2 Minute Medicine Rewind October 28, 2019

PD-1 blockade in advanced adrenocortical carcinoma

1. Pembrolizumab may provide clinically meaningful anti-tumor activity in the setting of adrenocortical carcinoma, particularly in tumors characterized by microsatellite instability and/or mismatch repair 

Evidence Rating Level: 2 (Good)

Adrenocortical carcinomas (ACC) are rare and typically carry a poor prognosis, with the majority of patients presenting with metastatic disease. Mitotane is the only FDA-approved medication for ACC, though has low efficacy and a limited therapeutic window. As there is some evidence of adrenalitis in patients receiving immune checkpoint blockade and the presence of programmed death-ligand 1 (PD-L1) expression by tumor cells, there is some basis for the evaluation of immunomodulation in ACC. Pembrolizumab is an anti-PD-1 monoclonal antibody. In this cohort study, 39 patients with advanced ACC received pembrolizumab 200 mg every 3 weeks, and were followed up for a median of 17.8 months to evaluate the immunogenicity of ACC. Researchers found that 23% of patients demonstrated a response to pembrolizumab (95% CI 11% to 39%). The disease control rate was 52% (95% CI 33% to 69%). Interestingly, of the 6 patients in the study with microsatellite instability (MSI) identified through mutation profiling of actionable cancer targets via MSIsensor or MMR deficiency (MMR-D), defined as any loss of DNA MMR protein expression, 33% responded to pembrolizumab therapy. MSI-H/MMR-D status is a known predictive biomarker of response to immune-based therapies. The remaining patients demonstrating an objective response had microsatellite stable tumors. The median progression-free survival was 2.1 months (95% CI, 2.0 months to 10.7 months), while the median overall survival was 24.9 months (95% CI 4.2 months to not reached). This study therefore shows that MSI-H/MMR-D tumors are not uncommon in ACC and that pembrolizumab may provide clinically meaningful antitumor activity in patients with this disease.

Trends in cardiovascular disease morbidity and mortality in American Indians over 25 years: the Strong Heart Study

1. The incidence and mortality associated with cardiovascular disease has decreased over a generation in a Native American cohort, however, improvements in age-specific mortality amongst females has not been consistently demonstrated

Evidence Rating Level: 2 (Good)

High morbidity and mortality rates owing to cardiovascular disease (CVD) have been observed in Native American populations, exceeding rates seen in other ethnic and/or racial groups. The Strong Heart Study (SHS) is a population-based cohort study of CVD in Native Americans that was initiated in 1988, and has led to the formation of the Strong Heart Family Study (SFHS), comprised of large multi-generation families. In this cohort study, researchers used data from the combined SHS and SFHS cohorts to evaluate temporal changes in CVD prevalence, incidence and CVD-related mortality risk in this group. Researchers found that at all age ages, CVD incidence was lower in more recent birth cohorts, and observed in both men and women subgroups. For CVD incidence, the magnitude of relative risk (RR) was relatively unchanged over the years amongst females (range 0.39 to 0.50), while the RR steadily declined in men. CVD mortality also declined consistently among men, while there was no consistent improvement in age-specific mortality risk among women when comparing birth cohorts. This study therefore shows that CVD incidence has declined over a generation in a Native American cohort. However, consistent improvements in female CVD-related mortality have not been demonstrated, pointing to a need for targeted public health interventions amongst female Native Americans.

Association of body mass index and extreme obesity with long-term outcomes following percutaneous coronary intervention

1. Patients with obesity undergoing percutaneous coronary intervention are typically younger with more cardiovascular risk factors, but may be less likely to experience procedural complications, short-term and long-term adverse outcomes, with the exception of patients considered extremely obese

Evidence Rating Level: 2 (Good)

It has been well established that obesity is associated with numerous adverse health outcomes and an increased risk of mortality. Interestingly, an “obesity paradox” has been described, where being obese or overweight may confer a protective effect for certain medical conditions when compared to patients with a normal body mass index (BMI). This may also be the case in the setting of percutaneous coronary intervention (PCI). In this cohort study, 25,413 patients that underwent PCI (January 2005-June 2017) were followed up for a median time of 4.4 years to evaluate the association between obesity and long-term survival after PCI. Of the patients comprising the cohort, 24.8% had a normal BMI while 3.3% were considered extremely obese (BMI ≥40). Researchers noted that with increasing BMI, patients were younger and exhibited more cardiovascular risk factors, including diabetes (p<0.001). Interestingly, however, with increasing BMI, the proportion of patients that presented non-ST-elevation acute coronary syndromes increased, whereas the proportion of patients presenting with ST-elevation myocardial infarction, out-of-hospital cardiac arrest, and cardiogenic shock decreased (p<0.001). With respect to PCI, there were no significant differences in the extent of coronary artery disease or lesion complexity between BMI groups, although drug-eluting stents were used more frequently in higher BMI patients (p<0.001). In addition, although overall infrequent, procedural complications were less common in higher BMI groups (p<0.04). In terms of clinical outcomes, specifically in-hospital and 30-day mortality, researchers observed a J-shaped association, where there was a steady decrease in mortality from the normal BMI group to the moderate obesity group, followed by a significant rise in mortality in the extreme obesity group (p<0.001). Similar relationships were noted between BMI and the incidence of major adverse cardiovascular events. Beyond 30 days, patients with moderate obesity had the lowest mortality rate at 12.2%, while patients with normal BMI or extreme obesity exhibited higher mortality rates at 19.2% and 14.1%, respectively. This study therefore shows that a moderately elevated BMI may be associated with reduced long-term mortality after PCI.

Effectiveness of clinical decision support tools on pediatrician adherence to peanut allergy prevention guidelines

1. Clinical decision support tools may improve pediatrician guideline adherence for peanut allergy prevention

Evidence Rating Level: 3 (Average)

The National Institute for Allergy and Infectious Disease recommends that clinicians screen infants age 4 to 6 months for peanut allergy (PA). In addition, it is recommended that infants deemed to be high risk (i.e. those with severe eczema and/or egg allergy) receive a specific IgE or allergy referral for assessment before they are introduced to peanut products. Clinical decision support (CDS) tools can help facilitate physician adherence to clinical guidelines. The Intervention to Reduce Early (Peanut) Allergy in Children (iREACH) initiative includes pediatrician training and CDS tools (i.e. order set for peanut specific IgE, allergy referral for high risk infants) implemented in electronic medical records (EMR) for well-child visits for infants age 4 to 6 months. In this study, researchers compared pediatrician adherence to peanut allergy prevention guidelines between a pediatric clinic that received the iREACH training module and CDS tool, to a second comparison clinic that received no EMR modification or training. At the iREACH clinic, data from 151 infants was collected and compared to a random sample of 312 infants from the comparison clinic. Of note, there were significant differences in demographic factors between the clinics where at the iREACH clinic there were more male infants (63.6% vs. 50.3%, p=0.007), more infants identified as black (29.8% vs. 0.6%, p<0.001) or of multiple/other races (49.0% vs. 8.3%, p<0.001). Researchers found that for infants at low-moderate risk, pediatricians were fully adherent to guidelines for 52.4% of infants in the iREACH clinic, as compared to 14.1% in the comparator clinic (p<0.001). Partial adherence was noted for 93.0% of infants in the iREACH clinic. For infants identified as high-risk, pediatrician adherence was 62.5%. Due to the limited sample size of high-risk infants at the comparator clinic, however, a difference could not be appreciated (p=0.44). As such, this study was limited by the small number of clinic sites studied and marked differences between infants seen at each clinic. Nonetheless, this study shows that improved pediatrician guideline adherence for peanut allergy prevention may be achieved with the use of CDS tools.

Association between parental income during childhood and risk of schizophrenia later in life

1. Parental income mobility may be inversely associated with the risk of developing schizophrenia later in life

Evidence Rating Level: 2 (Good)

There are clear associations between a number of mental health conditions and socioeconomic status. The link between parental socioeconomic position (SEP) and schizophrenia risk amongst offspring, however, has not been well studied. In this population-based cohort study, researchers used Danish national registry data (1980 to 2000) to follow 1,051,033 individuals as a means of exploring links between parental income and income mobility during childhood and subsequent schizophrenia risk. A unique feature of this study was the consideration of income, which can fluctuate, rather than parental educational attainment, which is largely fixed. Researchers found that there was an inverse association between parental income level and subsequent schizophrenia risk, where children from lower income families were at a higher risk. This association persisted upon adjustment for urbanization, parental mental health disorders, parental educational levels and changes in child-parent separation status. A dose-response association was noted with increasing amounts of time spent in a low-income group and increasing schizophrenia risk. This was seen regardless of parental income level at birth, where upward income mobility was associated with lower schizophrenia risk. Notably, individuals that were born and remained in the lowest income group at age 15 years exhibited an elevated risk (HR 4.12, 95% CI 3.71 to 4.58), exceeding that observed in those that experienced a rise from the lowest income quintile at birth to the second lowest at age 15 years (HR 2.80, 95% CI 2.4 to 3.17). Similar trends were noted in individuals that experienced downward income mobility between birth and 15 years, with increasing risks of developing schizophrenia. This study therefore shows that parental income mobility during childhood may be associated with schizophrenia risk.

Image: PD

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