Kaplan-Meier Log-rank Analysis Research Articles

The lymphocyte-to-monocyte ratio is a superior predictor of overall survival compared to established biomarkers in HCC patients undergoing liver resection

The aim of this study was to investigate the prognostic value of the lymphocyte-to-monocyte ratio (LMR) in patients undergoing hepatectomy and to compare it to established biomarkers including the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR). Medical records were retrospectively analyzed for 652 HCC patients undergoing hepatectomy at the Affiliated Tumor Hospital of Guangxi Medical University and the First People’s Hospital of Changde between April 2004 to April 2012. The correlation between the LMR and clinical variables were analyzed in Kaplan-Meier log-rank survival analysis and then multivariate Cox regression models trying to find relation with disease-free survival (DFS) and overall survival (OS). The area under the ROC curve (AUC) of the LMR(AUC:0.627) for predicting long-term survival was greater than that of the NLR(AUC:0.600) and the PLR(AUC:0.520).Multivariate analysis showed LMR to be an independent risk factor for OS (P = 0.002), and the NLR and PLR were not independently significant. Subgroup analysis also showed that LMR was significantly associated with poor DFS and OS in patients positive for HBsAg or with cirrhosis (both P < 0.001).Elevated preoperative LMR is an independently associated with poor OS and DFS in HCC patients following curative resection and appears to be superior to NLR and PLR.

Scaffold-Assisted Artificial Hair Implantation in a Rat Model.

Current treatments for alopecia with autograft hair transplantation face limitations that may preclude complete hair restoration and leave patients with donor site scars. Scaffold assisted artificial hair implantation as demonstrated in a rat model may provide an adjunct for hair restoration without donor site morbidity. To design and create porous high-density polyethylene (PHDPE) and expanded polytetrafluoroethylene (ePTFE) hair-bearing scaffolds and evaluate their biocompatibility in a rat model. For this single-institution randomized prospective animal study, 34 Sprague Dawley rats were randomly selected into 2 groups: 24 rats for direct implantation and 10 rats for delayed implantation. The direct-implantation group was randomly divided into 3 subgroups of 8 rats, which were observed for 2, 12, and 24 week. Each rat dorsum was implanted with 4 scaffolds-PHDPE and ePTFE with and without hair-in a randomized 4-quadrant manner. The rats in the direct-implantation group were observed to their selected time points of 2, 12, and 24 weeks. The rats in the delayed-implantation group were observed for 4 weeks at which, all well-healed scaffolds without hair were then percutaneously implanted with 2 follicular units of hair. These rats were then observed for another 4 weeks. During the clinical observation period, scaffolds were observed for signs of infection, extrusion, and persistence of follicular units. Following sacrifice, sagittal sections of scaffold and surrounding skin were fixed in formalin, stained with hematoxylin-eosin, and evaluated for degree of fibrovascular invasion and acute and chronic inflammation. Overall 94.5% (86 of 91) of the scaffolds were well healed at time of evaluation (2 week, 100% [32 of 32]; 12 week, 96.3% [26 of 27]; 24 week, 87.5% [28 of 32]); while 85.6% of artificial hair follicular units were intact at time of evaluation (2 week, 93.8% [30 of 32]; 12 week, 86.7% [26 of 30]; 24 week, 75.0% [21 of 28]). Within the delayed implant group 100% (19 of 19) of the hair-implanted scaffolds were well healed at 8 weeks, with 94.7% (36 of 38) of the follicular units intact; 100% of the delayed-hair implant scaffolds were well healed with 86.1% (36 of 38) of the follicular units intact. Kaplan-Meier log-rank analysis showed no significant difference in survival between ePTFE and PHDPE scaffolds, as well as scaffolds with hair and scaffolds without hair. Upon histological analysis, overall scaffolds with hair were noted to have greater chronic inflammation (95% CI, -0.81 to -1.10; P = .01), and PHDPE was noted to have significantly great fibrovascular integration (95% CI, -11.42 to -1.96; P = .01) compared with ePTFE. Overall, PHDPE and ePTFE hair bearing scaffolds were well tolerated in a rat model. Progressive loss of artificial hair may be percutaneously implanted without significant increases in infection or extrusion. NA.

Increased IFRD1 Expression in Human Colon Cancers Predicts Reduced Patient Survival.

Colon cancer (CRC) is the third most common cancer worldwide. CRC develops through combinations of genetic and epigenetic changes. However, there is marked heterogeneity in the "driver gene" mutational profiles within and among colon cancers from individual patients, and these are not sufficient to explain differences in colon cancer behavior and treatment response. Global modulation of the tumor landscape may play a role in cancer behavior. Interferon-related developmental regulator 1 (IFRD1) is a transcriptional co-regulator that modulates expression of large gene cassettes and plays a role in gut epithelial proliferation following massive intestinal resection. We address the hypothesis that increased IFRD1 expression in colon cancers is associated with poorer patient survival. Tumor and normal tissue from colon cancer patient cohorts from the USA, Spain, and China were used for this study. Cancers were scored for the intensity of IFRD1 immunostaining. The primary clinical outcome was overall survival defined as time from diagnosis to death due to cancer. Kaplan-Meier method and log-rank analysis were used to assess the association between IFRD1 expression and survival. Almost all (98.7%) colon cancers showed readily detectable IFRD1 expression, with immunoreactivity primarily in the tumor cytoplasm. High IFRD1 colon cancer expression was significantly associated with decreased 5-year patient survival. Patients in the American cohort with high IFRD1 expression had a poorer prognosis. We have demonstrated that high IFRD1 protein expression in colon cancer is associated with poorer patient prognosis, suggesting a potential role for IFRD1 in modulating tumor behavior.

CT-based assessment of visceral adiposity and outcomes for esophageal adenocarcinoma.

Various methods of quantifying and correlating obesity to outcomes for patients with esophageal adenocarcinoma (EA) have been evaluated. Published data suggest that quantification of adiposity may be more accurate than body mass index (BMI) as a prognostic factor. We report our analysis of adiposity as a prognostic factor in a series of patients with EA. This single institution retrospective review included patients with EA who underwent esophagectomy from 1994-2008. Patients with BMI <20 were excluded. Using the preoperative CT scan, the visceral (VFA), subcutaneous (SFA), and total abdominal fat (TFA) areas were calculated. Each was contoured on a Siemens Leonardo workstation at the level of the iliac crest (L4/5). The Hounsfield threshold was -30 to -130. Outcomes were analyzed using Kaplan-Meier method and log-rank analysis. Multivariate analysis (MVA) was performed using the Cox proportion hazard regression model. We identified 126 patients for the analysis. There were no statistically significant differences in overall survival or disease-free survival between groups above and below the medians for TFA, SFA, or VFA/SFA ratio. However, an increase in VFA was significantly associated with worsened OS and DFS when we further classified patients into quartiles. Patients with VFA ≥182 cm2 had larger tumor size (P=0.016), fewer involved lymph nodes (P=0.047), longer operating times (P=0.032), and were more likely to be males (P=0.042). Published data have demonstrated an association between treatment outcomes and degree of adiposity; our study found a correlation between VFA and OS and DFS in patients with EA. Median TFA, SFA, and VFA/SFA were not prognostic on MVA. While VFA >182 cm2 was associated with larger tumors, there were also fewer lymph nodes harvested in this group.

Treatment Patterns and Survival Outcomes of Patients With Small Cell Carcinoma of the Bladder: A National Cancer Database Analysis

Small cell carcinoma of the bladder (SCCB) is an aggressive neuroendocrine tumor that is associated with poorer outcomes than transitional cell carcinoma. Given the rarity of SCCB, there is no standard treatment algorithm. Many treatment strategies are largely extrapolated from small cell lung cancer, but surgical resection, specifically radical cystectomy (RC), remains a widely utilized treatment modality. We queried the National Cancer Database (NCDB) to assess treatment patterns and outcomes in this rare disease, and compared outcomes of RC with multimodality therapy for bladder preservation. We identified all SCCB cases in the NCDB diagnosed between 2004 and 2013. Inclusion criteria included cT1-4a N0 M0 with a pathologic diagnosis of SCCB and complete staging and treatment details available. Treatment groups included: no further treatment, chemotherapy alone (CT), radiation therapy alone (RT), combined chemoradiation therapy (CRT), RC alone, and RC plus chemotherapy (RC+C). Only patients receiving RT to the bladder or pelvis (>3000cGy) were considered in the RT groups. Overall survival (OS) was estimated by the Kaplan-Meier survival method, and log-rank and Cox analysis was used for univariate and multivariate analysis. A total 894 cases met inclusion criteria for analysis. Mean age was 72.0 years (range: 31 – 90). 695 (77.8%) patients were male. Mean follow-up was 26.5 months (range: 0.0 – 131.6). 677 (75.7%) of patients had Stage II or III disease. The most common treatment modality was CT alone (235 patients; 26.3%) followed by CRT (220 patients; 24.6%) and RC+C (206 patients; 23%). 139 patients (15.5%) had no further treatment after TURBT and 94 patients (10.6%) had either RT or RC alone without CT. The mean OS of the entire cohort was 44.0 months (95% CI, 40.4 –47.6). OS was significantly less for CT alone (38.9 months, 95% CI: 32.7-45.2) compared to both CRT (54.9 months, 95% CI: 47.3.7-62.4) and RC+C (56.9 months, 95% CI: 49.0-64.8) (P<0.0001). OS between CRT and RC+C was not significantly different (P=0.42). The mean age of those receiving CRT was 72.4 years versus 65.43 years for those receiving RC+C (P<0.001). Multivariate analysis controlling for age, stage, sex, race, year of diagnosis, facility type, facility location, and Charlson/Deyo Score showed improved OS for both CRT and RC+C (HR 0.42; 95% CI, 0.33-0.54; P <0.0001) and (HR 0.45; 95% CI, 0.34 – 0.59; P <0.001), respectively. Both RC+C and CRT are associated with improved OS compared to CT alone, RT alone, and RC alone for SCCB. Those undergoing CRT tended to be older than the surgery group. There is no significant difference in OS following RC+C or bladder preservation with CRT.

The clinicopathological features and risk factors of recurrence in patients with mucinous borderline ovarian tumors

Objective: To investigate the clinicopathological features and risk factors in patients with mucinous borderline ovarian tumors (MBOT). Methods: From 1999 to 2006, 66 MBOT patients in our hospital with more than ten-year follow-up were enrolled retrospectively. They were re-classified according to the literature. The clinicopathological features of different subgroups, including age, preoperative serum tumor markers, surgical methods, pathological features, surgical pathology staging, as well as the risk factors of recurrence and survival were analyzed. Results: Median age was 39 years in 66 patients. Before the surgery, 33.3% (20/60) patients had elevated CA125 and 51.7% (30/58) had elevated CA199. The accurate rate for fast frozen pathology of resected specimen was 73.4%. 21 patients underwent conservative surgery and 45 patients underwent extensive surgery. 57 patients underwent comprehensive operation and 43 cases (75.4%) resulted in stage Ⅰ. 48 of the 66 patients (72.7%) had intestinal-type tumors (IMBT) and 18 patients (27.3%) had endocervical-like tumors (EMBT). The median follow-up was 150 months. Eight recurrences (12.1%) were identified. The mean time between surgery to the initial recurrence was 26.4 months (13 to 50 months). Recurrence rate of IMBT was higher than that of EMBT (14.6% versus 5.6%) with no significance (P>0.05). All patients with pseudomyxoma had disease recurrence. Recurrence rate of stage Ⅲ patients was significantly higher than that of stage Ⅰ patients (33.3% versus 9.3%, P<0.05). During the follow-up period, tumor-related death occurred in 2 cases with a 10-year survival rate of 95.4%. Kaplan-Meier method and Log Rank analysis showed that clinical staging and peritonealmyxoma were adverse prognostic factors (P<0.05). Although the recurrence rate of patients undergoing conservative surgery was higher than that of patients with extensive surgery (23.8% versus 6.7%, P=0.047), the overall survival was almost the same between these two groups (P>0.05). Conclusions: MBOT patients have relatively good prognosis. IMBT are more common than EMBT subtypes, but recurrence rate and patient survival were almost the same between these two groups. Patients with pseudomyxoma was more likely to have disease recurrence. Patients who underwent conservative surgery resulted in higher recurrence rate but did not affect the overall survival of patient. Pseudomyxoma and clinical staging were adverse prognostic factors in MBOT patients.

Comparison of survival for partial vs. radical nephrectomy in young patients with T1a renal cell carcinoma treated at commission on cancer-accredited facilities and influence of comorbidities on treatment choice

PurposeThere is a paucity of data comparing effects of partial nephrectomy (PN) vs. radical nephrectomy (RN) on overall survival in young patients. In this study, the National Cancer Database was used to evaluate the survival outcomes of those treated with PN and RN, and influence of comorbidities on surgical treatment (PN vs. RN) in young patients while accounting for Charlson-Deyo Comorbidity Score (CDCS). Materials and methodsPatients between 20 and 44 years old (n = 9,849) surgically treated for pT1a renal cell carcinoma between 2004 and 2013 were identified from the National Cancer Database. Kaplan-Meier log-rank analysis and Cox proportional hazards model were performed to compare overall survival and calculate the hazard ratio between those undergoing RN and PN. Binary logistic regression was used to calculate odds ratios for receiving RN compared to PN. The effect measures in all models were adjusted for potential confounding factors. ResultsAfter adjusting for comorbidities, PN offered an overall survival advantage over RN (P<0.001, hazard ratio = 0.464, 95% CI: 0.359–0.601) at a mean follow-up of 48.4 months (0–130.96), including young patients with no comorbidities (P<0.001). Compared to those with a CDCS = 0, patients were more likely to be treated with RN if they had a CDCS>1 (odds ratios = 2.049, 95% CI: 1.527–2.750). ConclusionsYoung patients treated with PN demonstrate an overall survival advantage. This survival advantage is observed after an early follow-up even in those without comorbidities. It is still not clear if the survival advantage seen is due to treatment itself or selection bias.

Increased expression of IRF8 in tumor cells inhibits the generation of Th17 cells and predicts unfavorable survival of diffuse large B cell lymphoma patients.

The immunological pathogenesis of diffuse large B cell lymphoma (DLBCL) remains elusive. Searching for new prognostic markers of DLBCL is a crucial focal point for clinical scientists. The aim of the present study was to examine the prognostic value of interferon regulatory factor 8 (IRF8) expression and its effect on the development of Th17 cells in the tumor microenvironment of DLBCL patients. Flow cytometry, immunohistochemistry, and quantitative real-time PCR were used to detect the distribution of Th17 cells and related cytokines and IRF8 in tumor tissues from DLBCL patients. Two DLBCL cell lines (OCI-LY10 and OCI-LY1) with IRF8 knockdown or overexpression and two human B lymphoblast cell lines were co-cultured with peripheral blood mononuclear cells (PBMCs) in vitro to determine the effect of IRF8 on the generation of Th17 cells. Quantitative real-time PCR and Western blotting were used to investigate the involvement of retinoic acid receptor-related orphan receptor gamma t (RORγt) in the effect of IRF8 on Th17 cell generation. The survival of 67 DLBCL patients was estimated using the Kaplan-Meier method and log-rank analysis. The percentage of Th17 cells was lower in DLBCL tumor tissues than in PBMCs and corresponding adjacent benign tissues. Relative expression of interleukin (IL)-17A was lower, whereas that of interferon (IFN)-γ was higher in tumor tissues than in benign tissues. Co-culture with DLBCL cell lines inhibited the generation of Th17 cells in vitro. IRF8 upregulation was detected in DLBCL tumor tissues, and it was associated with decreased DLBCL patient survival. Investigation of the underlying mechanism suggested that IRF8 upregulation in DLBCL, through an unknown mechanism, inhibited Th17 cell generation by suppressing RORγt in neighboring CD4+ T cells. Tumor cells may express soluble or membrane-bound factors that inhibit the expression of RORγt in T cells within the tumor microenvironment. Our findings suggest that IRF8 expression could be a prognostic factor for DLBCL.

Combinatorial Ranking of Gene Sets to Predict Disease Relapse: The Retinoic Acid Pathway in Early Prostate Cancer.

Quantitative high-throughput data deposited in consortia such as International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA) present opportunities and challenges for computational analyses. We present a computational strategy to systematically rank and investigate a large number (210-220) of clinically testable gene sets, using combinatorial gene subset generation and disease-free survival (DFS) analyses. This approach integrates protein-protein interaction networks, gene expression, DNA methylation, and copy number data, in association with DFS profiles from patient clinical records. As a case study, we applied this pipeline to systematically analyze the role of ALDH1A2 in prostate cancer (PCa). We have previously found this gene to have multiple roles in disease and homeostasis, and here we investigate the role of the associated ALDH1A2 gene/protein networks in PCa, using our methodology in combination with PCa patient clinical profiles from ICGC and TCGA databases. Relationships between gene signatures and relapse were analyzed using Kaplan-Meier (KM) log-rank analysis and multivariable Cox regression. Relative expression versus pooled mean from diploid population was used for z-statistics calculation. Gene/protein interaction network analyses generated 11 core genes associated with ALDH1A2; combinatorial ranking of the power set of these core genes identified two gene sets (out of 211 - 1 = 2,047 combinations) with significant correlation with disease relapse (KM log rank p < 0.05). For the more significant of these two sets, referred to as the optimal gene set (OGS), patients have median survival 62.7 months with OGS alterations compared to >150 months without OGS alterations (p = 0.0248, hazard ratio = 2.213, 95% confidence interval = 1.1-4.098). Two genes comprising OGS (CYP26A1 and RDH10) are strongly associated with ALDH1A2 in the retinoic acid (RA) pathways, suggesting a major role of RA signaling in early PCa progression. Our pipeline complements human expertise in the search for prognostic biomarkers in large-scale datasets.

TERT promoter mutations and Ki-67 labeling index as a prognostic marker of papillary thyroid carcinomas: combination of two independent factors

Although most papillary thyroid carcinomas (PTCs) have a good prognosis, a small but certain fraction shows aggressive behavior. Therefore, a novel and well-performing molecular marker is needed. In the present study, we assessed the impact of the combination of the TERT promoter/BRAF mutations and Ki-67 labeling index (LI) as a prognostic marker in PTC patients. Of 400 PTC samples, 354 were successfully genotyped for both TERT promoter/BRAF and analyzed for Ki-67 LI. Based on the combination of the mutational status and Ki-67 LI, the cases were categorized into three groups: high-, middle-, and low-risk. The recurrence rates of low-, middle-, and high-risk group were 1.9% (6 of 323), 18.2% (4 of 22), and 44.4% (4 of 9), respectively. The Kaplan-Meier curve and log-rank analyses demonstrated that there were statistical differences between any two groups. The hazard ratios for recurrence remained significant after adjustment for age, sex, tumor size, and extrathyroidal extension (low vs. middle: 8.80, 95% CI: 2.35–32.92, p = 0.001; middle vs. high: 6.255, 95% CI: 1.13–34.51, p = 0.035). In conclusion, the combination of the TERT promoter/BRAFV600E mutations and Ki-67 LI performed excellent in predicting PTC recurrence and may be clinically useful.

Prognostic significance of serum chemerin levels in patients with non-small cell lung cancer.

Chemerin plays an important role in adipogenesis and chemotaxis of the innate immune system. The aim of this study was to explore the significance and prognostic value of serum chemerin levels in patients with non-small cell lung cancer (NSCLC). Serum specimens from 189 NSCLC patients and 120 healthy controls were collected. The levels of serum chemerin were measured by sandwich enzyme-linked immunosorbent assay (ELISA). The serum chemerin levels were significantly elevated in NSCLC patients compared with healthy controls (P < 0.001). Higher serum chemerin levels were associated with advanced TNM stage, lymph node metastasis, and distant metastasis. Area under receiver operating characteristic curve (ROC) for serum chemerin was 0.809 (95% CI: 0.722–0.896) at a sensitivity of 0.624 and of specificity 0.675. The cut-off value of chemerin was 1500 pg/ml for discriminating NSCLC from healthy controls. Kaplan-Meier log rank analysis revealed that the higher serum chemerin patients had a shorter overall survival (OS) and progression-free survival (PFS) compared with lower chemerin patients (P = 0.004, P = 0.001, respectively). Further univariate and multivariate Cox regression analysis showed that serum chemerin was an independent risk factor of prognosis of NSCLC patients. In conclusion, measurement of chemerin might be a useful diagnostic and prognostic biomarker for NSCLC patients.

Effect of diabetes on clinical efficacy of hepatic arterial chemoembolization in the treatment of non-hepatitis virus hepatocellular carcinoma

Objective To investigate the effect of diabetes on clinical efficacy of transcatheter arterial chemoembolization (TACE) in the treatment of non-viral hepatitis hepatocellular carcinoma (HCC). Methods Retrospectively analyzed the clinical data of 367 non-hepatitis virus HCC patients treated by TACE, included 153 diabetes mellitus cases (test group) and blood glucose of 214 patients was normal (control group). To assess the treatment effect after 1 month of TACE based on response evaluation criteria in solid tumors, include complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), and calculate the disease control rate. Through 6 to 75 months follow-up to observed long-term efficacy, record the time to progression (TTP) and overall survival (OS) time. Survival rate were analyzed using Kaplan-Meier method and Log-rank analysis by SPSS 16.0. The single-factor analysis was used to analyze variables which variables that differed were analyzed by Cox regression. Results The disease control rate of test group was 69.9% (107/153) and control group was 74.3% (159/214), the difference was no statistically significant (P=0.125). The median time to progression (mTTP) and median overall survival (mOS) of test group were 10.0 and 15.0 months; and the mTTP and mOS of control group were 14.0 and 19.0 months, the difference were statistically significant (P=0.023 and P= 0.026). Tumor diameter ≥4.5 cm, numbers of tumor ≥3, invasion of blood vessels, α-fetoprotein≥200 μg/L, Eastern Cooperative Oncology Group score and diabetes were risk factors for OS of HCC patients. Conclusion Diabetes is unfavorable factors for overall survival of non-hepatitis HCC tread by TACE. Key words: Diabetes mellitus; Carcinoma, hepatocellular; Chemoembolization, therapeutic; Prognosis

Lymphocyte/Monocyte Ratio is a Novel Predictor for Early Stage Extranodal Natural Killer/T-cell Lymphoma, Nasal Type.

Objective: Great heterogeneity exists in clinical behavior and survival outcome in patients with stage IE/IIE extranodal natural killer/T-cell lymphoma, nasal type (ENKTL). In this study, we proposed lymphocyte/monocyte ratio (LMR) as a new prognostic factor for these early stage ENKTL.Methods: We retrospectively examined the LMR as a prognostic variable in a cohort of 379 patients with newly diagnosed stage IE/IIE ENKTL. The relationship between the LMR and clinicopathologic variables were analyzed in Kaplan-Meier log-rank survival analysis, and the Cox proportional hazards model was used to determine the survival significance of the LMR for both progression-free survival (PFS) and overall survival (OS).Results: Patients were categorized into two different groups based on the LMR using cut-off value of 2.0. The 5-year PFS rates in the low and high LMR group were 43.9% and 62.7%, respectively, and the 5-year OS rates in the two groups were 59.1% and 77.7%, respectively. In multivariate analysis, low LMR at diagnosis was associated with worse PFS (hazard ratio 1.611, 95% confidence interval: 1.027-2.525, P =0.038) independent of age (P=0.033) and treatment stratagem (P<0.001), and indicated worse OS (hazard ratio 2.003, 95% confidence interval: 1.124-3.569, P =0.018) independent of age (P=0.007), LDH level (P=0.042), local tumor invasiveness (P=0.008), and treatment stratagem (P<0.001).Conclusion: The LMR is an independent prognostic factor for both DFS and OS in patients with stage IE/IIE ENKTL, and provides additional prognostic value beyond standard clinicopathological parameters.

Retraction Note to: Downregulation of microRNA-217 and microRNA-646 acts as potential predictor biomarkers in progression, metastasis, and unfavorable prognosis of human osteosarcoma.

Despite the progress in therapeutic targets, it remains dissatisfactory for most osteosarcoma patients with metastasis or recurrence osteosarcoma. Therefore, it is required to determine the involved mechanisms of osteosarcoma. The aim of this study was to investigate the expression level of MiR-217 and miR-646 and also their association with clinicopathological features in patients with osteosarcoma. Total RNA was purified from patients with osteosarcoma and noncancerous bone tissues, and then quantitative real-time PCR was applied to evaluate the expression level of microRNAs. Our result suggested that miR-217 expression was remarkably deceased in osteosarcoma bone tissue when compared with noncancerous bone tissues (mean ± SD 5.32 ± 1.231, 2.01 ± 0.78; P = 0.024) and miR-646 expression decreased in osteosarcoma bone tissue in comparison with normal tissues (mean ± SD 4.56 ± 1.45, 1.76 ± 1.24; P = 0.041). Our findings indicated that decreased expression of MiR-217 and miR-646 was strongly correlated with high tumor, node, and metastasis (TNM) stage (P = 0.015, P = 0.002) and large cancer diameter (P = 0.041, P = 0.053). Kaplan-Meier survival and log-rank analysis indicated that shorter overall survival was strongly linked to decreased expression of miR-217 and miR-646 (log-rank test P = 0.034, P = 0.026). In terms of miR-217, multivariate Cox proportional hazards model analysis has showed that reduction of miR-217 expression (P = 0.001), TNM stage (P = 0.046), and lymph node metastasis (P = 0.006) were independently linked to a short-time survival of patients. In terms of miR-646, low expression of miR-646 (P = 0.021), TNM stage (P = 0.052), and tumor size (P = 0.043) were independently associated with poor survival of patients as prognostic factors. Our findings suggested that downregulation of MiR-217 and miR-646 was associated with progression of osteosarcoma. MiR-217 and miR-646 may play a key role in suppression of tumor in osteosarcoma and would be applied as a novel therapeutic agent.

Diagnostic and prognostic value of serum periostin in patients with non-small cell lung cancer.

The periostin protein is expressed in a variety of human malignancies. The aim of this study was to explore the diagnostic and prognostic value of serum periostin levels in patients with non-small cell lung cancer (NSCLC). We measured serum periostin levels by ELISA in 296 NSCLC patients, 120 benign lung diseases (BLD) patients and 160 healthy controls. The levels of serum periostin in NSCLC patients were significantly elevated compared with those in healthy controls (P < 0.001) and BLD patients (P < 0.001). Using a cutoff value of 30.87 ng/ml, the sensitivity and specificity of periostin in differentiating between NSCLC patients and BLD patients, and between NSCLC patients and healthy controls was, 48.6 and 91.7%, and 51.4 and 97.5%, respectively. Kaplan-Meier log rank analysis revealed that the higher serum periostin levels group had a poorer progression-free survival (PFS) and overall survival (OS) compared with lower periostin group (P = 0.024, P = 0.015, respectively). Further univariate and multivariate Cox regression analysis showed that serum periostin was an independent risk factor of prognosis of NSCLC patients. In conclusion, our study suggests that serum periostin could be considered as a diagnostic and prognostic marker for NSCLC patients.

Serum levels of apolipoprotein E correlates with disease progression and poor prognosis in breast cancer.

ApoE has been reported to be associated with tumorigenesis and tumor progression. In this study, we explored the potential diagnostic and prognostic role of serum ApoE in breast cancer patients. Subject cohorts consisted of 152 normal healthy controls female and 257 breast cancer cases. Serum levels of ApoE were determined with turbidimetric immunoassay. The serum levels of ApoE were significantly elevated in breast cancer patients compared with normal healthy controls (45.82±13.96mg/L vs. 33.61±6.44mg/L, respectively, P<0.0001) and also significantly associated with TNM stage and lymph nodes status (all P<0.05). Area under receiver operating characteristic curve for serum ApoE discriminate breast cancer patients from controls was 0.786 with specificity of 0.974 and sensitivity of 0.541, the cut-off value of ApoE was 43.15mg/L. Kaplan-Meier log rank analysis showed that the high serum ApoE group (serum ApoE≥43.15mg/L) had a poorer progression-free survival and overall survival compared with low serum ApoE group (serum ApoE<43.15mg/L) (all P<0.05). In addition, univariate and multivariate Cox regression analysis displayed serum ApoE as an independent risk factor of breast cancer patients prognosis (all P<0.05). Serum ApoE played a role as serological biomarkers that indicated diagnostic and prognostic evaluation in breast cancer patients.

Multisite prediction of 4-week and 52-week treatment outcomes in patients with first-episode psychosis: a machine learning approach

At present, no tools exist to estimate objectively the risk of poor treatment outcomes in patients with first-episode psychosis. Such tools could improve treatment by informing clinical decision-making before the commencement of treatment. We tested whether such a tool could be successfully built and validated using routinely available, patient-reportable information. By applying machine learning to data from 334 patients in the European First Episode Schizophrenia Trial (EUFEST; International Clinical Trials Registry Platform number, ISRCTN68736636), we developed a tool to predict poor versus good treatment outcome (Global Assessment of Functioning [GAF] score ≥65 vs GAF <65, respectively) after 4 weeks and 52 weeks of treatment. To enable the unbiased estimation of the predictive system's generalisability to new patients, we used repeated nested cross-validation to prevent information leaking between patients used for training and validating the models. In pursuit of everyday clinical applicability, we retrained the 4-week outcome predictor with only the top ten predictors of the pooled prediction system and then tested this tool in 108 independent patients with 4-week outcome labels. Discontinuation and readmission to hospital events in patients with predicted poor versus good outcomes were assessed with Kaplan-Meier log-rank analyses, whereas generalised linear mixed-effects models were used to investigate the GAF-based predictions against several clinically meaningful outcome indicators, including treatment adherence, symptom remission, and quality of life. The generalisability of our outcome predictions were estimated with cross-validation (test-fold balanced accuracy [BAC] of 75·0% for 4-week outcomes and 73·8% for and 52-week outcomes), and leave-site-out validation across 44 European sites (BAC of 72·1% for 4-week outcomes and 71·1% for 52-week outcomes). We identified a smaller group of ten predictors still providing a BAC of 71·7% in 108 patients never used for model discovery. Unemployment, poor education, functional deficits, and unmet psychosocial needs predicted both endpoints, whereas previous depressive episodes, male sex, and suicidality additionally predicted poor 1-year outcomes. 52-week predictions identified patients at risk for symptom persistence, non-adherence to treatment, readmission to hospital and poor quality of life. Specifically among these patients, amisulpride and olanzapine showed superior efficacy versus haloperidol, quetiapine, and ziprasidone. Our results suggest that prognostic models operating on brief, patient-reportable pre-treatment data might provide useful insight into individualised outcome trajectories, optimising treatment selection, and targeted clinical trial designs. To embed these tools into real-world care, replication is needed in external first-episode samples with overlapping variables, which are not available in the field at present. The European Group for Research in Schizophrenia.

Abstract 5035A: Intratumoral HPV16-specific T-cells determine clinical outcome of HPV16+ oropharyngeal carcinomas

Abstract Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer. While the number of HNSCC cases is decreasing, the number of oropharyngeal SCC (OSCC) is rising, especially in young adults. OSCC are increasingly (45-90%) caused by human papillomavirus type 16 (HPV16). Intriguingly, patients with HPV-induced OSCC respond better to therapy than HPV-negative OSCC. This is independent of nodal status, age, stage, tumor differentiation or gender. We hypothesized that the expression of the viral antigens E6 and E7 in HPV16+ OSCC equips the immune system with two strong tumor-specific antigens resulting in the development of a type 1 T-cell immune contexture supporting the better response of HPV+ OSCC to standard therapy. To test our hypothesis we studied 87 patients with OSCC. The tumors of these patients were tested for the presence of HPV by GP5+/6+ PCR and the expression of p16 by immunohistochemistry. Moreover, fresh tumor tissue was dispersed, cryopreserved and subsequently used for in-depth analyses regarding the composition of the leukocyte infiltrates using a large set of antibodies either by CyTOF or BD Fortessa. In addition, T-cell reactivity was tested directly ex vivo and after a short-term culture period. 57% of OSCC patients were HPV16+ and they showed the best overall survival (p&amp;lt;0.0001, HR 6.9). Whereas none of 37 HPV-negative patients displayed intratumoral HPV16 E6/E7-specific T-cell reactivity this was detected in 25 of 40 (63%) HPV16+ OSCC. Notably, for most patients these T-cells were already detectable directly ex vivo, indicative for their activity in vivo. The presence of intratumoral HPV16-specific T-cell reactivity for the response of patients to therapy was extremely important for a better clinical outcome (p = 0.0003, HR 23.9) as estimated by Kaplan-Meier curves and log-rank analysis. Division of HPV16+ patients on the basis of p16 expression revealed that p16+ patients had a much better clinical outcome (p&amp;lt;0.0001, HR 11.8). In line with the notion that overexpression of p16 is directly associated with expression of the HPV16 E6 and E7 oncogenes, a strong association between p16 expression and HPV16-specific TIL reactivity was found (p&amp;lt;0.0001). Mechanistically, we found that OSCC cell lines promoted the differentiation of monocytes to M2 macrophages. In vitro experiments showed that the presence of HPV-specific T-cell secreted cytokines prevented this and was even able to redifferentiate macrophages into better antigen-presenting cells, both phenotypically (including co-stimulatory molecules) and functionally (more IL-12 and less IL-10 production). In addition, these cytokines mediated a direct effect on the tumor cell proliferation and metabolism, thereby slowing down tumor growth as well as changing their impact on myeloid cells in the tumor microenvironment. In conclusion, HPV-specific T cells elicited by HPV+ OSCC are highly predictive for response to therapy. Citation Format: Marij J. Welters, Lilly-Ann van der Velden, Vanessa J. van Ham, Ilina Ehsan, Renske Goedemans, Saskia J. Santegoets, Sjoerd H. van der Burg. Intratumoral HPV16-specific T-cells determine clinical outcome of HPV16+ oropharyngeal carcinomas. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5035A.

Molecular identification of miR-145 and miR-9 expression level as prognostic biomarkers for early-stage cervical cancer detection.

MicroRNAs (miRNAs) may act as carcinogen or tumor suppressor genes by targeting various biological molecules. Therefore, it is important to identify significant markers for prognosis, diagnosis treatment strategies of cancers. To evaluate the clinical importance and prognostic value of miR-9 and miR-145 in cervical cancer. miRNAs expression was detected using quantitative real-time polymerase chain reaction in cervical cancer specimens and adjacent normal tissues. MiR-9 up-regulated in cervical cancer specimens than adjacent normal tissues (9.743 ± 2.172 vs. 2.131 ± 1.083; P < 0.05). MiR-145 was decreased in cervical cancer specimens compared to corresponding normal tissues (2.189 ± 0. 724 vs. 7.173 ± 1.558 P < 0.05). In addition, increased expression of miR-9 was strongly linked to lymph node metastasis (P = 0.017) and vascular invasion (P = 0.011). On the other hand, the low expression of miR-145 was related to advanced FIGO stage (P = 0.007), lymph node metastasis (P = 0.02) and vascular invasion (0.026). Kaplan-Meier survival and log-rank analysis suggested that patients with high expression of miR-9 had shorter overall survival compared with those with low expression (log-rank test P = 0.028; P < 0.001). In addition, shorter overall survival time was remarkably linked to decreased expression of miR-145 (log-rank test P < 0.001). Multivariate Cox proportional hazards model analysis of miR-9 and miR-145 showed that FIGO stage (P = 0.011) high expression of miR-9 and low expression of miR-145 (P = 0.023; P = 0.031) were independent prognostic factors for overall survival of patients. miRNA-145 and 9 may be as potential prognostic marker in patients suffering from cervical cancer.

High serum haptoglobin level is associated with tumor progression and predicts poor prognosis in non-small cell lung cancer.

The overall survival time of non-small cell lung cancer (NSCLC) has not improved dramatically in recent decades. An important reason is the lacking of valuable biomarkers. Haptoglobin was reported to have activities of anti-inflammatory, anti-oxidant, autoimmune and tumor angiogenesis. However its potential role as a tumor biomarker was not well recognized. We used an immunoturbidimetry method to measure serum haptoglobin levels in 205 NSCLC patients, and 210 normal healthy controls. We found that serum haptoglobin levels were significantly elevated in NSCLC patients compared with normal healthy controls (1.985±1.039 mg/mLvs. 0.922 ± 0.495 mg/mL, respectively, P < 0.0001). Higher serum haptoglobin levels were associated with advanced TNM stage, lymph node metastasis, and distant metastasis. Area under receiver operating characteristic curve (ROC) for serum haptoglobin was 0.809 (95% CI: 0.767–0.852) at a specificity of 0.881 and sensitivity of 0.639. The optimal cut-off value of haptoglobin was 1.495 mg/mL for discriminating NSCLC from normal healthy controls. Kaplan-Meier log rank analysis revealed that the higher serum haptoglobin levels group had a poorer overall survival compared with lower haptoglobin group (the median survival was 12.0 weeks, 26.0 weeks, respectively, P < 0.01). Further univariate and multivariate Cox regression analysis showed that serum haptoglobin was an independent risk factor of prognosis of NSCLC patients (P < 0.01, P = 0.01, respectively). In conclusion, our study suggests that serum haptoglobin may act as useful clinical serological biomarkers in progression and prognostic evaluation in NSCLC.