HIV Treatment as Prevention: Optimising the Impact of Expanded HIV Treatment Programmes.


Resources for expanding ART in the short term may be limited, so the question is how to generate the most prevention benefit from realistic potential increases in the availability of ART. Although not a formal systematic review, here we review different ways in which access to ART could be expanded by prioritising access to particular groups based on clinical or behavioural factors. For each group we consider (i) the clinical and epidemiological benefits, (ii) the potential feasibility, acceptability, and equity, and (iii) the affordability and cost-effectiveness of prioritising ART access for that group. In re-evaluating the allocation of ART in light of the new data about ART preventing transmission, the goal should be to create policies that maximise epidemiological and clinical benefit while still being feasible, affordable, acceptable, and equitable.

 

Source: PLOS

 

 

 

 

 

 

MRI visualizes proton dose distribution.


“How can proton therapy not be clinically better than intensity-modulated radiation therapy?” That was the question posed by Thomas Bortfeld, PhD, speaking at the recent European Society for Radiotherapy and Oncology (ESTRO) annual meeting in Barcelona, Spain.

The answer lies in uncertainty over the range of the proton beam, surmised the Harvard Medical School professor of medical physics and director of the physics research division of the Massachusetts General Hospital (MGH) Department of Radiation Oncology and its Francis H. Burr Proton Therapy Center in Boston.

This uncertainty can be reduced by measuring the proton range in vivo. Several techniques are being investigated for this purpose, including dosimetry in body cavities; other possibilities are PET and prompt gamma imaging, which detect secondary particles created as the proton beam travels through the patient. But another option is the use of MRI to visualize the proton dose distribution, by imaging radiation-induced tissue changes, Bortfeld told ESTRO attendees.

The idea is to use MRI to image tissue changes that occur on a molecular level following proton irradiation. The technique has already been successfully used to infer the delivered dose in proton therapy of the spine. Here, irradiation causes the blood-producing bone marrow to be replaced by fat, which shows up as areas of increased intensity in post-treatment MR images.

While this MR imaging method works well for treatment of bony structures, can it be used elsewhere? Bortfeld cited an example in which contrast-enhanced MRI was used to observe changes in liver tissue following brachytherapy.

After treatment, a reduction in contrast uptake was seen in the treated areas of the liver. “We expected to see a similar effect for proton therapy, and we did,” he noted.

Bortfeld described a study performed at Massachusetts General Hospital in which MR images were recorded 2.5 months after five fractions of proton therapy. A reduced signal was seen in central parts of the liver. Contours of the area of signal reduction were in good agreement with the high-dose region in the treatment plan.

Bortfeld’s research group is also trying to understand the underlying molecular process, and believes that radiation-induced and cytokine-mediated changes of the irradiated liver cells disable the active contrast media uptake.

The main advantages of MRI range imaging are better spatial resolution and improved signal-to-noise ratio compared with PET. In comparison with prompt gamma imaging, MRI can offer 3D information combined with anatomical information. The main disadvantage at present is the delay between the start of treatment and the observation of changes in the MR image.

The key question now, therefore, is whether similar changes in MR images can be observed after just a few days of treatment. If this is possible, then small misalignments could be detected between proton fractions and compensated for in later treatments. He said that Christian Richter, PhD; Joao Seco, PhD; and colleagues from MGH are currently running a trial to determine the time point in the treatment process at which such changes can be observed.

Source: Radiation Oncology Digital Community.

Side effects persist after prostate cancer treatment.


Men who are treated for prostate cancer may still suffer side effects from treatment up to a decade later, a new study finds.

Researchers found that more than 500 men with cancer — including cancers caught through regular screening — ended up with poorer sexual function and more bladder control problems for up to 10 years afterward than men with no cancer diagnosis.

That might sound like a good trade-off for having your cancer found and treated.

But the issue is complicated. Prostate cancer is often slow-growing and may never get to the point that it threatens a man’s life.

And a number of studies have found no proof that using prostate-specific antigen (PSA) blood tests to screen men for prostate cancer actually saves lives.

Because of that the U.S. Preventive Services Task Force (USPSTF) — an expert panel with federal support — advises against routine prostate cancer screening.

With the benefits of screening in doubt, that makes the question of treatment side effects even more important.

“The reality is that right now, the screening decision and the treatment decision have to be made on an individual basis,” said Kathryn L. Taylor, of the Lombardi Comprehensive Cancer Center at Georgetown University in Washington, DC.

“This study doesn’t answer those questions for individuals,” said Taylor, who led the research.

But she said the findings do give men more information on the long-term side effects of prostate cancer treatment — whether it’s surgery, radiation, or hormone therapy.

Up to 10 years after treatment, more than 95% of men had some degree of sexual dysfunction, Taylor’s team found. And about half had urinary symptoms.

Past studies have found such lingering side effects, too. But they have been shorter-term — following men for as far as five years. And they’ve left some question as to whether the sexual and urinary problems could just be a product of aging, rather than prostate cancer treatment, Taylor explained.

These latest findings, reported in the Journal of Clinical Oncology, suggest it’s not simply the aging process that’s to blame.

That’s because Taylor’s team had data on men who’d taken part in a large clinical trial on prostate cancer screening.

The researchers were able to compare 269 men who’d had prostate cancer detected and treated after screening with 260 men who’d also been screened but remained cancer-free.

And when they accounted for the men’s age, overall health, and other factors, the group treated for cancer had worse sexual and urinary function up to 10 years later.

The same pattern held up among men in the trial arms who weren’t screened for prostate cancer and did or didn’t get diagnosed and treated.

Treatment options

That all suggests the blame lies with prostate cancer treatment, or possibly the cancer itself to some degree, according to Taylor.

“The bottom line is that the (prostate cancer) group was worse off,” Taylor said. And that’s something men should have in mind when deciding on prostate cancer screening, she and her colleagues say.

Once prostate cancer is detected, men have another big decision. If the cancer is early-stage, they can choose to put off treatment and instead have the cancer monitored to see if it’s progressing — what doctors call “active surveillance.”

Or they can go for treatment, with surgery being the usual option for earlier cancer.

“We like to tell men to think of it as one big question,” Taylor said.

That is, don’t think of the screening decision in isolation, she explained. Men should remember that if an early cancer is caught, they’ll have to decide on treatment, Taylor said.

Active surveillance, by definition, is not treatment — but it does mean regular PSA blood tests and periodic biopsies.

The USPSTF recommendation against routine prostate cancer screening does not preclude men from asking for it, or doctors from offering.

And Taylor pointed out that studies look at population-wide effects. Even if PSA screening has not cut overall death rates from prostate cancer, some men may benefit.

She suggested men “get educated” about prostate cancer and make a screening decision based on a careful discussion with their doctors.

In the U.S., just over 28,000 men will die of prostate cancer this year, according to the American Cancer Society. But close to 242,000 new cases will be diagnosed, many of which will be early cancers.

According to the National Cancer Institute, about half of all U.S. men diagnosed with prostate cancer in 2009 fell into the “low-risk” category — meaning their cancer was unlikely to progress.

 

Source: Journal of Clinical Oncology

 

Somatic Mutation Analysis of the SDHB, SDHC, SDHD, and RET Genes in the Clinical Assessment of Sporadic and Hereditary Pheochromocytoma.


Systemic analysis of somatic mutations of other susceptibility genes in syndromic tumors as well as apparently sporadic tumors in well-characterized specimens is lacking. Its clinical relevance has not been studied. Our objective was to determine the frequency of second allele inactivation in syndromic tumors and determine the frequency and potential clinical impact of somatic mutations and loss of heterozygosity (LOH) of the known susceptibility genes in syndromic and sporadic tumors. Nine tumor specimens from clinically characterized VHL mutation, five from SDHB mutation, four from SDHD mutation, two from RET mutation carriers, and eight from apparently sporadic cases were analyzed. Tumor DNA mutation screening of the SDHx, VHL, and RET genes and LOH analyses of the SDHx and VHL genes were performed. The Yates-corrected chi-squared test was used for comparison of the clinical data and the molecular-genetic results. Second allele inactivation in tumors was identified in 83 % of VHL, 80 % of SDHB, and 50 % of SDHD specimen. High prevalence of VHL (6/6, p = 0.024) and SDHB (7/7, p = 0.018) somatic mutations has been identified in the sporadic group compared to all others. In the group of the VHL tumors the SDHB somatic events were significantly lower (2/6; p  = 0.045). In 18/19 (95 %) of cases, we were able to demonstrate the presence of at least two concomitant affected susceptibility genes. We conclude that LOH is the most prevalent second allele-inactivating event. SDHB and VHL somatic mutation might play a role in the sporadic forms of tumor development. There is no clinical impact of mutation screening or LOH analysis of tumor specimens.

Source: Springerlinks/ Hormones and Cancer.

 

 

Suppression of Myc oncogenic activity by nucleostemin haploinsufficiency

Nucleostemin (NS), a nucleolar GTPase, is highly expressed in stem/progenitor cells and in most cancer cells. However, little is known about the regulation of its expression. Here, we identify the NS gene as a novel direct transcriptional target of the c-Myc oncoprotein. We show that Myc overexpression enhances NS transcription in cultured cells and in pre-neoplastic B cells from Eμ-myc transgenic mice. Consistent with NS being downstream of Myc, NS expression parallels that of Myc in a large panel of human cancer cell lines. Using chromatin immunoprecipitation we show that c-Myc binds to a well-conserved E-box in the NS promoter. Critically, we show NS haploinsufficiency profoundly delays Myc-induced cancer formation in vivo. NS+/−Eμ-myc transgenic mice have much slower rates of B-cell lymphoma development, with life spans twice that of their wild-type littermates. Moreover, we demonstrate that NS is essential for the proliferation of Myc-overexpressing cells in cultured cells and in vivo: impaired lymphoma development was associated with a drastic decrease of c-Myc-induced proliferation of pre-tumoural B cells. Finally, we provide evidence that in cell culture NS controls cell proliferation independently of p53 and that NS haploinsufficiency significantly delays lymphomagenesis in p53-deficient mice. Together these data indicate that NS functions downstream of Myc as a rate-limiting regulator of cell proliferation and transformation, independently from its putative role within the p53 pathway. Targeting NS is therefore expected to compromise early tumour development irrespectively of the p53 status.

Source: Oncogene.

Extended RET Gene Analysis in Patients with Apparently Sporadic Medullary Thyroid Cancer: Clinical Benefits and Cost.


RET sequencing has become an important tool in medullary thyroid cancer (MTC) evaluation and should be performed even in the absence of family history of MTC. The most commonly studied exons in index cases are 8, 10, 11, and 13–16. To address the ATA guidelines regarding the sequencing of the entire coding region of RET, we selected 50 patients with sporadic MTC (sMTC) without mutations in the hot spot regions of RET for extended investigation of exons 1–7, 9, 12, 17, 18, and 19. Twenty-seven of 50 patients presented with one or more features suggesting familial disease. We found only a new RET variant (p.Gly550Glu) in one patient with MTC. Several polymorphisms were observed, and their frequency was histogram scaled by exons and introns. Eight patients were also included for somatic mutation search. We estimated the sequencing cost by stratifying into four investigation approaches: (1) hot spot exons in a new patient, (2) the remaining exons if the hot spots are negative in a patient with suspected familial disease, (3) a relative of a carrier for a known RET mutation, and (4) tumor sequencing. In spite of the increasing number of variants being described in MTC, it appears that there is no direct clinical benefit in extending RET germ line analysis beyond the hot spot regions in sMTC. The cost evaluation in apparent sMTC using a tiered approach may help clinicians make more suitable decisions regarding the benefits of investigating only the hot spots against the entire coding region of RET.

Source: Springerlinks/ Hormones and Cancer.

 

Growth Hormone-Releasing Hormone Receptor Splice Variant 1 is Frequently Expressed in Oral Squamous Cell Carcinomas.


The expression of growth hormone-releasing hormone (GHRH) splice variant 1 (SV1) receptor in neoplastic lesions of the oral cavity was assessed. The sensitivity of HaCaT keratinocytes to GHRH analogs was also evaluated. Thirty-three benign precancerous oral lesions and 27 squamous cell carcinomas of the oral cavity were evaluated by immunohistochemistry for SV1 expression. SV1 expression in HaCaT keratinocytes was assessed by western blot. HaCaT proliferation was evaluated by cell counting. Anti-SV1 immunoreactivity was detected in only 9  % (three of 33) precancerous lesions (one hyperplasia and two dysplasias), while 44 % (12 of 27) carcinomas were positive for SV1 (p < 0.002). GHRH(1–29)NH2 and GHRH agonist JI-38 stimulated HaCaT proliferation in vitro, and this effect was blocked by GHRH antagonists. These results indicate that SV1 expression may be associated with the transition of precancerous lesions to carcinomas of the oral epithelium. GHRH antagonists may be useful for the management of the disease.

Source: Springerlinks/ Hormones and Cancer.

The Serious Problem of Overhydrating in Endurance Sports.


In an effort to prevent dehydration, it’s common for many endurance athletes to guzzle down large amounts of fluids before, during and after competing.

The American College of Sports Medicine (ACSM) even encourages this approach, stating that “the goal of drinking during exercise is to prevent excessive (>2% body weight loss from water deficit) dehydration and excessive changes in electrolyte balance to avert compromised performance.”i

But is this really the right thing, or the healthiest thing, to do?

Exercise scientist (and experienced endurance athlete) Dr. Tim Noakes doesn’t believe so — in fact, he points out at least a dozen deaths that have occurred in endurance events due to drinking too much fluid.

Intrigued as to how this problem came about, Dr. Noakes studied the hydration fad over the last few decades, then wrote a book about it, “Waterlogged: The Serious Problem of Overhydration in Endurance Sports.”

The topic is particularly dear to him because 30 years ago he personally advised people to drink as much as they could―only to find out later that this advice could be deadly.

The Problem With Drinking Too Much During Exercise

According to a survey by Loyal University researchers, over 36 percent of runners drink according to a preset schedule or to maintain a certain body weight.ii Another 9 percent drink as much as they can during races. These runners are choosing to ignore their body’s thirst mechanism and instead use other methods to dictate their water consumption, which they believe, mistakenly, to be superior.

Many buy into this belief, and health agencies and sports drinks advertisers have been spouting the misinformation for years. But as the Loyola researchers noted:iii

“These beliefs are frequently based on misconceptions about basic exercise physiology.”

Overhydrating will actually worsen athletic performance, not improve it. As you begin to consume too much water, your cells will start to swell, leading to such symptoms as gastrointestinal upset, dizziness, soreness and others. In severe cases, the sodium levels in your blood may drop to dangerously low levels, causing hyponatremia — a condition in which your cells swell with too much water. While most of your body’s cells can handle this swelling, your brain cells cannot, and most of the symptoms are caused by brain swelling.

This condition is most common among athletes, although anyone can be affected by drinking excessive amounts of water. Dr. Noakes explained:iv

“The brain swells, and because it is in a rigid skull, it cannot swell very much. The more it swells, the more pressure, and that eventually squeezes the arteries supplying blood to the brain. Ultimately, there is less oxygen getting to the brain, and certain parts become damaged. Once it affects your breathing centers, then you’re in real trouble, because it stops breathing, and that is essentially irreversible.”

Your Body is Designed to Tell You When to Drink

According to Dr. Noakes, the first drinking guidelines put out by The American College of Sports Medicine said that runners should “drink regularly during exercise,” which is fair advice. But then an individual working for the U.S. military published a paper saying that U.S. soldiers should drink 64 ounces of water per hour in order to improve performance.

Though the paper was not based on concrete evidence, it was widely embraced by the military, and then filtered through to the American College of Sports Medicine’s guidelines for runners. Today ACSM still recommends drinking “ahead of thirst,” a move that Dr. Noakes says “impairs exercise performance.” He uses the example of African hunters who were able to chase down an antelope for four to six hours in mid-day heat, without a source of fluids until after the hunt ended (when they would drink the animal’s blood and intestinal water). He continues:v

“Dehydration is not a disease, and it only has one symptom, and that is thirst. If you start to exercise, and you don’t drink, after a period of time, you will become thirsty—that’s your body’s way of telling you to drink.

The idea that you should drink ahead of thirst is absolutely nonsensical… why should humans be different from every other creature on earth to be told when and how to drink? The reality is you don’t need to be told when and how much to drink.

We have a 300 million year developed system that tells you with exquisite accuracy how much you need to drink and when you need to drink. It’s called thirst. If you rely on thirst you won’t ever become dehydrated, and you won’t also ever become overhydrated.”

Are Sports Drinks Really Necessary?

Aside from the now disproven dogma that you need to chug lots of water during exercise, it’s also commonly said that you need to replace your electrolyte balance … and sports drinks are positioned as the ideal way to do so. But according to Dr. James Winger, author of the Loyola study:vi

“There is no need to replace minerals during exercise, because the loss of minerals has no deleterious effect on the body.”

The fact of the matter is, sports drinks represent a nearly $4-billion market in the United States.vii And because of their glitzy marketing campaigns, which often feature celebrity athletes, many people are under the impression that these drinks are healthy and essential during or after a workout, offering such benefits as improved athletic performance, increased energy and superior hydration during exercise.

The leading brands of sports drinks on the market typically contain as much as two-thirds the sugar of sodas and more sodium. They also often contain high-fructose corn syrup (HFCS).

Fructose is known to be highly toxic when consumed at levels beyond which glycogen stores are replenished. The excess either converts to triglycerides in the liver, which in turn raises your risk of heart disease and does nothing to satisfy the immediate glucose needs of your cells, or accumulates in the blood where it reacts with proteins through the Malliard reaction (glycation), essentially  “gumming up the works” with destructive glycation byproducts that cause accelerated aging and diabetes complications, to name but a few of their adverse effects.

And if that’s not bad enough, crystalline fructose may be contaminated with arsenic, lead, chloride and heavy metals.

Many sports drinks also contain artificial sweeteners (they can lead to impaired kidney function, depression, headaches, infertility, brain tumors, and a long list of other serious health problems), artificial flavors and food coloring, which has been connected to a variety of health problems, including allergic reactions, hyperactivity, decreased IQ in children, and numerous forms of cancer.

Not to mention, sports drinks are up to 30 times more erosive to your teeth than water. And brushing your teeth won’t help because the citric acid in the sports drink will soften your tooth enamel so much it could be damaged by brushing.

It’s just not worth it, especially considering only a very small portion of exercisers work out hard enough that a sports drink might be necessary. They basically “work” because they contain high amounts of sodium (processed salt), which is meant to replenish the electrolytes you lose while sweating. But as Dr. Winger said, this isn’t even necessary during a marathon, let alone during most regular workouts:viii

““During a 26-mile marathon, there is no role during or after the race for oral supplementation of salt.”

And even then, if you did feel a beverage other than water was necessary, coconut water is a far better choice than virtually any commercial sports drink on the market.

So How Much Water is Healthy?

Even if you’re not an endurance athlete who is chugging 64 ounces of water an hour, you may still be stressing yourself unnecessarily regarding your water consumption. Scientific evidence to support the widely touted recommendation to drink eight glasses of water a day is also lacking, and has even been called “thoroughly debunked nonsense.”

Drinking eight 8-ounce glasses of pure water a day may not be likely to cause you harm; it’s just that the evidence is lacking on whether that is the magic number for everyone, and most likely it appears that it is not. The reality is that many people are dehydrated and would benefit from drinking more water each day, and from making water their primary source of fluids.

Your body will tell you when it’s time to replenish your water supply, because once your body has lost between one to two percent of its total water, your thirst mechanism lets you know that it’s time to drink some water!

The color of your urine will also help you determine whether or not you might need to drink more. As long as you are not taking riboflavin (vitamin B2, also found in most multi-vitamins), which fluoresces and turns your urine bright yellow, then your urine should be a very light-colored yellow. If it is a deep, dark yellow then you are likely not drinking enough water. If your urine is scant or if you haven’t urinated in many hours, that too is an indication that you’re not drinking enough. (Based on the results from a few different studies, a healthy person urinates on average about seven or eight times a day.)

But since your body is capable of telling you its needs, you needn’t worry about measuring your water intake or counting your glasses. Simply using thirst as a guide to how much water you need to drink is a simple way to help ensure your individual needs are met, day-by-day.

Of course, if it’s hot, exceptionally dry outside, or if you are engaged in exercise or other vigorous activity, you will require more water than normal. But again, if you drink as soon as you feel thirsty, you should be able to remain properly hydrated even in these cases.

Source: Dr. Mercola.