almost perfect (κ = 0.95) for fractures and substantial (κ = 0.75) for intracranial hemorrhage. PMCT was superior to autopsy in detecting facial bone and upper cervical spine fractures, and intraventricular hemorrhage. However, in some cases thin extra-axial blood collections were missed on PMCT.

Conclusions. – The agreement between PMCT and autopsy in detecting traumatic head injuries was good. Using a combination of both techniques increases the quality of postmortem evaluation because more lesions are detected.

Efficacy of post-dilatation during carotid artery stenting for unstable plaque using closed-cell design stent evaluated by optical coherence tomography

Publication date: Available online 4 April 2019

Source: Journal of Neuroradiology

Author(s): Kei Harada, Masahito Kajihara, Yukihiro Sankoda, Syunsuke Taniguchi


Background and Purpose: This study aimed to use optical coherence tomography (OCT) to evaluate the efficacy of post-dilatation (PD) after stent placement for unstable plaques during carotid artery stenting (CAS) using closed-cell design stent.

Materials and Methods: Twelve unstable carotid plaque lesions diagnosed by magnetic resonance imaging were evaluated by OCT during CAS. Pre-procedural minimum lumen diameter and area were 1.5 ± 0.6 mm and 2.6 ± 1.6 mm2, respectively. The lesion was pre-dilated with balloon catheters (diameter 4.8 ± 0.3 mm), and closed-cell stent was deployed. PD was performed with balloon catheters of the same size as those used for pre-dilatation. Minimum lumen diameter/area and in-stent tissue prolapse volume after stent placement and after PD were calculated by 2-dimensional cross section images. The number of the stent cells showing tissue prolapse and malapposition after stent-placement and after PD were calculated by 3-dimensional analysis.

Results: Compared to after stent placement, in-stent tissue prolapse volume (0.18 ± 0.10 to 0.22 ± 0.07 mm2/slice, p < 0.01), number of stent cells with any tissue prolapse (12.7 ± 8.2 to 21.0 ± 11.8%, p < 0.001) were significantly increased after PD; stent cells with ≥500-µm tissue prolapse (1.6 ± 1.1 to 0.7 ± 0.8%, p < 0.01) and stent malapposition (17.4 ± 7.2 to 14.0 ± 6.3%, p < 0.01) were significantly decreased.

Conclusions: PD after carotid stent placement caused increase in in-stent tissue prolapse volume and small tissue prolapse, however, the in-stent large tissue prolapse decreased, as the in-stent tissue prolapse may have been crushed into debris.


H22954, a novel long non-coding RNA down-regulated in AML, inhibits cancer growth in a BCL-2-dependent mechanism

Publication date: 10 July 2019

Source: Cancer Letters, Volume 454

Author(s): Xiaofei Qi, Yang Jiao, Chao Cheng, Feng Qian, Zixing Chen, Qingyu Wu


Long non-coding RNAs (lncRNAs) are important in cancer biology. In this study, we analyzed differentially expressed genes in CD34 + hematopoietic cells and identified a novel lncRNA, H22954, which was down-regulated in acute myeloid leukemia (AML) patients. In cultured AML cells and mouse xenograft models, H22954 expression inhibited cell proliferation and tumor growth, respectively. Bioinformatic analysis and RNA antisense purification assay indicated that H22954 targeted the 3' untranslated region of the BCL2 gene. In luciferase assays, H22954 expression inhibited BCL2 expression. In transfected K562 cells and mouse xenograft tumors, H22954 overexpression reduced BCL-2 protein levels and promoted cell death. In AML patients, H22954 expression inversely correlated with BCL-2 protein levels in bone marrow cells, blast cell numbers and disease prognosis. These results indicate that H22954 is a novel regulator of BCL-2 and that reduced H22954 expression may play an important role in the pathogenesis of AML.

IL1RN mediates the suppressive effect of methionine deprivation on glioma proliferation

Publication date: 10 July 2019

Source: Cancer Letters, Volume 454

Author(s): Kaikai Wang, Huailei Liu, Jiaqi Liu, Xiaoxiong Wang, Lei Teng, Jun Zhang, Yi Liu, Yizheng Yao, Jun Wang, Yuan Qu, Xin Chen, Fei Peng, Hongbo Liu, Ning Wang, Yingqiang Zhong, Xu Hou, Haiping Jiang, Ozal Beylerli, Xiang Liao, Xinjian Zhang


Metabolic abnormality is one of the hallmarks of cancer cells, and limiting material supply is a potential breakthrough approach for cancer treatment. Increasing researchers have been involved in the study of glioma cell metabolism reprogramming since the significance of IDH1 was confirmed in glioma. However, the molecular mechanisms underlying metabolic reprogramming induced by methionine deprivation regulates glioma cell proliferation remain unclear. Here we demonstrated that methionine deprivation inhibited glioma cell proliferation via downregulating interleukin 1 receptor antagonist (IL1RN) both in vitro and in vivo, methionine deprivation or knocking down IL1RN induced glioma cell cycle arrest. Moreover, we confirmed that IL1RN is a tumor associated gene and its expression is negatively correlated with the survival time of glioma patients. Altogether these results demonstrate a strong rationale insight that targeting amino acid metabolism such as methionine deprivation/IL1RN related gene therapy may offer novel direction for glioma treatment.

KIAA1199 promotes sorafenib tolerance and the metastasis of hepatocellular carcinoma by activating the EGF/EGFR-dependent epithelial-mesenchymal transition program

Publication date: 10 July 2019

Source: Cancer Letters, Volume 454

Author(s): Yanmin Xu, Huailong Xu, Mingyuan Li, Hua Wu, Yanhe Guo, Jun Chen, Juanjuan Shan, Xuejiao Chen, Junjie Shen, Qinghua Ma, Jingxia Liu, Meiling Wang, Wenxu Zhao, Juan Hong, Yanan Qi, Chao Yao, Qianzhen Zhang, Zhi Yang, Cheng Qian, Jianming Li


Patients with advanced hepatocellular carcinoma (HCC) will almost always develop acquired tolerance after sorafenib therapy, and the molecular mechanism of sorafenib tolerance remains poorly characterized. Here, using our established sorafenib-resistant HCC cell and xenograft models, we identified a novel gene, KIAA1199, which was markedly elevated among the differentially expressed genes involved in sorafenib tolerance. Moreover, elevated expression of KIAA1199 was positively correlated with a high risk of recurrence and metastasis and advanced TNM stage in HCC patients. Functionally, loss- and gain-of-function studies showed that KIAA1199 promoted the migration, invasion, and metastasis of sorafenib-resistant HCC cells. Mechanistically, KIAA1199 is required for EGF-induced epithelial-mesenchymal transition (EMT) in sorafenib-resistant HCC cells by aiding in EGFR phosphorylation. In summary, our data uncover KIAA1199 as a novel sorafenib-tolerant promoting gene that plays an indispensable role in maintaining sorafenib-resistant HCC cell metastasis.

Lemur tyrosine kinase 2 acts as a positive regulator of NF-κB activation and colon cancer cell proliferation

Publication date: 10 July 2019

Source: Cancer Letters, Volume 454

Author(s): Rongjing Zhang, Xiuxiu Li, Lumin Wei, Yanqing Qin, Jing Fang


Lemur tyrosine kinase 2 (LMTK2) belongs to both protein kinase and tyrosine kinase families. LMTK2 is less studied and little is known about its function. Here we demonstrate that LMTK2 modulates NF-κB activity and functions to promote colonic tumorigenesis. We found that LMTK2 protein was abundant in colon cancer cells and LMTK2 knockdown (LMTK2-KD) inhibited proliferation of colon cancer cells through inactivating NF-κB. In unstimulated condition, LMTK2 modulated NF-κB through inhibiting phosphorylation of p65 at Ser468. Mechanistically, LMTK2 phosphorylated protein phosphatase 1A (PP1A) to prevent PP1A from dephosphorylating p-GSK3β(Ser9). The p-GSK3β(Ser9) could not phosphorylate p65 at Ser468, which maintained the basal NF-κB activity. LMTK2 also modulated TNFα-activated NF-κB. LMTK2-KD repressed TNFα-induced IKKβ phosphorylation, IκBα degradation and NF-κB activation, implying that LMTK2 modulates TNFα-activated NF-κB via IKK. These results suggest that LMTK2 modulates basal and TNFα-induced NF-κB activities in different mechanisms. Animal studies show that LMTK2-KD suppressed colon cancer cell xenograft growth, decreased PP1A phosphorylation and increased p-p65(Ser468). Our results reveal the role and underlying mechanism of LMTK2 in colonic tumorigenesis and suggest that LMTK2 may serve as a potential target for chemotherapy of colon cancer.

Pseudophosphatase STYX promotes tumor growth and metastasis by inhibiting FBXW7 function in colorectal cancer

Publication date: 10 July 2019

Source: Cancer Letters, Volume 454

Author(s): Diao He, Zida Ma, Chao Fang, Jingjing Ding, Wenming Yang, Peng Chen, Libin Huang, Cun Wang, Yongyang Yu, Lie Yang, Yuan Li, Zongguang Zhou


Serine/threonine/tyrosine interacting protein (STYX), a member of protein tyrosine phosphatases, has recently been reported as a potential oncogene. However, the role of STYX in colorectal cancer (CRC) remains unknown. In this study, we found that STYX was highly expressed in CRC tissues and closely correlated with tumor development and survival of CRC patients. In vitro studies showed that overexpression of STYX promoted proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) and inhibited apoptosis in CRC cells, while STYX knockdown had the opposite effects. Consistently, in vivo experiments showed that overexpression of STYX promoted tumor growth and lung metastasis. Mechanically, STYX bound to the F-box and WD repeat domain-containing7 (FBXW7) protein and inhibited its function. Co-regulation of STYX and FBXW7 expression reversed the biological changes mediated by regulation of STYX expression alone in CRC cells. Additionally, FBXW7 expression was negatively associated with STYX expression in CRC tissues, and low STYX levels accompanying high FBXW7 levels predicted favorable prognosis of CRC patients. In conclusion, our results suggest that STYX plays an oncogenic role by inhibiting FBXW7 and represents a potential therapeutic target and prognostic biomarker in CRC.

Mycoplasma infection promotes tumor progression via interaction of the mycoplasmal protein p37 and epithelial cell adhesion molecule in hepatocellular carcinoma

Publication date: 10 July 2019

Source: Cancer Letters, Volume 454

Author(s): Min Kyu Kim, Su-Jin Shin, Hyun Min Lee, Hong Seo Choi, Jaemin Jeong, Hyunsung Kim, Seung Sam Paik, Mimi Kim, Dongho Choi, Chun Jeih Ryu


Hepatocellular carcinoma (HCC) is currently the third leading cause of cancer death worldwide. To study how mycoplasma infection affects HCC progression, we investigated the characteristics of mycoplasma-infected tumor tissues and circulating tumor cells (CTCs) in HCC patients. The mycoplasmal membrane protein p37 showed significant correlations with higher histologic stages and vascular invasion and predicted poor disease-free survival of HCC patients. p37-positive CTCs were detected in 42 out of 47 HCC patients (89%). p37-positive circulating cells were also detected in 4 out of 10 healthy donors (40%), and all were epithelial cell adhesion molecule (EpCAM)-positive. In HCC patients, most of p37-negative CTCs (95%) showed intermediate phenotype with neither EpCAM nor vimentin expression, but p37-positive CTCs were EpCAM-positive (44%), vimentin-positive (32%), and both negative (24%), suggesting that EpCAM-positive CTCs are enriched with mycoplasma infection. Mycoplasma infection promoted migratory capacity of HCC cells with increased expression of EpCAM. Immunoprecipitation analysis revealed that p37 associates with EpCAM. The results suggest that mycoplasma infection promotes tumor progression in HCC patients via interaction of the mycoplasmal p37 and EpCAM.

Cancer-associated fibroblasts-derived IL-8 mediates resistance to cisplatin in human gastric cancer

Publication date: 10 July 2019

Source: Cancer Letters, Volume 454

Author(s): Jing Zhai, Jiajia Shen, Guiping Xie, Jiaqi Wu, Mingfang He, Lili Gao, Yifen Zhang, Xuequan Yao, Lizong Shen


Chemoresistance remains the major obstacle to achieve optimal prognosis in gastric cancer patients, and the underlying molecular mechanisms of cancer-associated fibroblasts (CAFs) in gastric cancer chemoresistance remain poorly understood. We identified the high pretherapeutical serum IL-8 level in gastric cancer patients was associated with poor response to platinum-based therapy, and it increased gradually during neoadjuvant chemotherapy and it decreased after radical surgery. Immunohistochemistry assays showed that IL-8 was highly expressed in gastric cancer tissues in chemoresistant patients, and located in CAFs. Primary CAFs produced more IL-8 than the corresponding normal fibroblasts, and human stomach fibroblast line Hs738 secreted more IL-8 after co-cultured with conditioned media from AGS or MGC-803 cells. IL-8 increased the IC50 of cisplatin (CDDP) in AGS or MGC-803 in vitro. Simultaneously, IL-8 treatment enhanced the expression of PI3K, phosphorylated-AKT (p-AKT), phosphorylated-IKb (p-IKb), phosphorylated-p65 (p-p65) and ABCB1, and ABCB1 and p-p65 were overexpressed in tumor tissues of chemoresistant patients. Collectively, CAFs derived IL-8 promotes chemoresistance in human gastric cancer via NF-κB activation and ABCB1 up-regulation. Our study provides a novel strategy to improve the chemotherapeutical efficacy and the prognosis of gastric cancer.

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NT5DC2 promotes tumorigenicity of glioma stem-like cells by upregulating fyn

Publication date: 10 July 2019

Source: Cancer Letters, Volume 454

Author(s): Saisai Guo, Haowen Ran, Dake Xiao, Haohao Huang, Lanjuan Mi, Xinzheng Wang, Lishu Chen, Da Li, Songyang Zhang, Qiuying Han, Tao Zhou, Ailing Li, Jianghong Man


Glioblastoma (GBM) is an incurable primary brain tumor that is highly resistant to current treatments. Glioma stem-like cells (GSCs) are an aggressive population of glioma cells that not only initiate malignant growth, but also promote therapeutic resistance. Thus, targeting GSCs is critical for improving GBM treatment and ensuring complete eradication of the tumor. Here, we show that NT5DC2 (5′-Nucleotidase Domain Containing 2), a functionally unknown protein, plays a crucial role in GSC tumor initiation via upregulating Fyn expression. NT5DC2 is preferentially expressed in GSCs relative to the non-stem tumor cells. Knockdown of NT5DC2 significantly inhibits the GSC tumorsphere formation and cell viability in vitro, and tumorigenesis in vivo, thus, prolonging animal survival. Moreover, disruption of NT5DC2 in GSCs markedly reduces the expression of Fyn, a Src family proto-oncogene that has been implicated in the regulation of GBM progression. Importantly, the expression of NT5DC2 strongly correlated with increased aggression of human gliomas, but not that of other brain tumors. Taken together, our results uncover the function of NT5DC2 in GSC maintenance and highlight NT5DC2 as a promising therapeutic target for GBM.

Epigenetic regulation of UDP-Glucuronosyltransferase by microRNA-200a/-183: implications for responses to sorafenib treatment in patients with hepatocellular carcinoma

Publication date: 10 July 2019

Source: Cancer Letters, Volume 454

Author(s): Yang Ge, Shuzhen Chen, Wei Mu, Qian Ba, Jingquan Li, Peizhan Chen, Xianming Wang, Hui Wang


Patients receiving sorafenib treatment for hepatocellular carcinoma (HCC) experience different treatment efficacy. Personalized sorafenib treatment should be achieved through the identification of predictors of therapeutic response. In the current study, we found that high UGT1A9 expression indicated better prognosis for HCC patients treated with sorafenib after surgery. In silico analysis predicted microRNA-200a/-183 as potential regulators of the UGT1A gene family via binding to the shared UGT1A9 3′-UTR. A significant inverse correlation between microRNA-200a/-183 and UGT1A9 mRNA level was observed in a panel of HCC specimens. Direct binding was further demonstrated by luciferase reporter gene vector carrying wild-type or binding site truncated UGT1A9 3′-UTR. MicroRNA-200a/-183 downregulated UGT1A9 expression in a dose-dependent manner and significantly reduced sorafenib β-D-glucuronide formation in HCC cells. These data indicated that UGT1A9, under epigenetic regulation of microRNA-200a/-183, could predict patients who might benefit from adjuvant sorafenib treatment after surgery.

Prostate cancer cells hyper-activate CXCR6 signaling by cleaving CXCL16 to overcome effect of docetaxel

Publication date: 10 July 2019

Source: Cancer Letters, Volume 454

Author(s): Neeraj Kapur, Hina Mir, Guru P. Sonpavde, Sanjay Jain, Sejong Bae, James W. Lillard, Shailesh Singh


Molecular reprogramming in response to chemotherapeutics leads to poor therapeutic outcomes for prostate cancer (PCa). In this study, we demonstrated that CXCR6-CXCL16 axis promotes DTX resistance and acts as a counter-defense mechanism. After CXCR6 activation, cell death in response to DTX was inhibited, and blocking of CXCR6 potentiated DTX cytotoxicity. Moreover, in response to DTX, PCa cells expressed higher CXCR6, CXCL16, and ADAM-10. Furthermore, ADAM-10-mediated release of CXCL16 hyper-activated CXCR6 signaling in response to DTX. Activation of CXCR6 resulted in increased GSK-3β, NF-κB, ERK1/2 phosphorylation, and survivin expression, which reduce DTX response. Finally, treatment of PCa cells with anti-CXCR6 monoclonal antibody synergistically or additively induced cell death with ∼1.5–4.5 fold reduction in the effective concentration of DTX. In sum, our data imply that co-targeting of CXCR6 would lead to therapeutic enhancement of DTX, leading to better clinical outcomes for PCa patients.

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