Yinzhi Lai

Post-diagnosis hemoglobin change associates with overall survival of multiple malignancies – results from a 14-year hospital-based cohort of lung, breast, colorectal, and liver cancers

BackgroundAnemia refers to low hemoglobin (Hb) level and is a risk factor of cancer patient survival. The National Comprehensive Cancer Network recently suggested that post-diagnosis Hb change, regardless of baseline Hb level, indicates the potential presence of anemia. However, there is no epidemiological study evaluating whether Hb change has direct prognostic values for cancer patients at the population level.MethodsWe identified 6675 patients with a diagnosis of primary lung, breast, colorectal, or liver cancer who visited the Kimmel Cancer Center at the Thomas Jefferson University from 1998 to 2011. All patients had at least two Hb measurements within the first six months after diagnosis. We analyzed the main, dose-dependent, and time-dependent effects of Hb changes on patient survival.ResultsCompared to patients with a low Hb change (|∆Hb|≤2.6), those having a |∆Hb|>2.6 exhibited a significantly shorter survival (hazard ratio=1.40, 95% confidence interval 1.31-1.50, P=4.5 × 10-22, Plog rank=1.6 × 10-39). This association remained significant across the four cancer types. Bootstrap resampling validated these findings 100% of the time with P<0.01 in all patients and in patients of individual cancers. The association exhibited an apparent U-shape dose-dependent pattern. Time-dependent modeling demonstrated that the effect of Hb change on the survival of the overall patient population persisted for approximately 4.5 years after diagnosis.ConclusionPost-diagnosis Hb change associates with the survival of multiple cancers and may have clinical values in tailoring anti-anemia treatments. Because Hb level is frequently measured during cancer treatment, Hb changes may be a potentially important variable in building cancer prognosis models.

Cell-free circulating mitochondrial DNA content and risk of hepatocellular carcinoma in patients with chronic HBV infection.

Recent studies have demonstrated a potential link between circulating cell-free mitochondrial DNA (mtDNA) content and cancers. However, there is no study evaluating the association between circulating mtDNA as a non-invasive marker of hepatocellular carcinoma (HCC) risk. We conducted a nested case-control study to determine circulating mtDNA content in serum samples from 116 HBV-related HCC cases and 232 frequency-matched cancer-free HBV controls, and evaluate the retrospective association between mtDNA content and HCC risk using logistic regression and their temporal relationship using a mixed effects model. HCC cases had significantly lower circulating mtDNA content than controls (1.06 versus 2.47, P = 1.7 × 10−5). Compared to HBV patients with higher mtDNA content, those with lower mtDNA content had a significantly increased risk of HCC with an odds ratio (OR) of 2.19 (95% confidence interval [CI] 1.28–3.72, P = 0.004). Quartile analyses revealed a significant dose-dependent effect (Ptrend = 0.001) for this association. In a pilot longitudinal sub-cohort of 14 matched cases-control pairs, we observed a trend of dramatically decreased mtDNA content in cases and slightly decreased mtDNA content in controls, with a significant interaction of case-control status with time (Pinteraction = 0.049). Our findings suggest that circulating mtDNA is a potential novel non-invasive biomarker of HCC risk in HBV patients.

Heparin Promotes Cardiac Differentiation of Human Pluripotent Stem Cells in Chemically Defined Albumin-Free Medium, Enabling Consistent Manufacture of Cardiomyocytes

Cardiomyocytes can be differentiated from human pluripotent stem cells (hPSCs) in defined conditions, but efficient and consistent cardiomyocyte differentiation often requires expensive reagents such as B27 supplement or recombinant albumin. Using a chemically defined albumin‐free (E8 basal) medium, we identified heparin as a novel factor that significantly promotes cardiomyocyte differentiation efficiency, and developed an efficient method to differentiate hPSCs into cardiomyocytes. The treatment with heparin helped cardiomyocyte differentiation consistently reach at least 80% purity (up to 95%) from more than 10 different hPSC lines in chemically defined Dulbeccos modified Eagles medium/F‐12‐based medium on either Matrigel or defined matrices like vitronectin and Synthemax. One of heparins main functions was to act as a Wnt modulator that helped promote robust and consistent cardiomyocyte production. Our study provides an efficient, reliable, and cost‐effective method for cardiomyocyte derivation from hPSCs that can be used for potential large‐scale drug screening, disease modeling, and future cellular therapies. Stem Cells Translational Medicine 2017;6:527–538

The Doylestown Algorithm: A Test to Improve the Performance of AFP in the Detection of Hepatocellular Carcinoma

Biomarkers for the early diagnosis of hepatocellular carcinoma (HCC) are needed to decrease mortality from this cancer. However, as new biomarkers have been slow to be brought to clinical practice, we have developed a diagnostic algorithm that utilizes commonly used clinical measurements in those at risk of developing HCC. Briefly, as α-fetoprotein (AFP) is routinely used, an algorithm that incorporated AFP values along with four other clinical factors was developed. Discovery analysis was performed on electronic data from patients who had liver disease (cirrhosis) alone or HCC in the background of cirrhosis. The discovery set consisted of 360 patients from two independent locations. A logistic regression algorithm was developed that incorporated log-transformed AFP values with age, gender, alkaline phosphatase, and alanine aminotransferase levels. We define this as the Doylestown algorithm. In the discovery set, the Doylestown algorithm improved the overall performance of AFP by 10%. In subsequent external validation in over 2,700 patients from three independent sites, the Doylestown algorithm improved detection of HCC as compared with AFP alone by 4% to 20%. In addition, at a fixed specificity of 95%, the Doylestown algorithm improved the detection of HCC as compared with AFP alone by 2% to 20%. In conclusion, the Doylestown algorithm consolidates clinical laboratory values, with age and gender, which are each individually associated with HCC risk, into a single value that can be used for HCC risk assessment. As such, it should be applicable and useful to the medical community that manages those at risk for developing HCC. Cancer Prev Res; 9(2); 172–9. ©2015 AACR.

Modeling the overall survival of patients with advanced‐stage non‐small cell lung cancer using data of routine laboratory tests

Cancer patients undergo routine clinical monitoring with an array of blood tests that may carry long‐term prognostic information. We aimed to develop a new prognostic model predicting survival for patients with advanced non‐small cell lung cancer (NSCLC), based on laboratory tests commonly performed in clinical practice. A cohort of 1,161 stage IIIB or IV NSCLC patients was divided into training (n = 773) and testing (n = 388) cohorts. We analyzed the associations of 32 commonly tested laboratory variables with patient survival in the training cohort. We developed a model based on those significant laboratory variables, together with important clinical variables. The model was then evaluated in the testing cohort. Five variables, including albumin, total protein, alkaline phosphatase, blood urea nitrogen and international normalized ratio, were significantly associated with patient survival after stepwise selection. A model incorporating these variables classified patients into low‐, medium‐ and high‐risk groups with median survival of 16.9, 7.2 and 2.1 months, respectively (p < 0.0001). Compared with low‐risk group, patients in the medium‐ and high‐risk groups had a significantly higher risk of death at 1 year, with hazard ratio (HR) of 1.95 (95% CI 1.62–2.36) and 5.22 (4.30–6.34), respectively. These results were validated in the testing cohort. Overall, we developed a prognostic model relying entirely on readily available variables, with similar predictive power to those which depend on more specialized and expensive molecular assays. Further study is necessary to validate and further refine this model, and compare its performance to models based on more specialized and expensive testing.

Aspartate aminotransferase to platelet ratio index as a prospective predictor of hepatocellular carcinoma risk in patients with chronic hepatitis B virus infection

APRI (aspartate aminotransferase [AST] to platelet ratio index) is widely used to assess fibrosis and cirrhosis risk, especially in hepatitis C virus (HCV)‐infected patients. Few studies have evaluated APRI and hepatitis B virus (HBV)‐related hepatocellular carcinoma (HCC) risk. Prospective evidence is needed to assess whether APRI predicts HCC risk in HBV patients.

Postoperative hyperphosphatemia significantly associates with adverse survival in colorectal cancer patients

Hyperphosphatemia has been implicated in the development and treatment of various cancers. However, whether it can be used as a direct prognostic marker of colorectal cancer (CRC) has remained unexplored. Given new insights into the importance of hyperphosphatemia in CRC, we sought to evaluate the association of hyperphosphatemia with the clinical outcomes of this disease.

AT-rich interactive domain 2, p110α, p53, and β-catenin protein expression in hepatocellular carcinoma and clinicopathologic implications

AT-rich interactive domain 2 (ARID2), catenin (cadherin-associated protein), beta 1, 88kDa (β-catenin), tumor protein 53 (p53), and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (p110α) mutations are implicated in hepatocellular carcinoma (HCC); and previous work has contributed to thorough molecular characterization of these events. However, studies that assess the impact of these mutations on downstream protein expression, especially those that evaluate all 4 cancer markers simultaneously, are relatively lacking. Hence, the present study uses immunohistochemistry to assess protein expression patterns of ARID2, β-catenin, p53, and p110α in HCCs and adjacent nonneoplastic cirrhotic tissues from 58 explanted livers. Notably, this study is the first to our knowledge to investigate ARID2 protein expression in the liver. The frequency of ARID2 mutations detected using our immunohistochemistry method was similar to that reported in previous molecular studies. Furthermore, we found that loss of ARID2 protein expression may be associated with recurrence, although further studies must be done to validate these findings in a larger population. We found that expression patterns of the 4 cancer markers were independent of each other, suggesting separate pathways of hepatocarcinogenesis. We also did not observe an association between viral etiology and protein expression. Consistent with previous studies, overexpression of p53 correlated with poor differentiation. Lastly, 17.5% of HCCs paradoxically had diffuse loss of the oncoprotein p110α compared with strong expression in background cirrhotic liver. The exact mechanism is unclear, but enigmatic loss of oncoprotein function has been described in other carcinomas and could potentially have significant implications for the use of targeted mechanistic target of rapamycin (serine/threonine kinase) drug therapies.

A Routine Laboratory Data–Based Model for Predicting Recurrence After Curative Resection of Stage II Colorectal Cancer

Background: Use of chemotherapy in stage II colorectal cancer (CRC) is controversial because it improves survival only in some patients. We aimed to develop a statistical model using routine and readily available blood tests to predict the prognosis of patients with stage II CRC and to identify which patients are likely to benefit from chemotherapy. Methods: We divided 422 patients with stage II CRC into a training and a testing set. The association of routine laboratory variables and disease-free survival (DFS) was analyzed. A prognostic model was developed incorporating clinically relevant laboratory variables with demographic and tumor characteristics. A prognostic score was derived by calculating the sum of each variable weighted by its regression coefficient in the model. Model performance was evaluated by constructing receiver operating characteristic curves and calculating the area under the curve (AUC). Results: Significant associations were seen between 5 laboratory variables and patient DFS in univariate analyses. After stepwise selection, 3 variables (carcinoembryonic antigen, hemoglobin, creatinine) were retained in the multivariate model with an AUC of 0.75. Compared with patients with a low prognostic score, those with a medium and high prognostic score had a 1.99- and 4.78-fold increased risk of recurrence, respectively. The results from the training set were validated in the testing set. Moreover, chemotherapy significantly improved DFS in high-risk patients, but not in low- and medium-risk patients. Conclusions: A routine laboratory variable-based model may help predict DFS of patients with stage II CRC and identify high-risk patients more likely to benefit from chemotherapy.

Prospective and longitudinal evaluations of telomere length of circulating DNA as a risk predictor of hepatocellular carcinoma in HBV patients.

Prospective and longitudinal epidemiological evidence is needed to assess the association between telomere length and risk of hepatocellular carcinoma (HCC). In 323 cancer-free Korean-American HBV patients with 1-year exclusion window (followed for >1 year and did not develop HCC within 1 year), we measured the relative telomere length (RTL) in baseline serum DNAs and conducted extensive prospective and longitudinal analyses to assess RTL-HCC relationship. We found that long baseline RTL conferred an increased HCC risk compared to short RTL [hazard ratio (HR) = 4.93, P = 0.0005). The association remained prominent when the analysis was restricted to patients with a more stringent 5-year exclusion window (HR = 7.51, P = 0.012), indicating that the association was unlikely due to including undetected HCC patients in the cohort, thus minimizing the reverse-causation limitation in most retrospective studies. Adding baseline RTL to demographic variables increased the discrimination accuracy of the time-dependent receiver operating characteristic analysis from 0.769 to 0.868 (P = 1.0 × 10-5). In a nested longitudinal subcohort of 16 matched cases-control pairs, using a mixed effects model, we observed a trend of increased RTL in cases and decreased RTL in controls along 5 years of follow-up, with a significant interaction of case/control status with time (P for interaction=0.002) and confirmed the association between long RTL and HCC risk [odds ratio [OR] = 3.63, P = 0.016]. In summary, serum DNA RTL may be a novel non-invasive prospective marker of HBV-related HCC. Independent studies are necessary to validate and generalize this finding in diverse populations and assess the clinical applicability of RTL in HCC prediction.