Novel pretreatment nomograms based on pan-immune-inflammation value for predicting clinical outcome in patients with head and neck squamous cell carcinoma.

Background: The prognostic value of an effective biomarker, pan-immune-inflammation value (PIV), for head and neck squamous cell carcinoma (HNSCC) patients after radical surgery or chemoradiotherapy has not been well explored. This study aimed to construct and validate nomograms based on PIV to predict survival outcomes of HNSCC patients. Methods: A total of 161 HNSCC patients who underwent radical surgery were enrolled retrospectively for development cohort. The cutoff of PIV was determined using the maximally selected rank statistics method. Multivariable Cox regression and least absolute shrinkage and selection operator (LASSO) regression analyses were performed to develop two nomograms (Model A and Model B) that predict disease-free survival (DFS). The concordance index, receiver operating characteristic curves, calibration curves, and decision curve analysis were used to evaluate the nomograms. A cohort composed of 50 patients who received radiotherapy or chemoradiotherapy (RT/CRT) alone was applied for generality testing of PIV and nomograms. Results: Patients with higher PIV (≥123.3) experienced a worse DFS (HR, 5.01; 95% CI, 3.25-7.72; p<0.0001) and overall survival (OS) (HR, 5.23; 95% CI, 3.34-8.18; p<0.0001) compared to patients with lower PIV (<123.3) in the development cohort. Predictors of Model A included age, TNM stage, neutrophil-to-lymphocyte ratio (NLR), and PIV, and that of Model B included TNM stage, lymphocyte-to-monocyte ratio (LMR), and PIV. In comparison with TNM stage alone, the two nomograms demonstrated good calibration and discrimination and showed satisfactory clinical utility in internal validation. The generality testing results showed that higher PIV was also associated with worse survival outcomes in the RT/CRT cohort and the possibility that the two nomograms may have a universal applicability for patients with different treatments. Conclusions: The nomograms based on PIV, a simple but useful indicator, can provide prognosis prediction of individual HNSCC patients after radical surgery and may be broadly applicated for patients after RT/CRT alone.

Measurable Residual Disease Detected by Multiparameter Flow Cytometry and Sequencing Improves Prediction of Relapse and Survival in Acute Myeloid Leukemia.

The clinically ideal time point and optimal approach for the assessment of measurable residual disease (MRD) in patients with acute myeloid leukemia (AML) are still inconclusive. We investigated the clinical value of multiparameter flow cytometry-based MRD (MFC MRD) after induction (n = 492) and two cycles of consolidation (n = 421). The latter time point was proved as a superior indicator with independent prognostic significance for both relapse-free survival (RFS, HR = 3.635, 95% CI: 2.433-5.431, P <0.001) and overall survival (OS: HR = 3.511, 95% CI: 2.191-5.626, P <0.001). Furthermore, several representative molecular MRD markers were compared with the MFC MRD. Both approaches can establish prognostic value in patients with NPM1 mutations, and FLT3, C-KIT, or N-RAS mutations involved in kinase-related signaling pathways, while the combination of both techniques further refined the risk stratification. The detection of RUNX1-RUNX1T1 fusion transcripts achieved a considerable net reclassification improvement in predicting the prognosis. Conversely, for patients with biallelic CEBPA or DNMT3A mutations, only the MFC method was recommended due to the poor prognostic discriminability in tracking mutant transcripts. In conclusion, this study demonstrated that the MFC MRD after two consolidation cycles independently predicted clinical outcomes, and the integration of MFC and molecular MRD should depend on different types of AML-related genetic lesions.

Development and validation of a prognostic model for adult patients with acute myeloid leukaemia.

BACKGROUND: The high heterogeneity of acute myeloid leukaemia (AML) reflected in the patient- and disease-related factors accounts for the unsatisfactory prognosis despite the introduction of novel therapeutic approaches and drugs in recent years. METHODS: In the development set (n = 412), parameters including age, hematopoietic cell transplantation-comorbidity index, white blood cell count, hemoglobin, biallelic CEBPA mutations, DNMT3A mutations, FLT3-ITD/NPM1 status, and ELN cytogenetic risk status were identified as independent prognostic factors for overall survival (OS) in the multivariable Cox regression analysis. A nomogram combining these predictors for individual risk estimation was established thereby. FINDINGS: The prognostic model demonstrated promising performance in the development cohort. The calibration plot, C-index (0.74), along with the 1-, 2- and 3-year area under the receiver operating characteristic curve (AUC, 0.76, 0.79, and 0.74, respectively) in the validation set (n = 238) substantiated the robustness of the model. In addition to stratifying young (age ≤ 60 years) and elderly patients (age > 60 years) into three and two risk groups with significant distinct outcomes, the prognostic model succeeded in distinguishing eligible candidates for hematopoietic stem cell transplantation. INTERPRETATION: The prognostic model is capable of survival prediction, risk stratification and helping with therapeutic decision-making with the use of easily acquired variables in daily clinical routine. FUNDING: This work was supported in part by grants from the National Natural Science Foundation of China (81770141), the National Key R&D Program of China (2016YFE0202800), and Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support (20161406).

Genetic alteration patterns and clinical outcomes of elderly and secondary acute myeloid leukemia.

To illustrate the clinical and genetic features of elderly and secondary acute myeloid leukemia (AML) patients, we compared 145 elderly AML (e-AML) and 55 secondary AML (s-AML) patients with 451 young de novo AML patients. Both e-AML and s-AML patients showed lower white blood cell (WBC) and bone marrow (BM) blasts at diagnosis. NPM1, DNMT3A, and IDH2 mutations were more common while biallelic CEBPA and IDH1 mutations were less seen in e-AML patients. s-AML patients carried a higher frequency of KMT2A-AF9. In treatment response and survival, e/s-AML conferred a lower complete remission (CR) rate and shorter duration of event-free survival (EFS) and overall survival (OS) compared with young patients. In multivariate analysis, s-AML was an independent risk factor for OS but not EFS in the whole cohort. Importantly, intensive therapy tended to improve the survival of e/s-AML patients without increasing the risk of early death, and hematopoietic stem cell transplantation (HSCT) could rescue the prognosis of s-AML, which should be recommended for the treatment of fit patients.

Precision medicine for hepatocellular carcinoma: driver mutations and targeted therapy.

Hepatocellular carcinoma (HCC) is the third most frequent cause of tumor-related mortality and there are an estimated approximately 850,000 new cases annually. Most HCC patients are diagnosed at middle or advanced stage, losing the opportunity of surgery. The development of HCC is promoted by accumulated diverse genetic mutations, which confer selective growth advantages to tumor cells and are called "driver mutations". The discovery of driver mutations provides a novel precision medicine strategy for late stage HCC, called targeted therapy. In this review, we summarized currently discovered driver mutations and corresponding signaling pathways, made an overview of identification methods of driver mutations and genes, and classified targeted drugs for HCC. The knowledge of mutational landscape deepen our understanding of carcinogenesis and promise future precision medicine for HCC patients.

MRI detects brain reorganization after human umbilical tissue-derived cells (hUTC) treatment of stroke in rat.

Human umbilical tissue-derived cells (hUTC) represent an attractive cell source and a potential technology for neurorestoration and improvement of functional outcomes following stroke. Male Wistar rats were subjected to a transient middle cerebral artery occlusion (tMCAo) and were intravenously administered hUTC (N = 11) or vehicle (N = 10) 48 hrs after stroke. White matter and vascular reorganization was monitored over a 12-week period using MRI and histopathology. MRI results were correlated with neurological functional and histology outcomes to demonstrate that MRI can be a useful tool to measure structural recovery after stroke. MRI revealed a significant reduction in the ventricular volume expansion and improvement in cerebral blood flow (CBF) in the hUTC treated group compared to vehicle treated group. Treatment with hUTC resulted in histological and functional improvements as evidenced by enhanced expression of vWF and synaptophysin, and improved outcomes on behavioral tests. Significant correlations were detected between MRI ventricular volumes and histological lesion volume as well as number of apoptotic cells. A positive correlation was also observed between MRI CBF or cerebral blood volume (CBV) and histological synaptic density. Neurological functional tests were also significantly correlated with MRI ventricular volume and CBV. Our data demonstrated that MRI measurements can detect the effect of hUTC therapy on the brain reorganization and exhibited positive correlation with histological measurements of brain structural changes and functional behavioral tests after stroke. MRI ventricular volumes provided the most sensitive index in monitoring brain remodeling and treatment effects and highly correlated with histological and functional measurements.

Transplantation of marrow stromal cells restores cerebral blood flow and reduces cerebral atrophy in rats with traumatic brain injury: in vivo MRI study.

Cell therapy promotes brain remodeling and improves functional recovery after various central nervous system disorders, including traumatic brain injury (TBI). We tested the hypothesis that treatment of TBI with intravenous administration of human marrow stromal cells (hMSCs) provides therapeutic benefit in modifying hemodynamic and structural abnormalities, which are detectable by in vivo MRI. hMSCs were labeled with superparamagnetic iron oxide (SPIO) nanoparticles. Male Wistar rats (300-350 g, n=18) subjected to controlled cortical impact TBI were intravenously injected with 1 mL of saline (n=9) or hMSCs in suspension (n=9, approximately 3 × 10(6) SPIO-labeled hMSCs) 5 days post-TBI. In vivo MRI measurements consisting of cerebral blood flow (CBF), T2-weighted imaging, and 3D gradient echo imaging were performed for all animals 2 days post-TBI and weekly for 6 weeks. Functional outcome was evaluated with modified neurological severity score and Morris water maze test. Cell engraftment was detected in vivo by 3D MRI and confirmed by double staining. Ventricle and lesion volumetric alterations were measured using T2 maps, and hemodynamic abnormality was tracked by MRI CBF measurements. Our data demonstrate that treatment with hMSCs following TBI diminishes hemodynamic abnormalities by early restoration and preservation of CBF in the brain regions adjacent to and remote from the impact site, and reduces generalized cerebral atrophy, all of which may contribute to the observed improvement of functional outcome.