Background
Pulmonary arterial hypertension (PAH) is a rare, lethal disease associated with single gene disorders, connective tissue disease, exposures to anorexigens, and often idiopathic etiology. There is evidence that genes can modify the risk of PAH: 1) monogenic disorders associated with PAH are incompletely penetrant, and 2) not all patients with associated conditions at increased risk for PAH develop the disease. The renin angiotensin aldosterone system (RAAS) provides a set of candidate genes that could modulate pulmonary vascular disease similar to its effects on renal and peripheral vasculature.
Methods
We studied 247 subjects with PAH (177 subjects with idiopathic PAH (IPAH); 63 subjects with PAH/connective tissue disease (CTD); and 7 subjects with PAH associated with anorexigens). Subjects were genotyped for five common polymorphisms in angiotensinogen (AGT), angiotensin converting enzyme (ACE), cardiac chymase A (CMA1), angiotensin II type 1 receptor (AGTR1) and aldosterone synthase (CYP11B2). Genotypes were tested for associations with age at diagnosis, hemodynamic parameters at diagnosis, and/or response to acute pulmonary vasodilator testing at diagnosis.
Results
Associations were demonstrated for AGTR1 and age at diagnosis in IPAH (p=0.005). Homozygotes for the C1166 allele (n=13) were associated with an age at diagnosis 26 years later than subjects with A/A (n=139) or A/C (n=90) genotypes. No associations were demonstrated for AGT, ACE, CMA1, or CYP11B2.
Conclusions
The 1166C polymorphism in AGTR1 appears to be associated with a later age at diagnosis in IPAH suggesting that this pathway could be involved in the biologic variability that is known to occur in PAH.
Background
Evaluation of prior phase II trials for malignant peripheral nerve sheath tumors (MPNST) may help develop more suitable trial endpoints in future studies.
Methods
We analyzed outcomes of patients with recurrent or unresectable/metastatic MPNST enrolled on prior Sarcoma Alliance for Research through Collaboration (SARC) phase II trials and estimated the progression-free survival (PFS). PFS from SARC006 (NCT 00304083), the phase II trial of upfront chemotherapy in chemotherapy naïve patients, was analyzed separately. Impact of baseline enrollment characteristics on PFS was evaluated.
Results
Sixty-four patients (29 male, 35 female, median age 39 years (range 15-81)) with MPNST were enrolled on 1 of 5 trials of single agent or combination therapy that were determined to be inactive. Patients had received a median of 1 (range 0-5) prior systemic therapy, and most had undergone prior surgery (77%) and radiation (61%). Seventy-three percent had metastatic disease at enrollment. Median PFS was 1.77 months (95% CI, 1.61-3.45), and the PFS rate at 4 months was 15%. Greater number of prior systemic therapies and worse performance status were associated with inferior PFS. There was no significant difference in PFS based on age at enrollment, treatment trial, response criteria, presence of metastatic disease, disease site at enrollment, and prior surgery or radiation. In comparison, on the SARC006 trial the PFS rate at 4 months was 94% in 40 patients.
Conclusion
These data provide a historical baseline PFS that may be used as a comparator in future clinical trials for patients with MPNST.
RAS mutations are frequently observed in childhood B‐cell acute lymphoblastic leukemia (B‐ALL) and previous studies have yielded conflicting results as to whether they are associated with a poor outcome. We and others have demonstrated that the mitogen‐activated protein kinase–extracellular signal‐regulated kinase (MAPK) pathway can be activated through epigenetic mechanisms in the absence of RAS pathway mutations. Herein, we examined whether MAPK activation, as determined by measuring phosphorylated extracellular signal‐regulated kinase (pERK) levels in 80 diagnostic patient samples using phosphoflow cytometry, could be used as a prognostic biomarker for pediatric B‐ALL. The mean fluorescence intensity of pERK (MFI) was measured at baseline and after exogenous stimulation with or without pretreatment with the mitogen‐activated protein kinase kinase (MEK) inhibitor trametinib. Activation levels (MFI stimulated/MFI baseline) ranged from 0.76 to 4.40 (median = 1.26), and inhibition indexes (MFI stimulated/MFI trametinib stimulated) ranged from 0.439 to 5.640 (median = 1.30), with no significant difference between patients with wildtype versus mutant RAS for either. Logistic regression demonstrated that neither MAPK activation levels nor RAS mutation status at diagnosis alone or in combination was prognostic of outcome. However, 35% of RAS wildtype samples showed MAPK inhibition indexes greater than the median, thus raising the possibility that therapeutic strategies to inhibit MAPK activation may not be restricted to patients whose blasts display Ras pathway defects.
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