Glucocorticoid-induced osteoporosis: mechanisms, management, and future perspectives.


Glucocorticoids are widely used for their unsurpassed anti-inflammatory and immunomodulatory effects. However, the therapeutic use of glucocorticoids is almost always limited by substantial adverse outcomes such as osteoporosis, diabetes, and obesity. These unwanted outcomes are a major dilemma for clinicians because improvements in the primary disorder seem to be achievable only by accepting substantial adverse effects that are often difficult to prevent or treat. To understand the pathogenesis of glucocorticoid-induced osteoporosis, it is necessary to consider that the actions of glucocorticoids on bone and mineral metabolism are strongly dose and time dependent. At physiological concentrations, endogenous glucocorticoids are key regulators of mesenchymal cell differentiation and bone development, with additional regulatory roles in renal and intestinal calcium handling. However, at supraphysiological concentrations, glucocorticoids affect the same systems in different and often unfavourable ways. For many years, these anabolic and catabolic actions of glucocorticoids on bone were deemed paradoxical. In this Review, we highlight recent advances in our understanding of the mechanisms underlying the physiology and pathophysiology of glucocorticoid action on the skeleton and discuss present and future management strategies for glucocorticoid-induced osteoporosis.

Source: Lancet

 

 

 

9 Ways to Actually Do What You Love.


Here’s a list of 9 ways that you can actually implement into your life whatever it is that you love.

1. Find what you love

It’s hard to follow your passion if you have no idea which way it went. If you already know your passion, you’re ahead of the game. But if you don’t this is the place to start. Generally, if you don’t know what you love there might be a few things happening:

a. You haven’t encountered your passion yet: In this case, get out there and start experiencing life. Try anything that sounds remotely interesting. Look to your personality, your past and your own hopes and dreams for clues.

b. You’ve “forgotten” your passion: Maybe it’s been so long since you did a particular thing that you’ve forgotten the love you have for it. Or maybe the love you used to have for something has faded. Work to rekindle the flame or remember the core of why you loved what you loved, and apply that to something new.

c. You’re afraid: Maybe your passion eludes you because you’re too afraid of what it would mean to know what you’re passionate about. Did you have a bad experience pursuing a passion in the past? Are you afraid that your passion will call on you to be bigger, stronger, brighter, and more out-there in the world than you feel comfortable with? It’s time to face your fear.

2. Make yourself a priority

You’ll need to actually carve out the time to do whatever you love. It doesn’t have to be a lot of time – any amount dedicated to what you love will make your life better. But, to make yourself a priority, you’re going to have to practice the art of saying no. No to things that waste your time, to things you don’t want to do but feel you should, and to things you want, but that don’t actually make you happier.

3. Shift your mindset

It’s not groundbreaking to think that you can actually make time for your passion. What is groundbreaking though, is the shift that comes with actually knowing to your core that you can make time for your passion. It’s one thing to know it in your brain, and quite another to know it in your heart. Shift your heart so that you know that a passion-filled life is possible for you.

4. Consider other people

Sometimes the difficulty in doing what you love comes in the form of feeling you’ll be disappointing others by taking time away from them. You can choose to involve other people in your passion, or you can make room for others to enjoy their own passion. Make it ok in your relationships to pursue things on your own, knowing you come back together as more whole people.

5. Lower the bar

In my work as a coach, I help people find their passions and put them to work – literally. But you don’t have to be paid to do what you love. Sometimes this requirement is just too much out of the gate. For now, begin doing what you love to do. If you love writing, write. If you love cooking, cook. Don’t worry too much that it’s happening in your precious few “spare” hours. As it evolves, you may be able to find a way to make your passions pay the bills, but for now, just do what you love and don’t put so much pressure on yourself.

6. Do what you don’t love (with a happy heart)

Life is funny that way. But when you put your best energy into everything you do, you are rewarded. I can’t pretend to really know the mechanics of this, though I have some ideas. The point is, though, when you constantly push yourself to be the best you can be in any situation, you begin to invite abundance and opportunity into your life.

7. Be fearless

So often I see people get paralyzed by fear. Their brain fast forwards to a yet-to-happen event which causes them to stay stuck. “What happens if I’m not good enough? What happens if I can’t make it?” It’s these fears – fears in anticipation of something that hasn’t even had the chance to occur yet, that prevents some people from even starting. Rest in the knowledge that you can handle whatever comes your way. Then keep moving.

8. Be positive

It’s easy to be beaten down by life sometimes, and the view from deep in that rut is less than hopeful. Consciously cultivate a positive attitude. It will carry you through the days when it’s easy to give up on passion – the days when you call your passion names like “pipe-dream.”

9. Do what you love

Don’t waste too much time planning to do what you love. Just do it. Pick up that paintbrush, your guitar, or your running shoes. Remember that often the barriers to doing what we love are of our own creation. You love what you love for a reason. Now get out there and enjoy It !!

 

Source: purposefairy.com

 

 

love-do-love

Targeted Drug Benefits Some Patients with Advanced Lung Cancer.


The drug crizotinib (Xalkori) substantially lengthens the amount of time some patients with advanced lung cancer live without their disease progressing, according to findings from the first large clinical trial to test the targeted therapy.

Initial results from the trial were presented Sunday at the European Society for Medical Oncology Congress(ESMO) in Vienna, Austria.

The Food and Drug Administration (FDA) approved crizotinib last year to treat patients with advanced non-small cell lung cancer (NSCLC) whose tumors have a specific genetic mutation. The approval was based on smaller, nonrandomized trials that showed crizotinib could shrink tumors in many patients with the mutation—a genetic rearrangement involving the ALK gene.

Until now, crizotinib had not been shown to prolong progression-free or overall survival compared with standard chemotherapy.

“The results from the phase I and phase II trials were pretty remarkable,” said lead investigator, Dr. Alice Shaw of Massachusetts General Hospital. “We had high tumor response rates, which were impressive for just a single agent.”

A large randomized trial was necessary, Dr. Shaw explained, to confirm that the tumor responses translated into meaningful outcomes and to answer questions about whether patients whose tumors had this genetic mutation were more sensitive to any therapy, not just crizotinib.

The results from the phase I and phase II trials were pretty remarkable. We had high tumor response rates, which were impressive for just a single agent.

—Dr. Alice Shaw

“Patients who received crizotinib did significantly better,” she said. Progression-free survival was more than twice as long in patients treated with crizotinib compared with those who received chemotherapy—docetaxel (Taxotere) or pemetrexed (Alimta)—7.7 months versus 3 months.

Nearly 350 patients were enrolled in the trial, which involved 105 centers in 21 countries and was funded by the drug’s manufacturer, Pfizer. Patients in the trial had advanced NSCLC that had returned after their initial treatment and their tumors had the ALK gene rearrangement. A number of studies have shown that tumors in about 4 to 5 percent of patients with NSCLC have the mutation.

The results may be enough to support a change in the drug’s regulatory status. The FDA’s earlier approval was an accelerated approval, meaning the drug was likely to benefit patients and address an unmet clinical need.

With such approvals, however, the agency requires data from larger trials to confirm that the drug has a clinical benefit and to ensure that unanticipated side effects do not outweigh any clinical improvements. Pfizer has notified the FDA of the trial results, the company said, and will provide the agency with the complete data when available.

Questions about Overall Survival

The ultimate goal of treatment, of course, is to lengthen overall survival. At this point, the trial has not shown that treatment with crizotinib does that any better than standard chemotherapy. And in large part because of the trial’s design, there’s a good chance that it won’t be able to show an improvement, according to several researchers.

Patients in the trial who were randomly assigned to receive either docetaxel or pemetrexed and whose disease began to progress were allowed to cross over to treatment with crizotinib. The crossover rate, Dr. Shaw noted, was 87 percent.

It’s still early in the trial, so nothing definitive about overall survival can be said yet. But with that extent of crossover, “really, the chemo arm is just like the crizotinib arm,” Dr. Shaw added.

The failure to show an overall survival benefit should not dampen enthusiasm for crizotinib with these patients, stressed Dr. Ramaswamy Govindan of Siteman Cancer Center in St. Louis. It’s “entirely possible” that overall survival is improved with crizotinib, Dr. Govindan continued, but the crossover may make it impossible to see in this trial. “Unfortunately, that’s just the way things are,” he said.

No new concerns about the drug’s safety were raised in the trial. Consistent with earlier trials of crizotinib, visual disturbances—often described as floating streams of light in patients’ peripheral vision—were the most common side effect, along with diarrhea and nausea. But more patients who received chemotherapy stopped treatment due to side effects.

“At every level, crizotinib was superior to chemotherapy,” Dr. Shaw said, including improvements in symptoms, delay in the onset of new symptoms, and general quality of life.

“From an oncologists’ standpoint, it’s really gratifying to see patients reporting a better quality of life in what is essentially an incurable disease,” she said.

Overcoming Resistance

Historically, even following dramatic tumor reductions with crizotinib treatment—including complete tumor eradication—the disease almost always returns.

The situation closely parallels what has been seen in patients with advanced NSCLC whose tumors have mutations in the EGFR gene. Many of these patients initially have excellent responses to gefitinib (Iressa) or erlotinib (Tarceva), but the tumors almost always come back, explained Dr. Giuseppe Giaccone of NCI’s Center for Cancer Research.

One potential escape route for tumors may be the development of additional mutations in the ALK gene that interfere with crizotinib’s ability to bind to its target. “But that doesn’t seem to be the major mechanism,” Dr. Giaccone said. Alterations in other key genes that can fuel cancer cell proliferation, including EGFR and MET, also appear to allow tumors to resume growing, he added.

Ways to potentially overcome this resistance are already being studied in human trials.

Data from early stage trials of second-generation ALK-targeted drugs, for example, were also presented at the ESMO meeting. In a small phase I trial testing the experimental drug LDK378, tumor responses were seen in 81 percent of NSCLC patients whose tumors had the ALK mutation and whose disease had returned after crizotinib treatment.

Crizotinib’s rapid ascent from the lab to the clinic is ‘a great model for modern drug development.’

—Dr. Ramaswamy Govindan

Other approaches include targeting ALK and EGFR, either with a single drug that inhibits both targets or combinations of drugs. For example, Dr. Giaccone and his CCR colleagues are part of a phase I trial testing the combination of crizotinib and the experimental agent dacomitinib in patients with advanced lung cancer, including patients with EGFR and ALK mutations. Dacomitinib inhibits EGFR and other members of the same growth factor family. Early findings from the phase I trial were presented at ESMO.

Combining targeted drugs and further subdividing patients into molecularly defined subgroups will only increase from this point on, Dr. Giaccone stressed.

Dr. Govindan called crizotinib’s rapid ascent from the lab to the clinic “a great model for modern drug development.” It demonstrates that “patient selection is critical,” he said.

NCI cooperative group trials are already being planned to test crizotinib as the first-line therapuytreatment in patients with metastatic NSCLC with ALK mutations, he said. Pfizer has also initiated a phase III trial, PROFILE 1014, testing crizotinib as a first-line treatment in patients with ALK rearrangements.

 

 

Beyond ALK and EGFR

Patients with a different gene rearrangement may also benefit from crizotinib, according to another early-phase study presented at the ESMO meeting. In the trial, patients with advanced NSCLC whose tumors had rearrangements in the ROS1 gene, which occur in less than 2 percent of patients, also had substantial tumor responses.

Crizotinib “has remarkable activity [in these patients], nearly identical to what’s been seen in patients with ALK rearrangements,” explained Dr. Shaw, who was also an investigator on the trial.

Another gene, KRAS, is among the most frequently mutated genes in patients with the most common type of NSCLC, adenocarcinoma, and some studies suggest that KRAS mutations are associated with a poor prognosis. Results from the phase II GALAXY trial, also presented at the ESMO meeting, suggested that the drug ganetespib may have greater efficacy than standard chemotherapy in patients with adenocarcinoma and in patients with KRAS mutations whose disease has returned following initial treatment.

Ganetespib targets heat-shock protein (HSP) 90, a “chaperone” protein that helps other proteins carry out their functions. The drug is a second-generation HSP90 inhibitor that does not appear to have the toxicity issues of the first-generation HSP90 inhibitors, said the trial’s lead investigator, Dr. Suresh Ramalingam of the Winship Cancer Institute in Atlanta.

Further follow-up is needed before investigators can confirm a benefit, Dr. Ramalingam cautioned. Earlier this year, results from a clinical trial of another targeted therapy, selumetinib, also suggested it may improve survival in NSCLC patients with KRAS mutations.

Both trials offer some much-needed hope. “This is the biggest molecular subset of lung cancer patients,” Dr. Ramalingam said. “They’re in serious need of good treatment options.”

Source: NCI.