Day: 05/11/2013

Current status on the diagnosis and evaluation of pancreatic tumour in Asia with particular emphasis on the role of endoscopic ultrasound.

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In Asia, the incidence of pancreatic cancer in some countries has been increasing. Owing to most cases being diagnosed late, prognosis for pancreatic cancer remains dismal. It is clear the future for pancreatic cancer is early detection. While the possible presence of pancreatic masses is often first raised by non-invasive abdominal imaging such as computerized tomography (CT) and magnetic resonance imaging (MRI), smaller lesions and locoregional lymph node metastases are often not detectable by these means. Endoscopic ultrasonography (EUS) offers a higher sensitivity (93-100%) for the detection of small potentially curable pancreatic masses than other existing imaging modalities. It is also recommended to evaluate portal vein confluence, portal vein, celiac axis and SMA origin, and exclude respectability. Due to the closer proximity of EUS to the target structure, and lower rate of needle tract seeding, EUS-guided fine needle aspiration (FNA) of pancreatic mass is considered the most suitable tissue acquisition technique. Lastly, EUS also enables the performance of endoscopic interventions. Its performance can be further enhanced with newer techniques, including contrast enhanced ultrasound and elastrography. It is anticipated that in the near future, molecular technologies may make it possible to detect microscopic amounts of cancer in tissue or blood, predict relapse and survival after therapy, as well as determine optimal therapy.

 

 

 

 

Cross-stage and combination treatment for Barcelona Clinic of Liver Cancer stage B (intermediate stage) hepatocellular carcinoma.

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The American Association for the Study of Liver Diseases (AASLD) has approved practice guideline for patients with hepatocellular carcinoma (HCC) staging, originally developed by the Barcelona Clinic of Liver Cancer.1 The guidelines recommend that liver transplantation, surgical resection, and local ablation therapy, including percutaneous ethanol injection (PEI) and radiofrequency ablation (RFA), can all be considered as curative treatments for patients in the very early and early stages (stages 0 and A). Patients classified in the intermediate stage (stage B) should be treated by transcatheter arterial chemoemolization (transarterial chemoembolization [TACE]). Sorafenib, a multikinase inhibitor with both anti-angiogenic and antiproliferative properties, has been shown to prolong the median overall survival and the median time to progression (TTP) compared to placebo in two randomized, controlled trials (RCT).2,3 Thus, in the 2010 revision of the AASLD guidelines, it was proposed as the current standard of care (SOC) for patients in advanced-stage (stage C) HCC.

In actual fact, among the 22 recommendations in the AASLD guidelines for the management of HCC, only five (21%) can be categorized as supported by level I evidence, according to evidence-based medicine clinical practice guidelines. These five recommendations supported by level I evidence are: (i) HCC surveillance is recommended in high-risk patients; (ii) comparison between results of PEI and RFA; (iii) benefit of TACE; (iv) effects of sorafenib; and (v) no benefit of tamoxifen, anti-androgens, octreotide, or hepatic artery ligation/embolization. The proportion of level I evidence in this HCC guideline is lower than for AASLD chronic hepatitis B (CHB) practice guideline (28/90, or 31%).1 One reason for this is the acknowledged greater difficulty to conduct RCT for HCC than for CHB. Therefore, only adopting results from RCT is not feasible or practical for HCC management. Instead, information from well-conducted longitudinal outcomes research is important, although this notionally only provides level II evidence.

In this issue of the Journal of Gastroenterology and Hepatology, Kim et al. reported observations on 264 patients with stage B HCC who received TACE. Approximately one-third (n = 97) were free of progressive disease (PD[–]) during the first 6 months after TACE, and only one-eighth (n = 33) were PD(–) after a mean 18-month follow up.4 Although TACE is the only recommended treatment in AASLD guidelines for stage B patients, its efficacy remains unsatisfactory. We need more optimal treatment for patients with stage B HCC. In particular, we need to know whether cross-stage or combination use of existing treatment modalities can improve clinical outcomes.

The first issue is whether curative treatment could be used in the management for stage B patients. Conservative Milan criteria and expanded University of California, San Francisco (UCSF) criteria are the two most widely accepted indications for liver transplantation for patients with HCC.5 Some cases of stage B HCC might meet UCSF criteria and undergo liver transplantation. Although surgical resection is the treatment of choice for stage 0/A cases, it is impossible to conduct a RCT comparing this traditional treatment and placebo. The same argument applies to stage B patients. Several clinical outcome studies, including our own,6 have provided evidence of benefit from surgical resection for stage B patients. In particular, such studies provide undeniable evidence that stage B HCC patients selected for surgical resection obtained better survival than those who were treated by TACE. Several recent reviews in surgical literature also showed a better overall survival in cases with surgical resection than in those treated by non-surgical therapies, even though these patients were beyond stage 0/A7. However, surgical resection should not be the ordinary choice to treat stage B patients, as its application is limited to several factors. These include patients’ choice, liver functional reserve, skillful surgeons, and experienced hospitals for postoperative care.

Treating multiple nodular HCC patients with nodule numbers slightly more than three by RFA can sometimes be feasible.8 A meta-analysis of 10 RCT showed TACE combined with percutaneous ablation therapy, especially PEI, improved overall survival for large HCC.9 Mid-term outcomes of an RCT also showed that RFA combined with TACE was more effective than RFA alone in extending the ablated area; it required fewer treatment sessions and decreased local tumor progression rate for patients with intermediate-sized HCC.10 However, current settings for RFA or for combination treatment of TACE and RFA in the treatment of stage B patients are the same as for surgical resection. Therefore, the indications for the above treatment modalities in stage B patients should be documented in the future guidelines.

However, oral medication can be used more conveniently and widely than either surgical or percutaneous procedures. The only approved molecular target therapeutic agent, sorafenib, is currently recommended as the SOC for patients with stage C HCC. Several RCT have been or are being conducted to prove the benefits of combining sorafenib and SOC for patients with earlier stages.

A phase I trial has clarified possible adverse effects experienced by patients treated with a combination of TACE and sorafenib. The incidence of these is generally comparable with those with sorafenib alone; an exception is grade III thrombocytopenia, which might be more frequently noted in the former group.11 Phase II trials also showed that the combination of sorafenib and drug-eluting bead–TACE in patients with unresectable HCC is safe and well tolerated, with a majority of toxicities related to sorafenib. Preliminary data concerning efficacy are also promising.12 In an interim analysis of a phase III RCT in patients before transplantation, a potential superiority in TTP was disclosed in patients with combined treatment of TACE and sorafenib over TACE alone;13 the final results are anticipated soon. Another phase III RCT conducted in Japan and Korea concluded that sorafenib did not significantly prolong TTP in patients who responded to TACE. The result might have been due to delays in starting sorafenib after TACE and/or a low daily dose of sorafenib.14 Furthermore, two ongoing large-scaled RCT in stage B patients, that is, the Eastern Cooperative Oncology Group 1208 and Sorafenib or Placebo in Combination with Transarterial Chemoembolization for Intermediate-Stage Hepatocellular Carcinoma (SPACE), are currently exploring the benefits of combination therapy.

If the results of the afore-mentioned RCT favor combination treatment, should all patients be treated with a combination of TACE and sorafenib instead of TACE alone? The answer is absolutely “no”. Although TACE is now categorized as a non-curative treatment, some patients can be very well controlled or even cured by it. Thus, we should identify those patients with “TACE refractory” or “TACE failure” and then switch to sorafenib monotherapy, or add this agent to ongoing TACE.

Kim et al. proposed the term “stage progression” (SP),4 which they defined as the development of either vascular invasion or extrahepatic metastasis, or progression from stage B to stage C HCC during the course of TACE treatment. Their conclusion is that SP might be the end-point of TACE, so that cases with SP can be defined as “TACE refractory”. However, on the basis of the AASLD guidelines, stage C should not represent TACE refractory, and it is actually defined as out of the indications of TACE. “SP-free survival” should be the end-point of TACE in current practice. Thus, declaring that SP is representative as TACE refractory must be too late. They also concluded that the development of progression or the need for three sessions of TACE within the first 6 months could be predictive of TACE refractoriness. This finding is closer to the situation of “TACE refractory”.

The above issue has been documented in the 2010 version the Japan Society of Hepatology (JSH) guidelines,8 who clearly defined TACE failure or refractory as: (a) an intrahepatic lesion; (a-i) more than two consecutive incomplete necroses (depositions of lipiodol < 50%) are seen by response evaluation computed tomography (CT) within the treated tumors 4 weeks after adequately-performed TACE; (a-ii) more than two consecutive appearances of a new lesion (recurrence) are seen in the liver by response evaluation CT at 4 weeks after adequately-performed TACE; (b) appearance of vascular invasion; (c) appearance of extrahepatic spread; and (d) tumor marker: continuous elevation of tumor markers, even immediately after TACE. The JSH also gave the following recommendation: as hepatic arterial infusion chemotherapy is not effective for TACE failure patients, molecular-targeted therapy is the first choice of treatment.

Cases with tumor progression, followed by intensive TACE, should switch to sorafenib. Kudo and Ueshima reported 15 cases with complete response by sorafenib,15 and two of 90 cases in their center achieved complete response. In a literature review, more than 10 case reports like this can be found from PubMed. We have also experienced a case with complete response. It is believed that if patients are not suitable for TACE, the treatment modality should be switched to sorafenib. However, the indication of combination therapy of TACE and sorafenib is still controversy now. There was not evidence enough to use the combination therapy in all stage B patients initially as a purpose in preventing TAE refractory/failure. Repeated TACE could give significant survival benefits to metastatic HCC patients with conserved liver function and intrahepatic HCC T3 stage.16 Combination therapy should be considered in patients who can get any benefit from TACE for tumor control. However, TACE still has some serious adverse effects, such as deteriorating liver function and intolerance of post-TACE syndrome. For TACE-refractory cases without any contraindications of combination therapy of TACE and sorafenib, an RCT to compare sorafenib with and without TACE should be conducted to elucidate the difference between switching and adding on. Both overall survival and quality of life should be assessed in these studies.

In summary, the combination treatment of TACE and sorafenib is currently a hot issue. In the future, it could become an option for SOC for stage B HCC cases and might improve patient survival. However, more information from RCT and outcome research, such as the interesting data reported by Kim et al. in this issue,4 is required.

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References

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Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. Hepatology 2011; 53: 1020–2.

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Llovet JM, Ricci S, Mazzaferro V et al. Sorafenib in advanced hepatocellular carcinoma. N. Engl. J. Med. 2008; 359: 378–90.

Cheng AL, Kang YK, Chen Z et al. Efficacy and safety of sorafenib in patients in the Asia–Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2009; 10: 25–34.

Kim HY, Park JW, Joo J et al. Severity and timing of progression predict refractoriness to transarterial chemoembolization in hepatocellular carcinoma. J. Gastroenterol. Hepatol. 2012; 27: 1051–6.

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Mazzaferro V, Chun YS, Poon RT et al. Liver transplantation for hepatocellular carcinoma. Ann. Surg. Oncol. 2008; 15: 1001–7.

Wang JH, Changchien CS, Hu TH et al. The efficacy of treatment schedules according to Barcelona Clinic Liver Cancer staging for hepatocellular carcinoma—Survival analysis of 3892 patients. Eur. J. Cancer 2008; 44: 1000–6.

Chow PK. Resection for hepatocellular carcinoma: is it justifiable to restrict this to the American Association for the Study of the Liver/Barcelona Clinic for Liver Cancer criteria? J. Gastroenterol. Hepatol. 2012; 27: 452–7.

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Kudo M, Izumi N, Kokudo N et al. Management of hepatocellular carcinoma in Japan: Consensus-Based Clinical Practice Guidelines proposed by the Japan Society of Hepatology (JSH) 2010 updated version. Dig. Dis. 2011; 29: 339–64.

Wang W, Shi J, Xie WF. Transarterial chemoembolization in combination with percutaneous ablation therapy in unresectable hepatocellular carcinoma: a meta-analysis. Liver Int. 2010; 30: 741–9.

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Morimoto M, Numata K, Kondou M, Nozaki A, Morita S, Tanaka K. Midterm outcomes in patients with intermediate-sized hepatocellular carcinoma: a randomized controlled trial for determining the efficacy of radiofrequency ablation combined with transcatheter arterial chemoembolization. Cancer 2010; 116: 5452–60.

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Dufour JF, Hoppe H, Heim MH et al. Continuous administration of sorafenib in combination with transarterial chemoembolization in patients with hepatocellular carcinoma: results of a phase I study. Oncologist 2010; 15: 1198–204.

Pawlik TM, Reyes DK, Cosgrove D, Kamel IR, Bhagat N, Geschwind JF. Phase II trial of sorafenib combined with concurrent transarterial chemoembolization with drug-eluting beads for hepatocellular carcinoma. J. Clin. Oncol. 2011; 29: 3960–7.

Hoffmann K, Glimm H, Radeleff B et al. Prospective, randomized, double-blind, multi-center, Phase III clinical study on transarterial chemoembolization (TACE) combined with sorafenib versus TACE plus placebo in patients with hepatocellular cancer before liver transplantation—HeiLivCa [ISRCTN24081794]. BMC Cancer 2008; 8: 349.

Kudo M, Imanaka K, Chida N et al. Phase III study of sorafenib after transarterial chemoembolisation in Japanese and Korean patients with unresectable hepatocellular carcinoma. Eur. J. Cancer 2011; 47: 2117–27.

Kudo M, Ueshima K. Positioning of a molecular-targeted agent, sorafenib, in the treatment algorithm for hepatocellular carcinoma and implication of many complete remission cases in Japan. Oncology 2010; 78 (Suppl. 1): 154–66.

Yoo DJ, Kim KM, Jin YJ et al. Clinical outcome of 251 patients with extrahepatic metastasis at initial diagnosis of hepatocellular carcinoma: does transarterial chemoembolization improve survival in these patients? J. Gastroenterol. Hepatol. 2011; 26: 145–54.

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Hepatobiliary and Pancreatic: Detection of early hepatocellular carcinoma by enhanced magnetic resonance imaging..

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A woman, aged 75, with cirrhosis caused by hepatitis C had a routine ultrasound study for surveillance for hepatocellular carcinoma. A possible nodule was identified in segment VI but it was difficult to identify the contours or margins of the nodule. A contrast-enhanced ultrasound (US) study with perfluorobutane (Sonazoid®) showed no enhancement or washout of the nodule in either the vascular or Kupffer phases. Computed tomography (CT) during hepatic arteriography (CTHA) or arterial portography (CTAP) also failed to show a liver lesion (Figure 1, left and middle panel). In contrast, gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Primovist®)-enhanced magnetic resonance imaging (MRI) clearly revealed a low-signal nodule during the hepatobiliary phase (Figure 1, right). The appearance was consistent with either a dysplastic nodule or a well-differentiated hepatocellular carcinoma. As the nodule could not be detected on US or CT, we performed real-time virtual sonography synchronizing B-mode US images with the hepatobiliary phase of enhanced MRI which allowed for the same area to be displayed in real time as both MR and B-mode US images (Figure 2). Using this technique, the nodule was clearly visualized and an aspiration biopsy was performed. Histology revealed a well-to-moderately differentiated hepatocellular carcinoma that was treated by percutaneous radiofrequency ablation guided by real-time virtual sonography with contrast-enhanced MRI.

Radiofrequency ablation is widely used for the treatment of hepatocellular carcinoma. However, to achieve successful ablation, it is important to have a clear view of the margins of the nodule. Although most larger hepatocellular carcinomas are hypervascular, early carcinomas can be hypovascular and can be difficult to detect with contrast-enhanced US, contrast-enhanced CT or CT during hepatic arteriography. The recent introduction of contrast-enhanced MRI appears to have improved the detection of early liver tumors and may be helpful for the differentiation of early hepatocellular carcinoma from dysplastic nodules. Real-time virtual sonography is a system in which a B-mode US image can be synchronized with CT images. To our knowledge, this is the first report of the successful use of real-time virtual sonography with enhanced MRI for the detection and treatment of an early hepatocellular carcinoma. This technology may facilitate the diagnosis and treatment of hepatocellular carcinoma at an earlier stage.

Source: http://onlinelibrary.wiley.com

Gastrointestinal: Esophageal metastasis from hepatocellular carcinoma.

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A 63-year-old man visited our hospital because he was undergoing treatment of hepatocellular carcinoma (HCC) in 2007. Multinodular HCC had been detected, and he had been treated 8 times with transcatheter arterial chemoembolization and twice with radiofrequency ablation. In addition, he received endoscopic variceal ligation (EVL) and endoscopic injection therapy due to esophageal varices. Three years after commencing treatment, the patient represented with melena. Bleeding esophageal varices were diagnosed and EVL was performed. At this time, abdominal CT demonstrated multinodular-type HCC in both lobes of the liver, with tumor thrombi in the portal vein. Follow-up upper endoscopy revealed a post-EVL ulcer at the esophagogastric junction (Figure 1). Two months later, upper endoscopy was performed due to slight progression of anemia. Endoscopic examination showed two whitish polypoid masses at the site of EVL (Figure 2a), and a submucosal tumor-like protrusion was recognized on the oral side of the polypoid lesions (Figure 2b). Biopsy specimens obtained from the polypoid mass showed a tumor that was histologically consistent with HCC (Figure 3a) and that was focal positive staining for alphafetoprotein (Figure 3b) and glypican-3 (Figure 3c). After biopsy specimens were taken, argon plasma coagulation was performed at the biopsy site. The patient died of progressive hepatic failure one month later.

HCC is a common malignancy worldwide and extrahepatic metastasis in patients with HCC occurs frequently, in 30–75% of patients. Gastrointestinal involvement is seldom found, in only 4–12% of cases in autopsy series, whereas it has been reported that premortem-diagnosed gastrointestinal tract involvement is found in 0.5–2% of cases. The most commonly involved site was the duodenum, followed by the stomach, the colon, and the jejunum.

Portal blood flow can be reversed by increased intrahepatic resistance and arteriovenous communications in patients with liver cirrhosis associated with HCC, which may cause retrograde metastasis of HCC via the portal system. There are two different hypotheses concerning the way HCC metastasizes to the esophagus: either by direct invasion of the gastrointestinal tract via contiguation between the serosal side of a liver tumor and the esophagus, or via the hematogenous spread of tumor emboli infiltrating via the portal vein system and being disseminated by hepatofugal portal blood flow to the esophagus.

In our patient, the therapy for esophageal varices may have caused the esophageal metastasis of HCC. Tumor emboli in the portal system may have been trapped at the site where the variceal bloodstream was interrupted by EVL, and the metastatic tumor then could have grown and broken through the ulcer base due to EVL. The metastatic tumor from HCC in the esophagus showed a rapid increase in size, and it changed to the appearance of a submucosal mass. As the tumor size increased further, the shape of the esophageal metastasis appeared to change from a submucosal mass to a polypoid mass.

Source: http://onlinelibrary.wiley.com

Targeted drugs to tackle hepatitis C.

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But experts debate US screening recommendations.

John strains to recall the gap between learning that he had hepatitis C and deciding to get treated: it was either four years or five. His thinking is clouded by the combination of three drugs that he is taking to clear the infection. After the treatments’ other side effects set in — severe flu-like symptoms, depression and exhaustion — he took leave from his job as a chef in New York. John, whose name has been changed to protect his privacy, was at high risk of catching the virus, having once been addicted to crystal methamphetamine. But as a 51-year-old, he is also a baby boomer — a member of the generation born between 1945 and 1965 — millions of whom will face the disease and its sometimes harrowing treatment.

Better drugs are on the way. But the possibility of improved treatment is intensifying a debate about whether to screen a broad swathe of the US population for hepatitis C.

Last month, the pharmaceutical company Gilead, based in Foster City, California, submitted its hepatitis-C drug sofosbuvir to the US Food and Drug Administration for approval, after phase II trials showed a 100% success rate in a few patient groups when it was used in combination with existing drugs. Last week, the first phase III results showed similarly promising results (E. Lawitz et al. N. Engl. J. Med. http://doi.org/mcc; 2013).

The drug is one of at least ten in phase III trials in the United States that promise to improve results or reduce side effects. The first of these drugs could reach the market as early as 2014, and a recommendation from the US Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia, to screen an entire generation for the disease could create vast demand for them.

John is a part of a demographic time bomb. Up to 4 million Americans are infected with hepatitis C, which can irreparably damage the liver and lead to liver cancer, but because it inflicts injury slowly over decades, as many as 85% of carriers do not know that they have it. Baby boomers account for about 27% of the US population, but up to 75% of those infected with hepatitis C, possibly because injecting drugs — one infection route — was more common during their youth than in other eras. Last August, the CDC recommended screening the entire generation of people born between 1945 and 1965, as well as people in high-risk populations such as intravenous-drug users. The CDC predicts that generational screening would find an extra 800,000 cases and prevent at least 120,000 deaths. “We have an opportunity to make a real dent in the impact of the disease,” says Kimberly Page, an epidemiologist at the University of California, San Francisco.

 

John’s doctor, infectious-disease specialist Kristen Marks of Weill Cornell Medical College in New York, says that screening is especially important for baby boomers because early symptoms of hepatitis C, such as fatigue and malaise, are difficult to distinguish from signs of ageing. People dismiss symptoms, says Marks, and some might not remember trying intravenous drugs in their youth. Even if they do, she adds, “they might not tell their doctor”. A peak in cases of liver scarring from untreated hepatitis C is expected in the next few years (see ‘An approaching burden’). But with the new drugs on the horizon, now is an optimistic time for treatment, says Marks. “Historically, not having good treatments was a disincentive for screening,” she says. “Now, I think there’s a renewed interest.”

But last November, the US Preventive Services Task Force (USPSTF), a panel of experts assembled by the US Department of Health and Human Services, released a draft statement giving the screening recommendation a ‘grade C’. That means that doctors should consider birth year when deciding whether to offer screening, but should take other factors into account. The mediocre grade could discourage many health-care providers — including Medicaid, the provider for people with low incomes — from pushing screenings.

As with its controversial recommendations in 2009 and 2012 to limit screening for breast and prostrate cancer, the USPSTF has tried to balance the benefits of screening against the risk of unnecessary treatment. The combination therapies used to combat hepatitis C can cost US$1,100 per week and last for up to a year, with severe side effects. Other treatments cost $4,100 per week. (Gilead declined to comment on the future price of sofosbuvir-based treatments.)

“We have an opportunity to make a real dent in the impact of the disease.”

Roger Chou, an internal-medicine specialist at Oregon Health and Science University in Portland and a scientific reviewer for the USPSTF, adds that in most patients, the disease is imperceptible: only 20% of people develop liver scarring in the first 20 years of infection, according to the CDC. Of the few baby boomers that might be caught through additional screening, says Chou, some will not need to be treated.

But new drugs, however expensive, could change the calculus for doctors and patients, says Mark Eckman, a physician at the University of Cincinnati in Ohio, who has calculated that even screening the entire US population would be cost effective given the financial and personal burdens of living with liver diseases (M. H. Eckman et al. Clin. Infect. Dis. 56, 1382–1393; 2013).

For example, sofosbuvir, which is one of a set of new antiviral drugs that specifically target hepatitis C rather than viruses in general, can achieve success rates above 90% in combination treatments of just three months. The drug inhibits the virus’s RNA polymerase, preventing viral replication. It is also being tested without the classic combination drug of pegylated interferon, which boosts the immune system but causes harsh side effects.

The USPSTF is still reviewing its draft recommendations, but it is likely to make a final decision in the next few months, well before approval of sofosbuvir or other new drugs could alter the calculations.

That is too bad, says David Thomas, a viral-hepatitis specialist at Johns Hopkins University in Baltimore, Maryland, who argues that the next generation of drugs helps to justify wide-scale screening. “It makes a pretty easy case for doing something different,” he says.

Source: Nature

 

Meteor Shower from Halley’s Comet Peaks This Weekend.

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some of the remnants of the most famous of comets will briefly light up the early morning sky

The famed Halley’s Comet made its last pass through the inner solar system in 1986 and is not due back until the summer of 2061. But each time Halley sweeps around the sun, it leaves behind a dusty trail — call it “cosmic litter” — that is responsible for two meteor showers on Earth each year. The first of those “shooting stars” displays, the Eta Aquarid meteor shower, will peak on Sunday.

The Eta Aquarid meteor shower occurs each year in early May because the orbit of Halley’s Comet closely approaches the orbit of Earth in two places. The first is the May timeframe, which leads to the Eta Aquarids. The other point occurs in mid-October, producing the Orionid meteor shower.

When and Where to Watch

The Eta Aquarid meteor shower is predicted to peak early on Sunday morning, but dark skies and clear weather are vital to observe them. Under ideal conditions (a dark, moonless sky) about 55 to 60 of these very swift meteors might be seen per hour.

The meteor shower appears at about one-quarter of its peak strength for several days before and after May 5. This is a very good year to look out for the Eta Aquarid meteors from Halley’s Comet because the moon will be at a thin, waning crescent phase, and just 20-percent illuminated and providing little interference for viewing these swift streaks of light.

From places south of the equator, the Eta Aquarids typically put on very good show. Australian stargazers consider them to be the best meteor display of the year.

But for those watching from north of the equator, it’s a much different story.

Where to look

The apparent origin point of a meteor shower in the night sky is known as its radiant. For the Eta Aquarids, the radiant is found within the “Water Jar” of the constellation Aquarius, which begins to rise above the eastern horizon around 3 a.m. your local time. Unfortunately, this constellation never really gets very high as seen from north temperate latitudes. And soon after 4 a.m. local time, the morning twilight will begin to brighten the sky.

So if you are hoping to see up to 60 meteors per hour, forget it. With the radiant so low above the horizon, the majority of those meteors will be streaking below the horizon and out of sight.

In fact, from North America, typical Aquarid rates are only 10 meteors per hour at 26 degrees north latitude (Miami, Fla., or Brownsville, Texas), 5 per hour at around 35 degrees latitude (Los Angeles, Calif., or Cape Hatteras, N.C.) and practically zero to the north of 40 degrees (New York, Chicago, and Philadelphia).

“So,” you may be thinking, “What’s the point of getting up before dawn to watch?”

The answer: Despite the long odds, you still just might see something spectacular.

Catch an Earthgrazer, or comet crumb

For most, perhaps the best hope is perhaps catching a glimpse of a meteor emerging from the radiant that will skim the atmosphere horizontally — much like a bug skimming the side window of an automobile.

Meteor watchers call such shooting stars “earthgrazers” and they are known forspectacularly long, colorful, long-lasting trails.

“These meteors are extremely long,” Robert Lunsford of the International Meteor Organization explained. “They tend to hug the horizon rather than shooting overhead where most cameras are aimed.”

“Earthgrazers are rarely numerous,” NASA meteor expert Bill Cooke, a member of the Space Environments team at the Marshall Space Flight Center has said. “But even if you only see a few, you’re likely to remember them.”

If you do catch sight of one early these next few mornings, remember that you are likely seeing the incandescent streak produced by material which originated from the core of Halley’s Comet.

So it is that the shooting stars that we have come to call the Eta Aquarids are really an encounter with the traces of a famous visitor from the depths of space and from the dawn of creation.

Source: Space.com

 

Do We Have to Cool Down After Exercise?.

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If you’re like most people, the time you spend exercising is a valuable commodity that you’ve carefully planned and fit into your day. And when your workout is over, you may simply grab a quick shower or pull on a sweatshirt, skipping the post-exercise cool down because you’re eager to get on with your day.

Cooling down after exercise has long been touted as a necessary step to help prevent muscle soreness and improve recovery, but is it really?

The Case for Skipping Your Post-Exercise Cool Down

In 2007, one of the first studies on cooling down was published.1 The finding? Cooling down for 10 minutes after a workout had no impact on delayed-onset muscle soreness. Even though more than half a decade has passed, these results have yet to translate into practice, as most people are still under the impression that a cool down is beneficial.

Yet, newer research also suggests that the choice to cool down is simply one of personal preference – not one that will drastically impact your recovery. For instance:

  • Cooling down after performing strenuous forward lunges had no impact on muscle pain the next day among active adults; those who cooled down had the same amount of pain as those who did not2
  • Cooling down after soccer practice had no impact on performance, flexibility or muscle soreness the next day among professional soccer players3, 4

While it appears unlikely that cooling down has any real benefit in your post-workout recovery, muscle pain or next-day performance, it may help prevent the buildup of blood in your veins, which can lead to dizziness or fainting.5

The cool down also brings fresh blood into areas to help with lactic acid removal, while bringing your heart rate down to resting pulse quicker. A proper cool down also helps lower a raised heart rate down to resting heart rate safely.

Further, it may also help you to simply unwind after an intense workout, easing the transition back to your normal level of activity.

Personally I only cool down for three minutes after doing a high-intensity workout. If you are pushing your body to extremes it makes loads of sense to do a cool down, especially if you are close to or exceeding your maximum calculated heart rate (220 minus your age).

Static Stretching Before Exercise: Another Myth Busted

As with cool downs, stretching before exercise is another fitness dogma many of us wouldn’t dare neglect. After all, we’ve been told for decades that stretching is key for warming up your muscles and helping to prevent injuries.

However, pre-exercise static stretching generally hurts rather than helps your athletic and muscle performance, particularly when the stretch is held for 60 seconds or more.6 Static stretching is when you hold your muscle in a fixed position for a prolonged period, such as bending over to touch your toes.

This technique has been regarded as the gold standard for decades, but now research shows that it actually decreases the blood flow within your tissue creating localized ischemia (a restriction in blood supply) and lactic acid buildup. This can potentially cause irritation or injury of local muscular, tendinous, lymphatic, and neural tissues.

The evidence is so clear that the American College of Sports Medicine now advises against this form of stretching prior to your workouts. Unlike the cool down, however, which you can generally safely skip, all forms of stretching should not be avoided prior to exercise, only static stretching.

Dynamic stretching, on the other hand, has been shown to positively influence power, speed, agility, endurance, flexibility, and strength performance when used as a warm-up.7 And unlike cool-downs, warm-ups are very important and have been shown to help reduce and prevent muscle soreness.8

My favorite type of dynamic stretching is active isolated stretches developed by Aaron Mattes. With Active Isolated Stretching or AIS, you hold each stretch for only two seconds, which works with your body’s natural physiological makeup to improve circulation and increase the elasticity of muscle joints.

This technique also allows your body to help repair itself and prepare for daily activity. If you’re an avid exerciser, this news to overhaul your pre-workout stretches and your post-workout cool-down may come as a surprise, but these tips can help you to make the most of your workouts.

More Tips for Optimizing Your Workouts: The Benefits of Short and Intense Activity

f you’re excited at the prospect of cutting down your workout time by skipping your cool-down, you’ll be even more enthused to learn about high-intensity interval training (HIIT). Remember, if you do this type of exercise I do believe a three-minute cool down is important.

Researchers have repeatedly confirmed the superior health benefits of HIIT compared to traditional and typically performed aerobic workouts. For example, high-intensity interval-type training gives a natural boost to human growth hormone (HGH) production—which is essential for optimal health, strength and vigor—and has been shown to significantly improve insulin sensitivity, boost fat loss, and increase muscle growth. Anaerobic HIIT can be performed on a recumbent bike or an elliptical machine, or sprinting outdoors (with proper guidelines to avoid injury). You can even perform high-intensity strength training.

While there are a large number of variations, the HIIT routine I recommend involves going all out for 30 seconds and then resting for 90 seconds between sprints, as demonstrated in the video above The total workout is typically 8 repetitions. In all, you’ll be done in about 20 minutes, and you only need to perform HIIT two or three times a week.

Contrary to popular belief, extended extreme cardio actually sets in motion inflammatory mechanisms that damage your heart. So while your heart is indeed designed to work very hard, and will be strengthened from doing so, it’s only designed to do sointermittently, and for short periods—not for an hour or more at a time. This is the natural body mechanics you tap into when you perform HIIT.

How to Round Out Your Exercise Program

In addition to doing high-intensity interval exercises a couple of times a week, it’s wise to alternate a wide variety of exercises in order to truly optimize your health. As a general rule, as soon as an exercise becomes easy to complete, you need to increase the intensity and/or try another exercise to keep challenging your body. I recommend incorporating the following types of exercise into your program on days when you’re not doing HIIT:

  • Strength Training: If you want, you can increase the intensity by slowing it down. You need enough repetitions to exhaust your muscles. The weight should be heavy enough that this can be done in fewer than 12 repetitions, yet light enough to do a minimum of four repetitions. It is also important NOT to exercise the same muscle groups every day. They need at least two days of rest to recover, repair and rebuild.

For more information about using super slow weight training as a form of high-intensity interval exercise, please see my interview with Dr. Doug McGuff.

  • Core Exercises: Your body has 29 core muscles located mostly in your back, abdomen and pelvis. This group of muscles provides the foundation for movement throughout your entire body, and strengthening them can help protect and support your back, make your spine and body less prone to injury and help you gain greater balance and stability.

Exercise programs like Pilates, yoga, and Foundation Training are great for strengthening your core muscles, as are specific exercises you can learn from a personal trainer.

  • Stretching: As mentioned, my favorite type of stretching is Active Isolated Stretching (AIS) developed by Aaron Mattes. This technique allows your body to repair itself and prepare for daily activity. You can also use devices like the Power Plateto help you stretch.

Source: mercola.com

 

MAP kinase signaling and inhibition in melanoma..

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The mitogen-activated protein kinase (MAPK) pathway is critical to oncogenic signaling in the majority of patients with malignant melanoma. Driver mutations in both NRAS and BRAF have important implications for prognosis and treatment. The development of inhibitors to mediators of the MAPK pathway, including those to CRAF, BRAF, and MEK, has led to major advances in the treatment of patients with melanoma. In particular, the selective BRAF inhibitor vemurafenib has been shown to improve overall survival in patients with tumors harboring BRAF mutations. However, the duration of benefit is limited in many patients and highlights the need for understanding the limitations of therapy in order to devise more effective strategies. MEK inhibitors have proven to particularly active in BRAF mutant melanomas also. Emerging knowledge about mechanisms of resistance as well as a more complete understanding of the biology of MAPK pathway signaling provides insight into rational combination regimens and sequences of molecularly targeted therapies.

Source: Oncozene

 

Exercise Could Hold Key to Successful Cancer and Mental Health Treatment.

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run

Mounting evidence continues to show that exercise may be a key component in successful cancer prevention and treatment. Studies have also found that it can help keep cancer from recurring, so it’s really a triple-win.

Yet not surprisingly few oncologists ever tell their patients to engage in exercise beyond their simple daily, normal activities, and many cancer patients are reluctant to exercise, or even discuss it with their oncologist. Hopefully, you will not be one of them.

Most recently, research announced at the 2013 International Liver Congress1found that mice who exercised on a motorized treadmill for an hour each day, five days a week for 32 weeks, experienced fewer incidents of liver cancer than sedentary mice.

Exercise may also be absolutely crucial in the treatment of depression, according to recent research.2 I’ve often stated this, and the science continues to support this advice.

Meanwhile, mounting evidence condemns the “evidence-based” drug paradigm, as reviews keep finding that large amounts of published drug research is either seriously flawed or outright fraudulent — motivated of course by the financial interests of the funding party.

Might Exercise Be a Key to Cancer Cure?

Hepatocellular carcinoma (HCC) is a cancer that originates in your liver cells, and is one of the most common types of cancers. According to the featured article inMedical News Today,3 HCC accounts for just over five percent of all cancers worldwide, and causes an estimated 695,000 deaths annually.

According to the reported research,4 the first of its kind for this type of tumor, regular exercise may be the key to significantly reducing your chances for developing liver cancer.

The study involved two groups of mice: One group was fed a high fat diet, and then divided into two sub-groups — one that exercised and one that did not. The second group was fed a controlled diet, and also divided into sub-groups of exercise and non-exercise. According to the featured article:

“After 32 weeks of regular exercise, 71 percent of mice on the controlled diet developed tumors larger than 10mm versus 100 percent in the sedentary group. The mean number and volume of HCC tumors per liver was also reduced in the exercise group compared to the sedentary group.”

In the high-fat diet group, exercise decreased the development of non-alcoholic fatty liver disease. Professor Jean-Francois Dufour told Medical News Today:

“We know that modern, unhealthy lifestyles predispose people to non-alcoholic fatty liver disease which may lead to liver cancer; however it’s been previously unknown whether regular exercise reduces the risk of developing HCC. This research is significant because it opens the door for further studies to prove that regular exercise can reduce the chance of people developing HCC.

The results could eventually lead to some very tangible benefits for people staring down the barrel of liver cancer and I look forward to seeing human studies in this important area in the future. The prognosis for liver cancer patients is often bleak as only a proportion of patients are suitable for potentially curative treatments so any kind of positive news in this arena is warmly welcomed.”

Exercise Needs to be Part of the New Standard of Care for Cancer

But the benefits of exercise are not limited to prevention alone. It can also help you recuperate faster and help prevent recurrence of cancer. A report issued by the British organization Macmillan Cancer Support5 just last year argues that exercise really should be part of standard cancer care. It recommends that all patients getting cancer treatment should be told to engage in moderate-intensity exercise for two and a half hours every week, stating that the advice to rest and take it easy after treatment is an outdated view.

The organization offers loads of helpful information about the benefits of exercise for cancer patients on their website, and also has a number of videos on the subject, available on their YouTube channel

According to Ciaran Devane, chief executive of Macmillan Cancer Support:7

“Cancer patients would be shocked if they knew just how much of a benefit physical activity could have on their recovery and long term health, in some cases reducing their chances of having to go through the grueling ordeal of treatment all over again…”

Indeed, the reduction in risk for recurrence is quite impressive. For example, previous research has shown that breast and colon cancer patients who exercise regularly have half the recurrence rate than non-exercisers.8 Macmillan Cancer Support also notes that exercise can help you to mitigate some of the common side effects of conventional cancer treatment, including:

Reduce fatigue and improve your energy levels Manage stress, anxiety, low mood or depression Improve bone health
Improve heart health (some chemotherapy drugs and radiotherapy can cause heart problems later in life) Build muscle strength, relieve pain and improve range of movement Maintain a healthy weight
Sleep better Improve your appetite Prevent constipation

Exercise Can Also Benefit Your Mental Health — Even When Forced

Many recent studies have shown that exercise provides a level of protection against stress-related disorders and depression. But could it still work if it was prescribed and forced upon you, by doctor’s orders, for example; or if part of a mandatory program, such as high school students or military, who are required to participate whether they like it or not?

To find out, researchers at the University of Colorado Boulder devised an animal study to determine whether rats that were forced to exercise would experience the same stress- and anxiety-reduction as those who were free to choose if and when to exercise.

The rats exercised either voluntarily or forcibly for six weeks, after which they were exposed to a stressor. The following day, their anxiety levels were tested by measuring how long they froze when placed in an environment they’d been conditioned to fear. The longer the rats remained frozen, like “a deer in headlights,” the greater the residual anxiety from the previous day’s stressor. According to the lead author:9

“Regardless of whether the rats chose to run or were forced to run they were protected against stress and anxiety. The sedentary rats froze for longer periods of time than any of the active rats. The implications are that humans who perceive exercise as being forced — perhaps including those who feel like they have to exercise for health reasons — are maybe still going to get the benefits in terms of reducing anxiety and depression.”

Could 89 Percent of ‘Landmark’ Cancer Research Be Untruthful?

Findings such as the ones above, which demonstrate the significant benefits of lifestyle changes like exercise on your physical and mental health, become all the more important in light of mounting evidence showing that conventional drug treatment research has been sorely compromised by industry funding. As discussed in a recent GreenMedInfo article,10 the alleged “groundbreaking” results of nearly nine out of 10 cancer studies cannot be reproduced by any means!

“This means that to an extent, we have based our healthcare and clinical guidelines on fake studies that reported untruthful results in order to accommodate the interests of industrial corporations,” Eleni Roumeliotou writes.

“Cancer is a major killer in US. The American Cancer Society reports that in 2012, more than half a million Americans died from cancer, while more than 1.6 million new cases were diagnosed. Given the seriousness of these statistics and the necessity of evidence-based medicine, it would make sense to trust that honest, objective research is tirelessly trying to find the best cancer therapies out there.”

Alas, this trust in the scientific rigor of medical research appears to have been misplaced. First of all, nearly three-quarters of all retracted drug studies are due to falsification of data,11 meaning it’s not even a matter of misinterpretation of data; rather the data used to draw conclusions are pure fiction. Large numbers of patients can be affected when false findings are published, as the average lag time between publication of the study and the issuing of a retraction is 39 months. And that’s if it’s ever caught at all.

Last year, former drug company researcher Glenn Begley also showed that the vast majority of the “landmark” studies on cancer are unreliable — and a high proportion of those unreliable studies come from respectable university labs. Begley looked at 53 papers in the world’s top journals, and found that he and a team of scientists could NOT replicate 47 of the 53 published studies — all of which were considered important and valuable for the future of cancer treatments!

Part of the problem, they said, is that scientists often ignore negative findings in their results that might raise a warning. Instead, they opt for cherry-picking conclusions in an effort to put their research in a favorable light. The allegations appeared in the March 28 issue of the prestigious journal Nature.12

“It was shocking,” Begley said.13 “These are the studies the pharmaceutical industry relies on to identify new targets for drug development. But if you’re going to place a $1 million or $2 million or $5 million bet on an observation, you need to be sure it’s true. As we tried to reproduce these papers we became convinced you can’t take anything at face value.”

As if that’s not disturbing enough, Roumeliotou points out that Begley was not permitted to disclose which 53 cancer studies he evaluated and found to be without scientific merit. She writes:14

“…when they contacted the original authors and asked for details of the experiments, they had to sign an agreement that they would not disclose their findings or sources. This shows that the scientists, who published the tainted research, were all along, fully aware of the discrepancies of their articles and criminally conscious of the fact that they were misleading the medical and public opinion.”

Your Lifestyle has Tremendous Influence Over Your Health and Cancer Risk…

In light of the evidence supporting the notion that lifestyle changes, such as exercise, have a profound impact on human health and diseases of both mind and body, it would be foolish in the extreme to ignore such advice. Especially when you consider that the conventional drug paradigm is riddled with unreliable and outright fraudulent research — courtesy of the financial influence of the drug industry itself, which funds the vast majority of drug research.

Studies on exercise and other lifestyle changes however are less likely to be fraudulent simply because there’s no money to be made by coming to the conclusion that exercise may be helpful — unless it was funded by a gym franchise, perhaps…

Whether you’re trying to address your mental or physical health, I would strongly recommend you read up on my Peak Fitness program, which includes high-intensity exercises that can reduce your exercise time while actually increasing your benefits.

Now, if you have cancer or any other chronic disease, you will of course need to tailor your exercise routine to your individual circumstances, taking into account your fitness level and current health. Often, you will be able to take part in a regular exercise program — one that involves a variety of exercises like strength training, core-building, stretching, aerobic and anaerobic — with very little changes necessary. However, at times you may find you need to exercise at a lower intensity, or for shorter durations.

Always listen to your body and if you feel you need a break, take time to rest. But even exercising for just a few minutes a day is better than not exercising at all, and you’ll likely find that your stamina increases and you’re able to complete more challenging workouts with each passing day. In the event you are suffering from a very weakened immune system, you may want to exercise at home instead of visiting a public gym. But remember that exercise will ultimately help to boost your immune system, so it’s very important to continue with your program, even if you suffer from chronic illness or cancer.

Source: mercola.com

 

Novartis drug Ilaris® approved by FDA to treat active systemic juvenile idiopathic arthritis, a serious form of childhood arthritis.

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  • Ilaris® (canakinumab) is the first interleukin-1 beta inhibitor for the treatment of SJIA and the only treatment approved specifically for SJIA that is given as a monthly subcutaneous injection[1]

 

  • In Phase III studies, 84% of Ilaris-treated SJIA patients achieved significant improvement of systemic and arthritic symptoms (pediatric ACR30) after a single subcutaneous dose[1]

 

  • SJIA is a rare, disabling autoinflammatory disease with limited treatment options[2]; Ilaris is being investigated in other inflammatory conditions, including several rare diseases for which approved treatment options do not exist

 

 Novartis announced today that the US Food and Drug Administration (FDA) has approved Ilaris® (canakinumab) for the treatment of active systemic juvenile idiopathic arthritis (SJIA) in patients aged 2 years and older. Ilaris is the first interleukin-1 beta (IL-1 beta) inhibitor approved for SJIAand the only treatment approved specifically for SJIA that is given as a once-monthly subcutaneous injection[1]. SJIA is a rare and disabling form of childhood arthritis characterized by spiking fever, rash and arthritis that can affect children as young as 2 years old and can continue into adulthood[2],[3].

 

This approval was based on two Phase III trials in SJIA patients, aged 2-19, showing significant improvement in the majority of Ilaris-treated patients[1]. Study 1 showed that 84% of patients treated with one subcutaneous dose of Ilaris achieved the primary endpoint of the adapted pediatric American College of Rheumatology 30 (ACR30), compared to 10% achievement of ACR30 for placebo at Day 15[1]. In the open-label part of Study 2, 92 of 128 patients attempted “corticosteroid tapering”. Of those 92 patients, 62% were able to substantially reduce their use of corticosteroids, and 46% completely discontinued corticosteroids[1]. In the controlled portion of Study 2, there was a 64% relative reduction in the risk of flare for patients in the Ilaris group as compared to those in the placebo group (hazard ratio of 0.36; 95% CI: 0.17 to 0.75).

 

“In the US, this approval marks the second Ilaris indication for patients living with rare, autoinflammatory conditions,” said Timothy Wright, MD, Global Head of Development, Novartis Pharmaceuticals. “We are committed to studying Ilaris in other IL-1 beta mediated inflammatory diseases, including several rare diseases for which treatment options do not currently exist.”

 

SJIA affects 5-15 children per 100,000 in the United States,and is the most severe subtype of juvenile idiopathic arthritis[3]-[5]. Although the disease can be life-threatening, treatment options are limited. Corticosteroids are often used to treat symptoms and pain despite their long term use being associated with potentially serious adverse effects, including Cushing syndrome, growth suppression and osteoporosis[1],[6],[7].

 

Ilaris is being investigated in a number of rare autoinflammatory conditions, including Tumor Necrosis Factor Receptor-Associated Periodic Syndrome (TRAPS), colchicine-resistant Familial Mediterranean Fever (FMF) and Hyper IgD Syndrome (HIDS). Ilaris is considered an investigational agent for these conditions at this point in time. As such, the role that Ilaris could play in treating these conditions and potential benefit to patients is still being determined.

 

About the Pivotal Phase III Studies

Study 1, a 4-week, randomized, double-blind, placebo-controlled study, involved 84 patients between the ages of 2 and 19 years with active SJIA[1],[2]. Patients were treated with either a single subcutaneous dose of Ilaris (4 mg/kg, up to 300 mg) (n=43) or placebo (n=41)[1]. The primary endpoint was the proportion of patients achieving the adapted pediatric American College of Rheumatology (ACR) 30 response criteria and resolution of fever from baseline at Day 15[1]. This means that patients had at least a 30% improvement in systemic and arthritic symptoms versus baseline. The study met its primary endpoint.

 

Study 2, a two-part study, had an open-label, single-arm active treatment in Part I followed by a randomized, double-blind, placebo-controlled, event-driven withdrawal design in Part II[1]. A total of 177 patients between the ages of 2 and 19 years with active SJIA were enrolled in the study[1]. Some of these patients had previously participated in the Study 1. In Part I, patients received a subcutaneous dose of Ilaris (4 mg/kg, up to 300 mg) every 4 weeks[1]. The primary endpoint of Part I was to assess whether treatment with Ilaris allowed successful tapering of corticosteroids in at least 25% of SJIA patients who entered the study using a corticosteroid.

 

In Part II of the study, patients were randomized to either continue receiving Ilaris, or to receive placebo every 4 weeks (“placebo-after-Ilaris group”), until a pre-specified number (37) of flare-events (“flares”) had occurred[1]. The primary endpoint of Part II was to demonstrate that the time to flare was longer with Ilaris than with placebo.

 

The primary endpoints for Study 1 and Study 2 were all met.

 

About Ilaris

Ilaris is a selective, fully human, monoclonal antibody that inhibits IL-1 beta, which is an important part of the body’s immune system defenses[1]. Excessive production of IL-1 beta plays a prominent role in certain inflammatory diseases[8]. Ilaris works by neutralizing IL-1 beta for a sustained period of time, therefore inhibiting inflammation[1].

 

In addition to its approval for SJIA in the US, Ilaris is approved in the EU for the treatment of refractory gouty arthritis, and in more than 60 countries, including in the EU, US, Switzerland and Japan for the treatment of Cryopyrin-Associated Periodic Syndromes (CAPS), a rare, lifelong, genetic disorder with debilitating symptoms[1]. The approved indication may vary depending upon the individual country.

 

References:

  1. Ilaris [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2013.
  2. Woo P. Systemic juvenile idiopathic arthritis: diagnosis, management, and outcome. Nat Clin Pract Rheumatol 2006; 2(1):28-34.
  3. Ramanan AV, Grom AA. Does systemic-onset juvenile idiopathic arthritis belong under juvenile idiopathic arthritis? Rheumatology (Oxford) 2005; 44(11):1350-3.
  4. Beukelman T, Patkar NM, Saag KG, et al. 2011 American College of Rheumatology Recommendations for the Treatment of Juvenile Idiopathic Arthritis: Initiation and Safety Monitoring of Therapeutic Agents for the Treatment of Arthritis and Systemic Features. Arthritis Care & Research 2011; 63(4):465-482.
  5. Dewitt EM, Kimura Y, Beukelman T, et al. Consensus Treatment Plans for New-Onset Systemic Juvenile Idiopathic Arthritis. Arthritis Care & Research 2012; 64(7):1001-1010.
  6. U.S. National Library of Medicine (NLM), National Institutes of Health (NIH). Cushing Syndrome. Available at: http://www.nlm.nih.gov/medlineplus/ency/article/000389.htm. Last accessed: 12/12/12.
  7. Teitelbaum SL,Seton MP, Saag KG. Should Bisphosphonates be Used for Long-Term Treatment of Glucocorticoid-Induced Osteoporosis? Arthritis Rheum. 2011 February 63(2): 325-328. doi:10.1002/art.30135.
  8. Martinon F, Petrilli V.  Gout-associated uric acid crystals activate the NALP3 inflammasome.Nature 2006; 440(9): 237-241.

 

Source: Novartis newsletter