Sep 22, 2017

Power couple

The story

You went from the poster child for academic success to that girl who’s never at family functions the moment you started residency. But melanoma remains the poster child for immunotherapy, even as the field transforms oncology. Here’s an update on where things stand.

The spark

The immune-activating anti-CTLA-4 antibody ipilimumab ("ipi") shocked the world in 2010 when trial results found that it increased overall survival from 6 to 10 months in metastatic melanoma. The accompanying editorial, titled 'Treating Cancer by Targeting the Immune System’, looks like it's from the Flinstones in the 2017 era of immuno-everything oncology. CAR T cells have seen their first FDA approval in liquid cancers, and checkpoint inhibitors – more potent and less toxic than CTLA-4 blockade – have shown remarkable activity in cancers in the lung, kidney, bladder, and others. But if some is good than more is better, and investigators are evaluating whether combination immunotherapy with checkpoint inhibitors and anti-CTLA-4 antibodies improve outcomes. Just like the old days, melanoma leads the way.

The combo

Combination immunotherapy helps but is more toxic, say the 3-year outcomes from CheckMate 067. The trial evaluated combination ipi and checkpoint inhibitor nivolumab ("nivo") vs. nivo alone and ipi alone in 900 patients with advanced melanoma. Overall survival was 58% in the ipi-nivo group, 52% in the nivo group, and 34% in the ipi group. While a subset of patients found benefit from combination therapy, 60% had a severe adverse event vs. 20% of patients on nivo alone. More impressive were the long-term results themselves: median survival was 38 months in the nivo group and was not reached in the combo group. Compare that to a median survival of 6 months in 2010 and you can see what everyone's excited about.

The takeaway

Many hoped for more with combination immunotherapy in melanoma, but combo therapy remains under investigation in many other cancers with promising early results. In the meantime, the gains in this previously untreatable disease are stunning.

Say it on rounds

When the operator knows your name, list, and pager number

You like treatment with a personal touch. So do patients with idiopathic pulmonary fibrosis (IPF), a disease with an unpredictable but often lethal course. An analysis of genomic data in 425 IPF patients (no doubt drawn directly from your step-down unit and ICU) identified high and low-risk patient groups. High-risk profiles were associated with mortality rates twice as high as low-risk profiles and lower transplant-free survival. Genomic profiles changed with disease progression or therapy, and better identified those in need of urgent transplant than standard lung transplant referral guidelines.
Lancet Respir Med

When football's back, and all you can think of is bleeding risk

You're spending too much time in the cath lab. Current guidelines call for triple therapy with aspirin, a P2Y12 inhibitor, and warfarin after percutaneous intervention (PCI) in patients with atrial fibrillation (AF), but the regimen carries high bleeding risk. The REDUAL-PCI trial compared triple therapy to dual therapy with dabigatran and anti-platelet agents clopidogrel or ticagrelor in 2,700 post-PCI patients with AF. Clinically significant bleeding occurred in 15% of dual therapy patients vs. 27% in the triple therapy group, while the regimens were equally effective at preventing thromboembolic events.

When your constant left-swiping leaves you dateless on Friday night

Time to adjust your standards? A prospective population-based cohort study of 7,800 middle-aged and elderly patients with normal thyroid function found that those with high-normal free T4 levels on average died 3.5 years earlier and developed cardiovascular disease 3 years sooner than those with low-normal levels. Though high thyroid levels have previously been associated with an increased risk of CVD and death, this is the first study to demonstrate mortality variations within the reference range of thyroid function. It may be time to rethink what we call normal values.
JAMA Int Med

Brush up


Amyotrophic lateral sclerosis (ALS) acts about as swiftly as you do when you're one errand away from leaving work. The disease starts with focal weakness that progresses to respiratory muscle failure and death over just 3 - 5 years. It's more common than you think, with a cumulative lifetime risk of 1 in 400 in the US. Physiologically, the classic presentation involves fasciculations and muscle atrophy from lower motor neuron death mixed with hyperreflexia secondary to upper motor neuron sclerosis. About a fifth of patients will develop frontotemporal dementia during their course.

What's the evidence

For environmental risk factors in ALS? Oddly enough, time in the military is the most well-established exposure risk. A 2005 prospective cohort analysis of 500,000 men found that military service was associated with a 50% increased risk of death from ALS independent of time served or the branch of military service. Less surprisingly, smoking is implicated in ALS in a dose-dependent fashion, and there is an emerging role for preceding trauma.

What your pediatrics friends are talking about

Don't blame work for missing out on Selena Gomez's public life over the past few months. The singer had been laying low in prep for a kidney transplant for lupus. The shout-out she gave her best-friend-turned-donor on Instagram is doing wonders for transplant awareness in the peds community.

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