Primecuts-This Week in the Journals

By: Rory Abrams, MD

This past week the Mets became the 2015 National League Champions and are headed to the World Series. Larry David stole our hearts and minds after his impersonation of Bernie Sanders on SNL. Joe Biden officially announced he is not running for President in 2016. And Nike announced it will manufacture a limited number of the self-lacing shoes from Back To The Future 2, which will be auctioned off to raise money for Parkinson’s Disease research and the Michael J. Fox Foundation. Now on to some of the lead medical studies this week.

Anti-oxidants and Skin Cancer

Major news outlets hyped the dangers of antioxidant consumption from sources such as “blueberries,” citing they may promote tumor metastasis. [1]

The original study’s aim was to better understand metabolic changes in metastatic tumors. The authors first characterized the potential of human melanoma lines to form new tumors when explanted into immunodeficient mice. Successfully metastasizing melanomas were found to have higher levels of NADPH, a critical enzyme within the folate pathway that recycles glutathione, which is known to help with oxidative stress. To test whether increased glutathione promotes tumor metastasis, three highly metastatic melanoma cell lines were injected into mice and received either subcutaneous N-acetyl cysteine (NAC) or control. The authors found a 10-fold increase in tumor formation with NAC (p<0.0001). The opposite effect occurred when poisoning the folate pathway with low-dose methotrexate or via gene knockout of specific folate pathway enzymes. This led to at least a 50% decrease in both tumor formation and quantity circulating tumor cells in all three melanoma lines (p<0.05). [2] This pre-clinical data led to the conclusion that antioxidants might promote tumor metastasis. However, whether this is true in humans or in all tumors and for all antioxidants is unclear.

A separate phase 3 double-blind randomized control trial published this week showed that antioxidant compounds might also have protective effects in cancer. Investigators tested vitamin B3 in the prevention of skin cancer in patients with a history of previous non-melanoma skin cancers. The rationale for using Vitamin B3 is that Vitamin B3 is a precursor of nicotinamide adenine dinucleotide (NAD+), an essential co-factor for ATP production, which is otherwise depleted with UV-radiation induced DNA damage. The study included 386 patients who underwent dermatological evaluations every 3-month for 18-months to evaluate for new skin lesions. The results showed that at 12-months, there were 23% fewer new non-melanoma skin cancers with a number needed to treat (NNT) of 2.2 for basal cell carcinoma and 5.0 for squamous cell carcinoma. Vitamin B3 also led to a 13% greater decline in the number of actinic keratoses from baseline in the nicotinamide group vs. the placebo group, which equates to 3 – 5 fewer per patient on average. However how the number of actinic keratoses corresponds to risk of recurrent malignancy is unclear. There was no comparative benefit during the 6-month post-intervention surveillance period after nicotinamide was discontinued nor were there any adverse effects throughout the study. [3] Overall this study provides support for the role of vitamin B3 as a chemoprevention agent in patients at high risk for recurrent non-melanoma skin cancer as it is safe, well tolerated and cheap. However it remains unclear whether this will lead to true clinical benefit as non-melanoma tumors are frequently slow growing and easy to excise. Larger and longer studies are necessary to assess effects on morbidity and mortality.

These two recent studies present opposing conclusions regarding the harm or benefit of antioxidants in cancer. One possibility is that antioxidants provide a protective effect during tumor initiation but a deleterious effect during tumor progression. This could explain why Vitamin B3/nicotinamide decreases the risk of new tumors while NAC promotes melanoma metastasis. Alternatively, the biology of non-melanoma and melanoma tumors may be different. Either way, the role of antioxidants in cancer is likely to be more complex than represented in the popular press. Additional pre-clinical and clinical trials will be essential to further understand the effects of antioxidants on cancer.

Inherited determinants of Crohn’s disease and ulcerative colitis phenotypes: a genetic association study

The management of Inflammatory Bowel Disease (IBD) remains challenging, despite or perhaps in spite of the well regarded pathologic dichotomy between Crohn’s disease (CD) and Ulcerative Colitis (UC). Published this week were the results of the largest genome-wide association study (GWAS) to date of 29,838 IBD patients from 49 worldwide medical centers. The study took into consideration various sub-phenotypic characteristics such as age, age at diagnosis, smoking status, disease location and familial IBD to establish a personalized predictive model of IBD. All cases were evaluated on Immunochip array for 156,154 genetic polymorphisms with an average of 10-year follow-up to assess disease location, severity and progression. Three significant genome-wide loci, NOD2, MHC, and MST1, were associated with disease location. Consistent with prior reports, their study nicely confirmed that NOD2 haplotypes were most strongly associated with ileal CD, whereas MHC haplotypes were more strongly associated with colonic CD. Perhaps most interestingly, they found that alleles typically associated with UC were stronger predictors of colonic CD location than were alleles associated with CD in general (ileal vs. colonic OR 0.32, 95% CI 0.29-0.41). [4] Thus, their model favors the notion that IBD exists on a spectrum from ileal CD to colonic CD to UC, implying that the current dichotomous framework may be insufficient for stratifying patients into one diagnosis. Future studies evaluating IBD therapies may benefit from further sub-specification of genetic Crohn’s disease sub-type.

A Randomized Clinical Trial for the treatment of Acute Low Back Pain with Naproxen and either Cyclobenzaprine, Oxycodone/Acetaminophen, or Placebo.

Acute low back pain is incredibly common, with more than 2.5 million ED visits in the U.S. each year for this complaint. There is significant variability in how aggressive clinicians may be in recommending a treatment regimen, with limited evidence for superiority of one regimen over the other. To see if there was a benefit of different treatment regimens, a double-blinded RCT compared 107 patients presenting to an urban ED with non-traumatic, non-radicular, acute low back pain, and were assigned to either naproxen + placebo, naproxen + cyclobenzaprine, or naproxen + oxycodone/acetaminophen. The patients were assessed using a 0 – 10 pain scale and the Roland-Morris Disability Questionnaire (RMDQ) for functional impairment. At 1-week follow-up, all three groups improved equally and there was no statistical difference in terms of pain or functional status between the treatment arms (9.8/24 for placebo, 10.1/24 for cyclobenzaprine, and 11.1/24 for oxycodone/acetaminophen). [5] The study is limited by the small study size and the confounding treatment effect of naproxen. Generalizability is limited by the notable exclusion of acute radicular and traumatic back pain as these presentations are common to the urgent/emergent/office settings. Nevertheless, this well designed clinical trial should challenge clinicians to reconsider prescribing these adjunctive medications in the acute setting.

A Randomized, Controlled Trial of Total Knee Replacement

Lastly, moving onto painful, stiff knees (something Mets fans hope they won’t hear about in the post-season) is the first RCT of the effectiveness of total knee replacement (TKR). 100 patients with moderate-to-severe OA were assigned to either unilateral TKR + 12-weeks of non-surgical treatment or just the 12-weeks of non-surgical treatment alone. The primary endpoint was assessment with the Knee injury and Osteoarthritis Outcome Score (KOOS), which evaluates from 0 (worst) to 100 (best) their pain, ability to perform ADLs, knee-related quality of life, and other symptoms. [6] By 12-months follow-up, 1 patient assigned to the TKR group received only non-surgical intervention, whereas 13 patients (26%) assigned to the non-surgical group ultimately underwent TKR. Despite this crossover, intention-to-treat analysis revealed significantly greater average improvement of KOOS scores in the TKR group (32.5 points to an average score of 80/100) vs. non-surgical group (16.0 points to an average score 64.5/100) at 12-months. Although conservative treatment alone yielded significant improvement in pain and function, the combination of therapy plus TKR was significantly better. However even treatment with TKR left patients with significant symptoms and physical deficits. Further breakdown of the individual KOOS subscales, and secondary endpoints (times on the up-and-go test, 20m walk tests and EQ-5D description index) were also statistically improved in the TKR group. Despite these seeming benefits, there were however substantially more adverse events observed in the TKR group, 24 vs. 6 overall (p=0.005), especially the occurrence of DVT. [7] This study demonstrates the benefit of TKR but also in the value of conservative management and patient education, thus reinforcing the importance of balancing these benefits with the risks of surgery.

QuickCuts

October 27, 2015

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