Postoperative treatment without radioiodine has noninferior outcomes following thyroidectomy

1. Patients with low-risk thyroid cancer undergoing thyrodectomy, who did not receive radioiodine post-operatively, did not show inferior functional, structural, and biological recurrence outcomes.

2. Patients with higher thyroglobulin levels were shown to have a higher frequency of functional, structural, and biological abnormalities.

 

Study Rundown: Following thyroidectomy, the standard postoperative treatment regimen for patients with low-risk thyroid cancer is ablation using radioiodine (iodine-131) after recombinant human thyrotropin injection to prevent a recurrence. However, retrospective studies have suggested that radioiodine may not be necessary in improving recurrence outcomes in low-risk cases. The objective of this phase 3 ESTIMABL2 randomized control trial was to evaluate whether the absence of radioiodine would yield noninferior outcomes. Following thyroidectomy, patients were randomized to either receive ablation with postoperative radioiodine or no radioiodine. The primary objective measured the percentage of “events”, which were related to functional, structural, and biological abnormalities at 3 years follow-up. These endpoints were based upon measures such as radioiodine uptake, ultrasonography imaging, thyroglobulin and thyroglobulin antibody levels, and incidence of recurrence. Secondary endpoints analyzed the quality of life and anxiety measures. The study found that both groups had similar proportions of patients with a primary event supporting that the group receiving no radioiodine was non-inferior. A correlation was also found between those with higher thyroglobulin levels with a greater frequency of events. Neither group experienced adverse events related to treatment. Together, this study supports the discontinued use of radioiodine following thyroidectomy in patients with low-risk thyroid cancer. The results of this study are potentially limited by a short follow-up time.

In-Depth [randomized controlled trial]: In this phase 3 randomized control trial named Essai Stimulation Ablation 2 (ESTIMABL2), 730 patients with low-risk thyroid cancer (differentiated, T1a or 1b status, N0 or Nx) who underwent curative resection by thyroidectomy were randomly assigned to receive either postoperative radioiodine (1.1 GBq) following the second dose of recombinant human thyrotropin or no radioiodine. Groups were stratified for the trial site and lymph node status. Patients were assessed using ultrasonography, and for serum thyroglobulin and thyroglobulin antibody levels until the follow-up period of 3 years after randomization. Patients receiving radioiodine also underwent whole-body scanning to assess any abnormal foci of radioiodine uptake. The primary endpoint was the proportion of patients that encountered an event, which comprised of either abnormal radioiodine uptake on whole-body scanning (functional), abnormal ultrasonography (structural), or excessive thyroglobulin or thyroglobulin antibody levels (biological). Secondary endpoints assessed, via questionnaire, measures of quality of life, anxiety, fear or recurrence, and gland dysfunction. The study found that 4.1% of the group receiving radioiodine experienced an event, compared to 4.4% in the no-radioiodine group, yielding a non-significant between-group difference of -0.3% (95% confidence interval [CI], -2.7 to 2.2). Similar scores were found across all secondary endpoint measures across both groups. When assessed for prognostic factors for primary event occurrence, the study found that patients with higher thyroglobulin levels (>1 ng/mL) were at higher risk. Furthermore, no differences in mutation analyses and adverse events were found. Taken together, the study found that not administering radioiodine was not inferior to the current standard practice of radioiodine administration, potentially sparing this subgroup of low-risk thyroid cancer patients from recommended radioiodine treatment.

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Infusion of Young Blood Reverses Age-Related Impairments in Mice

A newly published study from Stanford University found that an infusion of young blood can counteract and reverse pre-existing effects of brain aging at the molecular, structural, functional and cognitive level in mice.

Something — or some things — in the blood of young mice has the ability to restore mental capabilities in old mice, a new study by Stanford University School of Medicine investigators has found.

If the same goes for humans, it could spell a new paradigm for recharging our aging brains, and it might mean new therapeutic approaches for treating dementias such as Alzheimer’s disease.

In the study, published online May 4 in Nature Medicine, the researchers used sophisticated techniques to pin down numerous important molecular, neuroanatomical and neurophysiological changes in the brains of old mice that shared the blood of young mice.

But they also conducted a critical experiment that was far from sophisticated, said Tony Wyss-Coray, PhD, the senior author of the study and a professor of neurology and neurological sciences. The scientists simply compared older mice’s performance on standard laboratory tests of spatial memory after these mice had received infusions of plasma (the cell-free part of blood) from young versus old mice, or no plasma at all.

“This could have been done 20 years ago,” said Wyss-Coray, who is also senior research career scientist at the Veterans Affairs Palo Alto Health Care System. “You don’t need to know anything about how the brain works. You just give an old mouse young blood and see if the animal is smarter than before. It’s just that nobody did it.”

Wyss-Coray has co-founded a biotechnology company, Alkahest, to explore the therapeutic implications of the new study’s findings. He serves as the director of Alkahest’s scientific advisory board.

The study’s lead author, Saul Villeda, PhD, now has an active lab of his own as a faculty fellow in anatomy at the University of California-San Francisco. Villeda was a graduate student at Stanford and, briefly, a postdoctoral scholar under Wyss-Coray’s direction when the bulk of the work was performed.

Reversing impairments

“We’ve shown that at least some age-related impairments in brain function are reversible. They’re not final,” Villeda said.

Previous experiments by Wyss-Coray, Villeda and their colleagues, described in a paper published in 2011 in Nature, had revealed that key regions in the brains of old mice exposed to blood from young mice produced more new nerve cells than did the brains of old mice similarly exposed to blood from old mice. Conversely, exposing young mice to blood from old mice had the opposite effect with respect to new nerve-cell production, and also reduced the young mice’s ability to navigate their environments.

But that earlier work didn’t directly assess the impact of young mouse blood on older mice’s behavior. This time, the researchers checked both for changes within nerve circuits and individual nerve cells and for demonstrable improvements in learning and memory. First, they examined pairs of mice whose circulatory systems had been surgically conjoined. Members of such pairs, known as parabiotic mice, share a pooled blood supply.

Wyss-Coray’s group paid special attention, in these parabiotic mice, to a brain structure called the hippocampus. In both mice and humans, this structure is critical for forming certain types of memories, notably the recollection and recognition of spatial patterns. “That’s what you need to use when, for example, you try to find your car in a parking lot or navigate around a city without using your GPS system,” Wyss-Coray said.

Experience alters hippocampal activity and anatomy. Studies have found, for instance, that a veteran London cabdriver’s hippocampus is larger than it was when the driver was first hired, and larger than the average person’s. The hippocampus is also extremely vulnerable to the normal aging process, showing early erosion in function as people grow older. In dementia such as Alzheimer’s disease, this hippocampal deterioration is accelerated, leading to an inability to form new memories.

“We know that detrimental anatomical and functional changes occur in the hippocampus as mice and people get older,” said Villeda. “This is just from natural aging. We’re all heading in that direction.”

When the investigators compared hippocampi from old mice whose circulatory systems had been conjoined with those of young mice to hippocampi from old mice that had been paired with other old mice, they found consistent differences in a number of biochemical, anatomical and electrophysiological measures known to be important to nerve-cell circuits’ encoding of new experiences for retention in the cerebral cortex.

Recharging old brains

The hippocampi of older mice that had been conjoined to younger mice more closely resembled those of younger mice than did the hippocampi of older mice similarly paired with old mice. The old mice paired with young mice made greater amounts of certain substances that hippocampal cells are known to produce when learning is taking place, for example. Hippocampal nerve cells from older members of old-young parabiotic pairs also showed an enhanced ability to strengthen the connections between one nerve cell and another — essential to learning and memory.

“It was as if these old brains were recharged by young blood,” Wyss-Coray said.

Villeda, Wyss-Coray and their associates next subjected regular older mice to a test in which the mice were trained to quickly locate a submerged platform in a water-filled container. The mice had to speedily orient themselves using memory cues provided by their surroundings. The investigators injected old mice intravenously with plasma from young or old mice and ran them through the test. Typically, untreated older mice did poorly compared to young mice, as they did when injected with plasma from old mice. But if they were infused with young mice’s plasma they did much better.

This was likewise the case on another test in which mice were trained to freeze in fear when plunked into a particular environment. The better they recognized that environment, the longer they would freeze. Older mice typically freeze for a shorter period of time than younger ones do. Again, “freezing” times for older mice given young plasma, but not old plasma, increased significantly.

Finding the factors

In both tests, the improvement vanished if the plasma provided to the old mice had first been subjected to high temperatures. Heat treatment can denature proteins, so this hints that a blood-borne protein, or group of them, may be responsible for the cognitive improvements seen in old mice given young mouse plasma.

“There are factors present in blood from young mice that can recharge an old mouse’s brain so that it functions more like a younger one,” Wyss-Coray said. “We’re working intensively to find out what those factors might be and from exactly which tissues they originate.”

“We don’t know yet if this will work in humans,” he said, adding that he hopes to find out sooner rather than later. A near-term goal of his company is to test this proposition through a clinical trial.

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IIT Delhi 3D prints human skin

Researchers at the Indian Institute of Technology (IIT) Delhi have successfully 3D bio-printed human skin models that have certain anatomically relevant structural, mechanical and biochemical features similar to native human skin. The bio-printed skin produced in the lab by the team is already being used by a company for experiments.

The bio-printed skin model will have wide applications in testing cosmetics. It can also reduce and probably even replace testing on animals.

It can also be used for testing dermatology drugs on human skin and at a future date even help in testing drugs for personalised medicine.

Testing on animals

The European Commission has prohibited testing finished cosmetic products and cosmetic ingredients on animals. It even prohibits marketing of finished cosmetic products and ingredients in the European Union.

The skin is composed of two important layers — the inner dermis (made of fibroblasts) and the outer epidermis (keratinocytes, melanocytes). The junction between the two layers is not flat but is undulatory or wavy. The undulatory morphology is important as it provides biochemical cues and mechanical support to the epidermis layer, provides structural stability to the skin by making the two layers adhere to each other, and not allow cells to cross the junction.

Unlike the currently available tissue-engineered skin equivalents, the team  was successful in creating this wavy junction in the bioprinted skin model.

The undulatory junction was designed using 3D CAD and 10 layers of dermis were constructed through bioprinting followed by eight layers of epidermis. “We designed the pattern so that both layers fit and the interface had a wavy pattern,” says Prof.  Silk bioink mixed with fibroblasts was used for growing the dermis, while bioink mixed with keratinocytes and melanocytes was used for growing the epidermis.

No shrinkage

The bioprinted skin also retained the original dimension without any shrinkage for up to three weeks. Traditionally, collagen used for developing skin constructs start shrinking within a few weeks thus affecting the morphology. Testing on such skin constructs therefore cannot be carried out beyond one week.

The bioink containing the cells are deposited in a criss-cross pattern leaving gaps in between. “The keratinocytes in the epidermis were seen migrating and filling the pores. This type of migration, which was very clear and striking, and cellular self-assembly recapitulate wound healing-like situation in native skin,” says the first author of the paper.

The keratinocytes in the epidermis differentiate and form into four distinct layers. “We studied three proteins — fibronectin, cytokeratin 1 and 14 — that are biomarkers of keratinocyte differentiation. They are produced in the bioprinted skin though the amount was comparatively less than native skin,” he says.

Most importantly, gene and protein expression analysis showed 60% similarity in gene expression between bioprinted and native skin. “We identified 56 proteins expressed in bioprinted skin which play an important role in skin development, extracellular matrix organisation and keratinocyte differentiation,” says the co-author of the paper. 

“We will now explore the possibility of growing hairs on the bioprinted skin,” says the Dr. 

Prof.’s team has already developed a 3D construct for hair follicle structure in collaboration with a company.

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