2 Minute Medicine Rewind May 27, 2019

Treatment and Long-Term Clinical Outcomes of Incidental Pulmonary Embolism in Patients With Cancer: An International Prospective Cohort Study

Venous thromboembolism (VTE) is a common complication in patients with cancer. Often, VTEs are incidentally detected on imaging studies undertaken for cancer staging or evaluation of treatment response. Current guidelines recommend that the same anticoagulant treatment be used for both incidental pulmonary embolism (PE) and symptomatic PE in patients with cancer. However, these recommendations are largely based on risk estimates from retrospective data. In this prospective cohort study, 695 patients with active cancer and a recent diagnosis of PE were followed up to assess the long-term clinical outcomes of incidentally detected PE. These outcomes included recurrent VTE, major bleeding, and all-cause mortality during the 12-month follow-up period. At baseline, the mean age of the study population was 66 years, 58% of the patients were male, and 64% had metastatic disease. Colorectal cancer was the most common cancer type (21%), followed by lung cancer (15%) and gynecologic cancers (11%). Anticoagulant therapy was initiated in 97% of patients, and most patients received low-molecular-weight heparins (89%). The median overall treatment duration was 216 days (IQR 136 to 360 days).  Researchers found that the cumulative incidence of recurrent VTE was 6.0% (95% CI 4.4% to 8.1%), and 78% of events occurred during the on-treatment period. There was no significant difference in the incidence of recurrent VTE between patients with subsegmental PE and those with proximal PE (6.4% vs. 6.0%, respectively, HR 1.1, 95% CI 0.37 to 2.9, p=0.93). Researchers also found that major bleeding occurred in 5.7% of patients (95% CI 4.1% to 7.7%), and 43% of patients died (95% CI 39% to 46%) during the 12-month follow-up period. Overall, results from this study demonstrate that recurrent VTE is common in patients with cancer who received anticoagulation treatment for incidental PE, and that these patients also have a substantial risk of major bleeding and death.

Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial

Patients with a history of occlusive vascular disease who are on antithrombotic therapy are at an increased risk of intracerebral hemorrhage. Generally, antithrombotic therapy is discontinued after intracerebral hemorrhage in these patients. However, no published randomized trials have studied the long-term safety of antithrombotic therapy in survivors of intracerebral hemorrhage. In this randomized, controlled, open-label trial, 537 patients taking antithrombotic therapy (antiplatelet or anticoagulant) for the prevention of occlusive vascular disease and who subsequently developed intracerebral hemorrhage and discontinued antithrombotic therapy were assigned to restart or avoid antiplatelet therapy. Patients were then monitored for recurrent symptomatic intracerebral hemorrhage for a median of 2.0 years (IQR 1.0 to 3.0 years). At baseline, patients were on average 76 years old, and approximately two-thirds were male. At the onset of intracerebral hemorrhage, 50% of the participants were taking aspirin, approximately 25% were taking clopidogrel, and approximately 20% were taking oral anticoagulation. Researchers found that more patients who were allocated to avoid antiplatelet therapy experienced a recurrence of intracerebral hemorrhage as compared to those who were allocated to antiplatelet therapy (9% vs. 4% respectively, HR 0.51, 95% CI 0.25 to 1.03, p=0.060); however, this difference was not statistically significant. Furthermore, there were no statistically significant differences in the rate of major bleeding events nor the rate of major occlusive vascular events between the groups. This study was limited by low recruitment, as only 537 of 720 intended participants were recruited. In summary, this study does not demonstrate a clear risk of recurrent intracerebral hemorrhage after an initial intracerebral hemorrhage in patients maintained on antiplatelet therapy for occlusive vascular disease, suggesting that the benefits of secondary prevention may outweigh the risks in these patients.

Genomic characterization of metastatic breast cancers

Several late-stage cancers have been shown to acquire genomic alterations during disease evolution. In patients with breast cancer, 20% of metastatic tumors develop ESR1 mutations during endocrine therapy. However, the full spectrum of possible genomic alterations in metastatic breast cancer has not been described. In this study, the tumors of 617 patients with metastatic breast cancer (mBC) were sequenced using whole-exome sequencing to investigate the potential clinical relevance of all enriched somatic alterations. At baseline, 381 patients had hormone receptor positive (HR+)/HER2- breast cancer, 182 had triple-negative breast cancer, and 30 had HER2+ breast cancer. Researchers found that 21 genes were significantly mutated across the cohort or in at least one clinical subgroup (q<0.1). To determine which genes were differentially altered in mBC versus early breast cancer (eBC), the frequency of alterations observed in the study was compared to that in the Cancer Genome Atlas (TCGA). In patients with HR+/HER2- breast cancer, 9 driver genes were more frequently mutated in mBCs: TP53 (29%), ESR1 (22%), GATA3 (18%), KMT2C (12%) NCOR1 (8%), AKT1 (7%), NF1 (7%), RIC8A (4%) and RB1 (4%). Mutations in TP53, RB1, or NF1 were associated with a poor outcome in HR+/HER2- mRBCs (HR 2.20, 95% CI 1.57 to 3.07, p<0.001; HR 2.37, 95% CI 1.15 to 4.81, p=0.019; HR 1.91, 95% CI 1.09 to 3.35, p=0.024, respectively). Moreover, copy number analysis revealed that 18 amplicons were more frequently observed in HR+/HER2- mBCs than in eBCs. An analysis of mutational signatures demonstrated that HR+/HER2- mBCs exhibited an increase in 5 mutational signatures as compared to HR+/HER2- eBCs (p<0.001), and a decrease in 1 mutational signature. In multivariate analysis, 3 of the mutational signatures that were increased in mBCs, S10 (HR 1.67, 95% CI 1.20 to 2.32, p=0.002), S13 (HR 1.80, 95% CI 1.28 to 2.53, p=0.001) and S17 (HR 1.52, 95% CI 1.09 to 2.14, p=0.015), were associated with a poor outcome. Finally, mBCs showed an increase in mutational burden and clonal diversity compared to eBCs. In summary, this study identified several somatic alterations associated with poor outcomes in metastatic breast cancer, suggesting that early identification of these variants could inform therapy selection and may improve prognostication in these patients.

Robot assisted training for the upper limb after stroke (RATULS): a multicentre randomised controlled trial

Upper limb functionality is often compromised after a stroke, leading to distressing long-term consequences and a diminished quality of life. Therefore, optimizing upper limb recovery in these patients is imperative. A 2018 Cochrane review reported that robot-assisted arm training (RT) improved upper arm function, but the clinical significance of this result remains unclear due to study heterogeneity and variation in quality of the included studies. In this randomized, multicenter, controlled trial, 770 patients with moderate or severe upper limb functional limitation between one week and five years after their first stroke were assigned to receive either robot-assisted arm training, an enhanced upper limb therapy program (EULT), or usual care to study the impact on upper limb function success, defined using the Action Research Arm Test (ARAT), at 3 months. Robot-assisted training and EULT were provided for 45 min, three times per week for 12 weeks. The RT program integrated training with all three modules of the MIT-Manus robotic gym (shoulder-elbow module, wrist module, hand module integrated on to the shoulder-elbow module). The EULT program primarily consisted of repetitive functional task practice. Researchers found that at three months, there was no significant difference in upper limb functional recovery between RT and EULT (OR 0.78, 98.3% CI 0.48 to 1.27), nor between RT and usual care (OR 1.17, 98.3% CI 0.70 to 1.96). Similarly, there was no significant difference between EULT and usual care (OR 1.51, 98.3% CI 0.90 to 2.51). There were more adverse events in the RT group and the EULT group than in the usual care group, but none of these were related to a trial intervention. Overall, this study does not support the use of a robot-assisted training program using the MIT-Manus robotic gym for patients with upper limb functional limitations after stroke.

Liver Fibrosis and Metabolic Alterations in Adults with Alpha1 Antitrypsin Deficiency Caused by the Pi*ZZ Mutation

Alpha-1 antitrypsin (AAT) is a major protease inhibitor responsible for the inhibition of neutrophil elastase and proteinase 3. Alpha-1 antitrypsin deficiency (AATD) is a genetic disease that can lead to accelerated destruction of lung parenchyma and accumulation of AAT in hepatocytes. Severe AATD is caused mainly by the homozygous Pi*Z (Glu342Lys) mutation. While lung disease has been well-described in Pi*Z homozygotes (Pi*ZZ carriers), liver disease remains poorly characterized in these patients. In this cohort study, 554 Pi*ZZ carriers (403 in an exploratory cohort, and 151 in a confirmatory cohort) and 234 adults without the Pi*Z mutation (non-carriers), all without previously known liver disease, were studied to assess liver disease burden. Researchers found that the mean alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma-glutamyl transferase (GGT) activities were higher in Pi*ZZ carriers than non-carriers (80% vs. 66% of the upper limit of normal (ULN), 74% vs. 62% of ULN, and 100% vs. 58% of ULN, respectively, p<0.001 for all). Furthermore, transient elastography revealed that the average liver stiffness measurements were higher in Pi*ZZ carriers than in non-carriers (6.7±5.8 versus 4.6±1.7 kPa respectively, p<0.001). Additional tests for liver fibrosis corroborated this result, overall suggesting that 20 to 36% of Pi*ZZ carriers had significant liver fibrosis, and that advanced liver fibrosis was 9 to 20 times more likely in Pi*ZZ carriers as compared to non-carriers. Male sex, age over 50 years, increased levels of ALT, AST, or GGT, and low numbers of platelets were associated with higher liver fibrosis burden, but there was no correlation between the severity of lung and liver involvement. Pi*ZZ carriers had a higher burden of liver steatosis than non-carriers as revealed by controlled attenuation parameter measurements (267±57 versus 246±56 dB/m respectively, p<0.001). Carriers of Pi*ZZ also had lower serum concentrations of triglyceride, low, and very low-density lipoprotein cholesterol than non-carriers. Similarly, Pi*Z-overexpressing mice showed more liver steatosis and less expression of apolipoproteins A4 and C2 than their non-transgenic littermates, consistent with impaired hepatic secretion of lipid. A limitation of this study was the lack of invasive methods to measure liver fibrosis. Overall, this study represents the largest systematic phenotypic evaluation of liver disease in Pi*ZZ carriers to date, and underlines the importance of regular assessment of liver enzymes and liver fibrosis in Pi*ZZ carriers.

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