Incidence and predictors of elevated postpartum alanine aminotransferase in chronic hepatitis B mothers: a prospective study protocol.

BACKGROUND: The majority of HBeAg-positive mothers with chronic hepatitis B have high levels of viremia and inactive disease with normal alanine aminotransferase (ALT) during pregnancy. In addition, postpartum disease activation and ALT flare have been reported in the range of 15 - 35%. However, the current International Association Guidelines have not provided clear recommendations and a risk-stratified monitoring schedule. Furthermore, data are lacking on the definition of normal ALT in the postpartum period in mothers with chronic hepatitis B. The clinical features and ALT flare patterns in HBeAg-positive mothers versus HBeAg-negative mothers are not fully explored. Thus, we design a cohort study to investigate the aforementioned area and generate data to assist healthcare providers in better managing mothers with hepatitis B. We aim to assess the frequency of postpartum ALT flares and predictors for such events. METHOD: This study is a single-center and prospective cohort study (n = 360) that consists of two groups of patients including HBsAg-positive mothers (n = 120) and healthy mothers without HBV infection (n = 240). In HBeAg-positive mothers, antiviral therapy during late pregnancy is permitted to prevent Mother-to-child transmission (MTCT) but discontinued at delivery if there is no further indication for the treatment. Mothers are enrolled at the gestational weeks of 12-24. After delivery, both mothers and their infants will be followed up until postpartum week 24. Clinical and laboratory data are collected every 4 weeks during the study except there are no follow-up visits at the postpartum weeks 16 and 20. The primary objective is the proportion of patients with postpartum ALT flares. The secondary objectives are independent risk factors during pregnancy for predicting postpartum ALT flares and the normal range of postpartum ALT levels in healthy mothers. DISCUSSION: The current study focuses on the incidence of postpartum ALT flares in mothers with chronic hepatitis B including subgroup analysis based on HBeAg status. The data will have several clinical implications, such as providing evidence for an appropriate monitoring schedule in CHB mothers after delivery. Further analyses on predictors of such events may assist clinicians in identifying mothers who might develop severe postpartum ALT flares. The data generated from healthy mothers have the potential to identify the patterns of ALT changes during pregnancy and postpartum, so we can gain a better understanding of the normal range of ALT in this subpopulation. TRIAL REGISTRATION NUMBER AT THE CHINESE CLINICAL TRIAL REGISTRY: ChiCTR2200061130.

Preliminary Study on the Relationship of BRAF Mutations with the Outcome of the First 131I Radiotherapy and Malignant Biological Characteristics in Papillary Thyroid Carcinoma.

OBJECTIVE: To investigate the relationship of BRAF mutation with the outcome of the first postoperative 131I treatment and malignant biological characteristics in papillary thyroid carcinoma (PTC). METHODS: Thirty-three patients with PTC who underwent their first 131I treatment after total thyroidectomy were enrolled in this study. BRAF mutation in postoperative tumor tissue and circulating tumor DNA (ctDNA) in peripheral blood at the time of 131I treatment were detected. According to the status of BRAF mutation, all patients were divided into 2 groups in each category of tumor tissues and ctDNA, respectively: 1) BRAF mutation, 2) BRAF wild-type. The Fisher's exact test was performed to analyze the relationship of BRAF mutation in either tumor tissue or ctDNA with the outcome of the first 131I treatment and malignant characteristics of PTC. RESULTS: BRAF mutation was detected in tumor tissues in 25 patients (25/33,75.8%), and all the patients had single mutation site. In ctDNA, BRAF mutation was detected in 5 patients (5/33, 15.2%), and all the patients had single mutation site. In both tumor tissues and ctDNA, BRAF mutation showed no relationship with the outcome of first 131I treatment and the malignant biological characteristics (P>0.05). CONCLUSION: The value of BRAF mutation alone might be limited in predicting therapeutic outcome of the first 131I treatment in PTC. No definitive relevance was found between BRAF mutation and malignant biological features in PTC.

Kaempferol induces ROS-dependent apoptosis in pancreatic cancer cells via TGM2-mediated Akt/mTOR signaling.

BACKGROUND: Kaempferol, a natural flavonoid, exhibits anticancer properties by scavenging reactive oxygen species (ROS). However, increasing evidence has demonstrated that, under certain conditions, kaempferol can inhibit tumor growth by upregulating ROS levels. In this study, we aimed to investigate whether kaempferol effectively suppresses pancreatic cancer through upregulation of ROS, and to explore the underlying molecular mechanism. METHODS: PANC-1 and Mia PaCa-2 cells were exposed to different concentrations of kaempferol. Cell proliferation and colony formation were evaluated by CCK-8 and colony formation assays. Flow cytometry was performed to assess the ROS levels and cell apoptosis. The mRNA sequencing and KEGG enrichment analysis were performed to identify differentially expressed genes and to reveal significantly enriched signaling pathways in response to kaempferol treatment. Based on biological analysis, we hypothesized that tissue transglutaminase (TGM2) gene was an essential target for kaempferol to induce ROS-related apoptosis in pancreatic cancer. TGM2 was overexpressed by lentivirus vector to verify the effect of TGM2 on the ROS-associated apoptotic signaling pathway. Western blot and qRT-PCR were used to determine the protein and mRNA levels, respectively. The prognostic value of TGM2 was analyzed by Gene Expression Profiling Interactive Analysis (GEPIA) tools based on public data from the TCGA database. RESULTS: Kaempferol effectively suppressed pancreatic cancer in vitro and in vivo. Kaempferol promoted apoptosis in vitro by increasing ROS generation, which was involved in Akt/mTOR signaling. TGM2 levels were significantly increased in PDAC tissues compared with normal tissues, and high TGM2 expression was positively correlated with poor prognosis in pancreatic cancer patients. Decreased TGM2 mRNA and protein levels were observed in the cells after treatment with kaempferol. Additionally, TGM2 overexpression downregulated ROS production and inhibited the abovementioned apoptotic signaling pathway. CONCLUSIONS: Kaempferol induces ROS-dependent apoptosis in pancreatic cancer cells via TGM2-mediated Akt/mTOR signaling, and TGM2 may represent a promising prognostic biomarker for pancreatic cancer.

A Notch-Dependent Inflammatory Feedback Circuit between Macrophages and Cancer Cells Regulates Pancreatic Cancer Metastasis.

Notch activation has been detected in pancreatic ductal adenocarcinoma (PDAC). However, its role in PDAC metastasis remains unknown. In this study, we identify a Notch-dependent feedback circuit between pancreatic cancer cells and macrophages, which contributes to PDAC metastasis. In this circuit, miR-124 regulated Notch signaling in cancer cells by directly targeting the Notch ligand Jagged 1. Autoamplified Notch signaling promoted the recruitment and activation of macrophages to a tumor-supporting M2-like phenotype via downstream IL8, CCL2, IL1α, and uPA paracrine signaling. In turn, activated macrophage-derived IL6 activated the oncogenic transcription factor STAT3 that directly repressed miR-124 genes via a conserved STAT3-binding site in their promoters, thereby promoting cancer cell epithelial-mesenchymal transition and invasion. Disrupting this circuit suppressed liver metastasis in mouse models. Thus, our study suggests that manipulation of this Notch-dependent circuit has a therapeutic potential for the treatment of PDAC metastasis. SIGNIFICANCE: This study provided potential therapeutic targets and robust preclinical evidence for PDAC treatment by interrupting feedback signaling between cancer cells and macrophages with targeted inhibitors.

Long-term cardiovascular disease mortality among 160 834 5-year survivors of adolescent and young adult cancer: an American population-based cohort study.

AIMS: Our aim was to assess the risk of cardiovascular disease (CVD) mortality in US 5-year survivors of adolescent and young adult (AYA) cancer compared with those of the general population and contemporaneous 5-year survivors of childhood cancer. METHODS AND RESULTS: A total of 160 834 5-year AYA cancer survivors (aged 15-39 years at diagnosis) were included, representing 2 239 390 person-years of follow-up. Overall, 2910 CVD deaths occurred, which was 1.4-fold [95% confidence interval (CI) 1.3-1.4] that expected in the general population, corresponding to 3.6 (95% CI 3.2-3.9) excess CVD deaths per 10 000 person-years. The highest risk of cardiac mortality was experienced after Hodgkin's lymphoma (HL), and the highest risk of cerebrovascular mortality was observed with central nervous system (CNS) tumours. Even survivors in their 6th and 7th decades of life, the risk of CVD mortality remained markedly higher than that of the matched general population. Competing risk analysis showed that the cumulative mortality of CVD was elevated among AYA cancer survivors compared with childhood cancer survivors during the whole study period. CONCLUSION: Long-term AYA cancer survivors have a greater risk of CVD mortality than the US general population and childhood cancer survivors. Vulnerable subgroups, especially survivors of HL and CNS tumours, require continued close follow-up care for cardiovascular conditions throughout survivorship.

Paeonol Inhibits Pancreatic Cancer Cell Migration and Invasion Through the Inhibition of TGF-ß1/Smad Signaling and Epithelial-Mesenchymal-Transition.

PURPOSE: Paeonol, a natural product derived from the root of Cynanchum paniculatum (Bunge) K. Schum and the root of Paeonia suffruticosa Andr. (Ranunculaceae) has attracted extensive attention for its anti-cancer proliferation effect in recent years. The present study examined the role of paeonol in suppressing migration and invasion in pancreatic cancer cells by inhibiting TGF-ß1/Smad signaling. METHODS: Cell viability was evaluated by MTT and colonial formation assay. Migration and invasion capabilities were examined by cell scratch-wound healing assay and the Boyden chamber invasion assay. Western Blot and qRT-PCR were used to measure the protein and RNA levels of vimentin, E-cadherin, N-cadherin, and TGF-ß1/Smad signaling. RESULTS: At non-cytotoxic dose, 100 µΜ and 150 µΜ of paeonol showed significant anti-migration and anti-invasion effects on Panc-1 and Capan-1 cells (p<0.01). Paeonol inhibited epithelial-mesenchymal-transition by upregulating E-cadherin, and down regulating N-cadherin and vimentin expressions. Paeonol inhibited TGF-ß1/Smad signaling pathway by downregulating TGF-ß1, p-Smad2/Smad2 and p-Smad3/Smad3 expressions. Further, TGF-ß1 attenuated the anti-migration and anti-invasion capacities of paeonol in Panc-1 and Capan-1 cells. CONCLUSION: These findings revealed that paeonol could suppress proliferation and inhibit migration and invasion in Panc-1 and Capan-1 cells by inhibiting the TGF-ß1/Smad pathway and might be a promising novel anti-pancreatic cancer drug.

Impact factors for the outcome of the first 131I radiotherapy in patients with papillary thyroid carcinoma after total thyroidectomy.

OBJECTIVE: To investigate the impact factors of the outcome of the first 131I treatment in patients with papillary thyroid carcinoma (PTC) after total thyroidectomy. METHODS: Three hundred and fifty-three patients [256 females, 97 males, average age (43.58 ± 12.33 years)] with PTC after total thyroidectomy who underwent 131I treatment from July 2014 to August 2017 were retrospectively analyzed. Curative efficacy of 131I treatment was assessed 6 months afterward. Therapeutic outcome was determined according to thyrotropin (TSH)-stimulated thyroglobulin (sTg) level, 131I diagnostic whole-body scan (Dx-WBS) after 131I treatment and other imaging modalities. Twelve possible factors affecting the therapeutic outcome of 131I treatment including patients' gender, age, interval between surgery and 131I treatment, primary tumor size and extrathyroidal extension (ETE), number and range of primary tumor lesions, result of 99mTcO4- thyroid scan, number of metastatic lymph nodes (LN), pre-treatment laboratory measurements [TSH, sTg and Tg antibody (TgAb)], therapeutic dose of 131I and result of 131I post-treatment whole-body scan (Rx-WBS) were analyzed using univariate and multivariate logistic regression. The receiver operator characteristic (ROC) curve and diagnostic cutoff value were analyzed to evaluate the predictive value of the significant quantitative impact factors for the outcome of 131I treatment. RESULTS: The curative rate of the first 131I treatment in patients with PTC after total thyroidectomy was 62.32% (220/353). Univariate analysis indicated that gender, age, number and range of primary tumor lesions, number of metastatic LN, pre-treatment sTg and TgAb, therapeutic dose of 131I and result of 131I Rx-WBS (all P < 0.05) were significant factors affecting the outcome of 131I treatment. Multivariate analysis revealed that the numbers of metastatic LN (regression coefficient = 1.170) and sTg (regression coefficient = 0.280) were significant impact factors (all P < 0.001). The regression equation was: Logit P = - 3.997 + 1.170 × number of metastatic LN + 0.280 × sTg (χ2 = 210.68, P < 0.001). Taking sTg as a predictive factor for the outcome of the first 131I treatment, the area under the curve (AUC) of ROC for sTg was 0.917 (95% CI 0.890-0.944). The cutoff value of sTg was 2.69 ng/mL with a sensitivity of 92.48% (123/133) and specificity of 74.09% (163/220). CONCLUSION: Patients with PTC after total thyroidectomy with low pre-treatment sTg level and few lymph node metastases are more likely to be cured by the first 131I treatment.

TAM Infiltration Differences in "Tumor-First" and " ZHENG-First" Models and the Underlying Inflammatory Molecular Mechanism in Pancreatic Cancer.

BACKGROUND: Syndrome ( ZHENG in Chinese) in traditional Chinese medicine (TCM) refers to the intrinsic characteristics of a pathological process at a certain stage; these characteristics are influenced by internal and external environments and reveal the nature of a disease. Proper syndrome differentiation is the basic principle that guides clinical treatment. OBJECTIVE: To have a good understanding of tumor progression and the different mechanisms related to ZHENG that have occurred before and after tumor development and to explore the valid evaluation criteria of different pancreatic cancer syndromes to improve the guiding role of TCM syndrome differentiation in pancreatic cancer treatment. METHODS: In this study, we established mouse subcutaneous pancreatic cancer models, namely, Con (control), Pi-Xu (Spleen-Deficiency), Shi-Re (Dampness-Heat), and Xue-Yu (Blood-Stasis). Then, for the first time, we compared the different effects of " ZHENG-first" (referring to a different disease status that occurred before tumor occurrence) and "Tumor-first" (referring to the change in the tumor microenvironment and the resulting changes in the state of the body) conditions on tumor progression and evaluated the associated molecular mechanisms. RESULTS: We found that tumor growth in the " ZHENG-first" and "Tumor-first" conditions was different. In the "Tumor-first" model, the tumor growth in the Pi-Xu group was faster than that in the other groups. However, in the " ZHENG-first" model, the tumor growth trend was most obvious in the Shi-Re group. There was a difference in tumor-associated macrophage infiltration between the 2 models. The expression levels of the inflammatory cytokines IL-6, IL-10, and P-STAT3 were also differentially altered. CONCLUSION: The emergence of ZHENG conditions before or after tumor occurrence had different impacts on pancreatic cancer development, and these impacts may be related to differences in tumor-associated macrophage infiltration and the involved inflammatory cytokines IL-6, IL-10, and P-STAT3. The study results uncovered the molecular basis of syndrome differentiation in pancreatic cancer progression, which might provide more specific guidance for TCM treatment of pancreatic cancer.

Serum lactate dehydrogenase predicts prognosis and correlates with systemic inflammatory response in patients with advanced pancreatic cancer after gemcitabine-based chemotherapy.

Serum lactate dehydrogenase (LDH) concentrations correlate with tumor progression and poor outcome. We evaluated the predictive value of serum LDH level for overall survival (OS) of patients with advanced pancreatic cancer after gemcitabine-based chemotherapy. We retrospectively enrolled 364 patients with locally advanced or metastatic pancreatic adenocarcinoma who were then allocated to training (n = 139) and validation cohorts (n = 225). We evaluated the association between serum LDH levels and OS as well as with markers of systemic inflammation, including neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR) and lymphocyte/monocyte ratio (LMR). Kaplan-Meier analyses revealed that low serum LDH levels in the training cohort significantly correlated with longer OS. Multivariate analysis identified the serum LDH levels as an independent prognostic predictor of OS (p = 0.005). Serum LDH levels correlated positively with NLR and PLR and correlated negatively with LMR. Similar results were obtained for the validation cohort, except that multivariate analysis identified the serum LDH level as a significant prognostic predictor and only a statistical trend for OS (p = 0.059). We conclude that serum LDH levels were associated with the systemic inflammatory response and served as a significant prognostic predictor of OS. Serum LDH levels predicted OS in patients with advanced pancreatic cancer after gemcitabine-based palliative chemotherapy.

A novel systemic inflammation response index (SIRI) for predicting the survival of patients with pancreatic cancer after chemotherapy.

BACKGROUND: Predicting survival is uniquely difficult in patients with pancreatic cancer who receive chemotherapy. The authors developed a systemic inflammation response index (SIRI) based on peripheral neutrophil, monocyte, and lymphocyte counts and evaluated the ability of the SIRI to predict the survival of patients with pancreatic cancer who received chemotherapy. METHODS: The SIRI was developed in a training set of 177 patients who had advanced pancreatic cancer and received palliative chemotherapy. The ability of the SIRI to predict a patient's survival after chemotherapy was validated in 2 independent cohorts (n = 397). RESULTS: Compared with patients who had an SIRI <1.8, patients in the training cohort who had an SIRI ≥1.8 had a shorter time to progression (TTP) (hazard ratio [HR], 2.348; 95% confidence interval, 1.559-3.535; P = .003) and shorter overall survival (OS) (HR, 2.789; 95% confidence interval, 1.897-4.121; P < .001). Comparable TTP and OS findings were observed in 2 independent validation cohorts. Multivariate analysis confirmed that the SIRI was an independent prognostic factor for both TTP and OS. In addition, compared with no change, an increase in the SIRI at week 8 was associated with poor TTP and OS, whereas a decrease in the SIRI was associated with improved outcomes. In addition, high SIRI scores were correlated with higher serum levels of interleukin 10, C-C motif chemokine ligand 17 (CCL17), CCL18, and CCL22 and with a shortened TTP. CONCLUSIONS: The SIRI can be used to predict the survival of patients with pancreatic adenocarcinomas who receive chemotherapy, potentially allowing clinicians to improve treatment outcomes by identifying candidates for aggressive therapy. Cancer 2016;122:2158-67. © 2016 American Cancer Society.

Hyperfibrinogen Is Associated With the Systemic Inflammatory Response and Predicts Poor Prognosis in Advanced Pancreatic Cancer.

OBJECTIVE: The aim of this study was to examine the prognostic prediction value of plasma fibrinogen level for overall survival (OS) in patients with advanced pancreatic cancer. METHODS: A total of 321 patients with locally advanced or metastatic pancreatic adenocarcinoma were retrospectively recruited. The association between plasma fibrinogen level and OS was analyzed. We also evaluated the relationship between plasma fibrinogen level and the systemic inflammatory response markers: the neutrophil-lymphocyte ratio, platelets/lymphocyte ratio, and lymphocyte/monocyte ratio. RESULTS: High plasma fibrinogen levels were significantly correlated with shorter OS in patients with advanced pancreatic cancer (175 days for patients with high fibrinogen levels vs 357 days for patients with low fibrinogen levels; log rank, 22.949; P < 0.001). Multivariate analyses confirmed that plasma fibrinogen level was an independent prognostic predictor for OS (hazard ratio, 2.184; 95% confidence interval, 1.574-3.032; P < 0.001). Receiver operating characteristic analyses showed that including plasma fibrinogen level alongside traditional factors (tumor stage and CA 19-9) significantly improved prognostic prediction capability (traditional model area under the curve of 0.62 versus combined model area under the curve of 0.708; P = 0.016). In addition, plasma fibrinogen level was positively correlated with neutrophil-lymphocyte ratio and platelets/lymphocyte ratio and negatively correlated with lymphocyte/monocyte ratio. CONCLUSIONS: Hyperfibrinogen is associated with the systemic inflammatory response and predicts poor prognosis for advanced pancreatic cancer.