Objective: All-trans retinoic acid (ATRA)/arsenic trioxide (ATO) combination therapy for newly diagnosed acute promyelocytic leukemia (APL) has yielded high efficacy in clinical trials, but there are few studies focusing on the long-term follow-up of survival and complications. Methods: In this study, we followed up 217 patients with newly diagnosed APL treated with ATRA/ATO combination therapy between 2001 and 2010. Health assessment for long-term complications and quality of life was performed for 112 of these patients, meanwhile the arsenic retention in their plasma, urine, hair and nails was detected by inductively coupled argon plasma mass spectrometry (ICP-MS). Results: A total of 199 patients (91.7%) achieved complete remission (CR). The estimated 10-year event-free survival (EFS), overall survival (OS), disease-free survival (DFS) and cumulative incidence of relapse (CIR) were 78.0%, 86.3%, 87.0% and 12.0%, respectively. High white blood cell (WBC) count remained as the only unfavorable prognostic factor for remission duration and led to significant differences between low-to-intermediate and high-risk groups in EFS (82.1% vs. 63.9%, P=0.016), DFS (90.6% vs. 73.1%, P=0.008) and CIR (8.0% vs. 26.9%, P=0.003). For the 112 patients who received health assessment, there were no significant long-term complications associated with ATRA/ATO therapy, except for higher incidence of grade-1 liver dysfunction (15.2%) and hepatic steatosis (42.9%) compared to healthy controls (both P<0.001). The arsenic concentration in patients¡¯ plasma and urine excreted quickly to normal level right after the cessation of ATO, even lower than that of healthy controls (P<0.001 and P=0.009, respectively). However, in patients¡¯ hair and nails it slowly decreased to normal after 6 months off ATO, with no significant difference than the healthy controls. The results revealed no general retention of arsenic in patients during the long-term follow-up. And the quality of life was satisfactory in almost all patients. Conclusion: This study with long-term follow-up clearly demonstrated that ATRA/ATO in newly diagnosed APL patients was associated with long-term survival, particularly for patients with low-to-intermediate risk diseases, as well as few complications, minimal arsenic retention and good quality of life. Table 1 Estimated 10-year Survival by Different Risk Stratification EFS OS DFS CIR Total 78.0% 86.3% 87.0% 12.0% Sanz¡¯s risk stratification Low-risk 82.4% 89.7% 89.6% 8.2% Intermediate-risk 81.8% 88.2% 91.0% 8.0% High-risk 63.9% 78.4% 73.1% 26.9% P value 0.048* 0.165 0.029* 0.009** WBC-based stratification Low-to-intermediate-risk 82.1% 88.8% 90.6% 8.0% High-risk 63.9% 78.4% 73.1% 26.9% P value 0.016* 0.069 0.008** 0.003** *P<0.05, **P<0.01 Table 2 Major Abnormalities in the Assessment of Long-term Complications (patients No.=112) Abnormal Findings Patients No. (%) Healthy Controls No. (%) P value Lower WBC count 1 (0.9)† 0 1.000 Cardiovascular events Elevated myocardial enzymes 5 (4.5)# 1 (0.9) 0.212 Long Q-T interval 0 0 / T wave change 14 (12.5) 15 (13.4) 0.842 Echocardiogram abnormality 1 (0.9)ǂ 0 1.000 Liver, kidney and GI dysfunction Liver dysfunction 17 (15.2) 2 (1.8) <0.001 Elevated creatinine 0 0 / Albuminuria 1 (0.9)ǂ 0 1.000 Fecal occult blood test 0 0 / Hepatic steatosis 48 (42.9) 20 (17.9) <0.001 Diabetes 6 (5.4) 5 (4.5) 0.757 Neurological disorders 1 (0.9)¡ì 1 (0.9) D 1.000 Potential secondary tumor Elevated serum tumor markers 3†ø / / Thoracic neoplasm on CXR 0 0 / Abdominal neoplasm on BUS 0 0 / Skin lesion 8 (7.1) ŋ 5 (4.5) ¦Ë 0.391 Breast cancer 1 (0.9) 0 1.000 † 1 patient was later diagnosed as the 3rd relapse of APL. ££No acute myocardial infarction. 2 had histories of heart diseases before APL. ǂ 1 patient had rheumatic heart disease 1 week after initial therapy, who also had albuminuria probably due to diabetes. ¡ì 1 patient had depression prior to APL and well controlled by Deanxit. D 1 had essential tremor. ø 3 patients had a mild and transient elevation in NSE, CEA and CA125, respectively, and retests were normal. ŋ 2 patients had hyperpigmentation, 1 had hypopigmentation and 5 had hyperkeratosis/hyperplasia. ¦Ë 2 had hyperpigmentation and 3 had hyperkeratosis. Figure 1 Figure 1. Figure 2 Figure 2. Figure 3 Figure 3. Disclosures Zhao: National Natural Science Foundation of China (81300451): Research Funding. Chen:National High-tech R&D Program (863 Program) (2012AA02A505): Research Funding.
Previous studies showed that low PPARG expression was associated with poor prognosis of lung adenocarcinoma (LA) with limited mechanisms identified. We first conducted a large-scale literature-based data mining to identify potential molecular pathways where PPARG could exert influence on the pathological development of LA. Then a mega-analysis using 13 independent LA expression datasets and a Pathway Enrichment Analysis (PEA) was conducted to study the gene expression levels and the functionalities of PPARG and the PPARG-driven triggers within the molecular pathways. Finally, a protein-protein interaction (PPI) network was established to reveal the functional connection between PPARG and its driven molecules. We identified 25 PPARG-driven molecule triggers forming multiple LA-regulatory pathways. Mega-analysis using 13 LA datasets supported these pathways and confirmed the downregulation of PPARG in the case of LA (p=1.07e−05). Results from the PEA and PPI analysis suggested that PPARG might inhibit the development of LA through the regulation of tumor cell proliferation and transmission-related molecules, including an LA tumor cell suppressor MIR145. Our results suggested that increased expression of PPARG could drive multiple molecular triggers against the pathologic development and prognosis of LA, indicating PPARG as a valuable therapeutic target for LA treatment.
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