Can Epstein-Barr virus-deoxyribonucleic acid load after induction chemotherapy combined with American Joint Committee on Cancer stage determine the chemotherapy intensity of locally advanced nasopharyngeal carcinoma?

BACKGROUND: Induction chemotherapy (IC) comprising docetaxel, cisplatin, and fluorouracil (TPF), combined with concurrent chemoradiotherapy (CCRT) effectively improves the survival rate of locally advanced nasopharyngeal carcinoma (LA-NPC). Selecting patients whose risk of tumor recurrence and metastasis is high and the appropriate chemotherapy intensity is a concern. We combined tumor-node-metastasis staging with the load of Epstein-Barr virus (EBV) after IC to select the individualized chemotherapy strength. METHODS: The clinical data and prognostic factors of patients with stage III-IV LA-NPC treated with TPF IC combined with CCRT were analyzed retrospectively. The conventional treatment group received the standard three cycles TPF IC combined with CCRT. For the new treatment group, the cycles of IC were determined according to whether the EBV-DNA disappeared completely after a certain course of IC, if so, subsequent IC was stopped and the chemoradiotherapy stage was entered. Propensity score matching (PSM) was performed at a ratio of 1:1 to balance baseline characteristics. Survival outcomes and adverse events between the conventional treatment group and the new method treatment group were compared. RESULTS: The study included 256 patients, among whom 192 were matched successfully into 96 pairs. The patients were followed up for a median of 51 months. The proportions of patients receiving three, two, and one cycle of IC after PSM in the routine and new treatment cohorts were 93.8%, 3.1%, 3.1% versus 21.9%, 49.0%, 24.0%, respectively. However, their 3-year distant metastasis-free survival, local recurrence-free survival, progression-free survival, and overall survival did not differ significantly. The incidence of grade 3-4 neutropenia toxicity in CCRT decreased significantly in patients receiving the new treatment method compared with that in the conventional treatment group (p = 0.026). CONCLUSION: Combining TNM stage and EBV-DNA load after IC to determine the courses of IC in patients with LA-NPC did not alter the curative effect but decreased toxicity.

Adjuvant Sorafenib Following Radiofrequency Ablation for Early-Stage Recurrent Hepatocellular Carcinoma With Microvascular Invasion at the Initial Hepatectomy.

Background: The efficacy of radiofrequency ablation (RFA) for patients with early-stage recurrent hepatocellular carcinoma (HCC) with microvascular invasion (MVI) at the initial hepatectomy is limited. Our study aimed to explore whether adjuvant sorafenib following RFA could improve the situation. Methods: We retrospectively included 211 patients with early-stage (tumor number of ≤3 and tumor size of 2-5 cm) recurrent HCC with MVI at the initial hepatectomy who underwent adjuvant sorafenib following RFA or RFA alone in 13 centers from June 2013 to June 2020. In the combination group, sorafenib of 400 mg twice daily was administered within 7 days after RFA. Overall survival (OS) and recurrence-free survival (RFS) were compared. Subgroup analysis based on MVI grade was performed. MVI grade was based on the practice guidelines for the pathological diagnosis of HCC and included M1 (≤5 MVI sites, all located within adjacent peritumoral liver tissues 0-1 cm away from the tumor margin) and M2 (>5 MVI sites, or any MVI site located within adjacent peritumoral liver tissues > 1 cm away from the tumor margin). Results: A total of 103 patients received the combination therapy and 108 patients received RFA alone. The combination therapy provided better survival than RFA alone (median RFS: 17.7 vs. 13.1 months, P < 0.001; median OS: 32.0 vs. 25.0 months, P = 0.002). Multivariable analysis revealed that treatment allocation was an independent prognostic factor. On subgroup analysis, the combination therapy provided better survival than RFA alone in patients with M1 along with either a tumor size of 3-5 cm, tumor number of two to three, or alpha-fetoprotein (AFP) > 400 µg/L, and in those with M2 along with either a tumor size of 2-3 cm, one recurrent tumor, or AFP ≤ 400 µg/L. Conclusions: Adjuvant sorafenib following RFA was associated with better survival than RFA alone in patients with early-stage recurrent HCC with MVI at the initial hepatectomy. Moreover, MVI grade could guide the application of adjuvant sorafenib.

A Pre-Operative Prognostic Score for Patients With Advanced Hepatocellular Carcinoma Who Underwent Resection.

BACKGROUND: Previous studies demonstrated a promising prognosis in advanced hepatocellular carcinoma (HCC) patients who underwent surgery, yet a consensus of which population would benefit most from surgery is still unreached. METHOD: A total of 496 advanced HCC patients who initially underwent liver resection were consecutively collected. Least absolute shrinkage and selection operator (LASSO) regression was performed to select significant pre-operative factors for recurrence-free survival (RFS). A prognostic score constructed from these factors was used to divide patients into different risk groups. Survivals were compared between groups with log-rank test. The area under curves (AUC) of the time-dependent receiver operating characteristics was used to evaluate the predictive accuracy of prognostic score. RESULT: For the entire cohort, the median overall survival (OS) was 23.0 months and the median RFS was 12.1 months. Patients were divided into two risk groups according to the prognostic score constructed with ALBI score, tumor size, tumor-invaded liver segments, gamma-glutamyl transpeptidase, alpha fetoprotein, and portal vein tumor thrombus stage. The median RFS of the low-risk group was significantly longer than that of the high-risk group in both the training (10.1 vs 2.9 months, P<0.001) and the validation groups (13.7 vs 4.6 months, P=0.002). The AUCs of the prognostic score in predicting survival were 0.70 to 0.71 in the training group and 0.71 to 0.72 in the validation group. CONCLUSION: Surgery could provide promising survival for HCC patients at an advanced stage. Our developed pre-operative prognostic score is effective in identifying advanced-stage HCC patients with better survival benefit for surgery.

Anti-PD-1 Immunotherapy and Radiotherapy for Stage IV Intrahepatic Cholangiocarcinoma: A Case Report.

Due to the unsatisfactory robustness of current predictive biomarkers in many cases, application of immunotherapy in advanced cancers with limited treatment options, such as stage IV intrahepatic cholangiocarcinoma (ICC), was quite common. Hence, strategies to enhance the therapeutic effect of immunotherapy or to extend the scope of potential beneficial patients were urgently needed. Combination of radiotherapy and anti-programmed death receptor-1 (PD-1) immunotherapy was a promising one, since they were found to have a synergistic anti-tumor effect in animal models and a couple of patients. We here present a 68-years-old male with chemotherapy-intolerable stage IV ICC, whose primary tumor had low PD-L1 expression level, scarce CD8+ cells in tumor microenvironment, high microsatellite instability (MSI), and high tumor mutation burden (TMB). These biomarkers showed a conflicting prediction of the treatment response and clinical benefit of anti-PD-1 immunotherapy. Combination therapy of anti-PD-1 immunotherapy and radiotherapy was adopted as first-line treatment for the patient. After six cycles of immunotherapy, shrinkage of the primary liver tumor and metastatic lymph nodes happened, alongside with new lung metastasis, which indicated a mixed response. Radiotherapy was then administered to both the liver and lung lesions, accompanied with continued immunotherapy. The combined therapy eventually led to a complete response for both the primary tumor and all metastases without treatment-related adverse effects. The patient has survived for 26 months after the combined therapy and remains tumor-free currently. This case demonstrates the high inconsistency between immunotherapy response biomarkers and the synergetic anti-tumor effect of immunotherapy and radiotherapy in ICC.

The presence of microvascular invasion guides treatment strategy in recurrent HBV-related HCC.

OBJECTIVES: We used the status of microvascular invasion (MVI) at primary resection to help treatment selection for hepatitis B virus-positive (HBV+) recurrent hepatocellular carcinoma (rHCC) patients in Barcelona Clinic Liver Cancer (BCLC) stage B-C. METHODS: From 2009 to 2017, we enrolled 221 consecutive HBV+ rHCC patients at BCLC stage B-C who underwent re-resection (RR), radiofrequency ablation (RFA), or transarterial chemoembolization (TACE). Post recurrence survival (PRS) and overall survival (OS) were compared between RR/RFA and TACE according to MVI status. A one-to-one propensity score matching analysis was performed. RESULTS: For MVI(-) patients, the median PRS was 62.3 months for the RR/RFA group and 21.1 months for the TACE group (p = 0.039). The corresponding OS was 71.4 months and 26.6 months, respectively (p = 0.010). For MVI(+) patients, the median PRS in the RR/RFA group and TACE group was 14.7 months and 10.1 months (p = 0.115). The corresponding OS was 23.4 months and 16.4 months, respectively (p = 0.067). After matching, the dominance of RR/RFA over TACE remained in MVI(-) patients for both PRS (62.3 months vs 15.3 months, p = 0.019) and OS (98.1 months vs 33.4 months, p = 0.046). No significant difference was found in MVI(+) patients for either PRS (14.7 months vs 11.8 months, p = 0.593) or OS (23.4 months vs 28.1 months, p = 0.662). CONCLUSIONS: MVI status definitely helps select treatment options in HBV+ rHCC patients. For MVI(-) patients, RR/RFA provided better survival than TACE while for MVI(+) patients, TACE shared similar survival outcomes. KEY POINTS: • This study aimed at the determination of the optimal treatment options (ablation /resection vs TACE) in case of recurrent HBV-related HCC. • It showed that MVI status, established at primary resection of HCC, was a powerful marker for selecting the best treatment option in these patients. • In MVI(-) patients, RR/RFA achieved a better survival than TACE. In MVI(+) patients, TACE shared similar survival.

TBH score: a new model to predict and prevent severe liver damage after chemotherapy for cancer patients.

PURPOSE: To explore a quantitative predictive model for the risk of chemotherapy-induced severe liver damage (CISLD). MATERIALS AND METHODS: In total, 3870 consecutive cancer patients initially treated with chemotherapy were retrospectively collected and randomly assigned to a training (n=2580) or internal validation (n=1290) set in a 2:1 ratio to construct and validate the model. Additional external validation was performed using another data set (n=413). A total of 486 patients were prospectively enrolled to assess the clinical significance of the model. CISLD was defined as grade ≥3 hepatotoxicity. RESULTS: CISLD was found in 255 (9.9%), 128 (9.9%) and 36 (8.7%) patients in the training, internal and external validation sets, respectively. Serum triglyceride, body mass index and history of hypertension formed the basis of the score model. Patients could be stratified into low, intermediate and high-risk groups with <10%, 10-30% and >30% CISLD occurrence, respectively. This model displayed a concordance index (C-index) of 0.834 and was validated in both the internal (C-index, 0.830) and external (C-index, 0.817) sets. The incidence of CISLD was significantly reduced in those who received preventive hepatoprotective drugs compared to those who did not among patients assessed as the intermediate risk group (8.9% vs 17.5%, p=0.042) and the high risk group (15.6% vs 55.8%, p=0.043). CONCLUSIONS: The new score model can be used to accurately predict the risk of CISLD in cancer patients undergoing chemotherapy. Clinically, this can be translated into a reference tool for oncologists in the clinical decision-making process before chemotherapy to provide appropriate prevention and interventions for patients with a high risk of CISLD.

Development and external validation of a nomogram for predicting the overall survival of patients with stage II nasopharyngeal carcinoma after curative treatment.

Objective: To facilitate decision-making support for individual patients, development and external validation of a nomogram was undertaken to reveal prognostic factors and predict the value of concurrent chemoradiotherapy (CCRT) compared with radiotherapy (RT) for stage-II nasopharyngeal carcinoma (NPC) patients. Methods: Clinical data of 419 and 309 patients with American Joint Committee on Cancer (2017) stage-II NPC in two institutions in China were collected retrospectively. Overall survival (OS) and progression-free survival were compared using Kaplan-Meier estimates. Cox regression analysis was used to identify the prognostic factors for building the nomogram. Predictive accuracy and discriminative ability were measured using the Concordance Index. Results: Finally, there were 24 and 20 deaths in the development and validation group, respectively. Patients with stage T2N1, N1 stage, involvement of retropharyngeal and unilateral cervical lymph nodes, and who had RT alone had worse OS (P=0.019, 0.035, 0.003 and 0.010, respectively; log-rank test) than patients with stage T1N1 and T2N0, N0 stage, involvement of retropharyngeal or unilateral cervical lymph nodes, and CCRT, respectively. After multivariate analysis of the training set, age, neutrophil-to-lymphocyte ratio, therapy type, and pretreatment plasma concentration of Epstein-Barr virus DNA were independent prognostic factors of OS. A nomogram was established externally by involving all the factors stated above. The Concordance Index for the established nomogram to predict the OS of the training set was 0.793 (95% CI 0.689-0.897), and 0.803 (95% CI 0.696-0.910) in the validation set. Conclusion: These data suggest that the nomogram was validated externally, could predict long-term outcome accurately, and enable accurate stratification of risk groups for stage-II NPC. Our model facilitated individualized care of NPC patients.

Treatment selection of recurrent hepatocellular carcinoma with microvascular invasion at the initial hepatectomy.

BACKGROUND: Recurrent hepatocellular carcinoma (rHCC) patients with microvascular invasive (MVI) positive at first resection usually had poorly differentiated tumors and worse survivals. The optimal treatment for this population remains to be elucidated. METHODS: We retrospectively analyzed 319 rHCC patients with MVI-positive at first resection from June, 2009 to June, 2017. Survival and costs between curative treatments [re-resection (RR) and radiofrequency ablation (RFA)] and transarterial chemoembolization (TACE) were compared. Subgroup comparisons were made in patients in Barcelona Clinic Liver Cancer (BCLC) stage 0-A and BCLC stage B-C, respectively. A one-to-one propensity score matching (PSM) was used to diminish bias. RESULTS: In BCLC stage 0-A, 98 received RR/RFA, and 49 received TACE. The median overall survival (OS) of RR/RFA group was not reached, while the OS of TACE group was 26.3 months (P=0.001). After matching, the OS of the RR/RFA group was longer than that of the TACE group (39.5 vs. 26.3 months, P=0.045). In BCLC stage B-C, 137 patients received TACE, 11 received RR and 24 received RFA. The median OS was 29.8 months, 17.9 months and 11.1 months for RR, RFA and TACE group, respectively. No significant difference was found between RR and TACE (P=0.237) or RFA and TACE (P=0.484) after matching. Costs of the TACE group was significantly lower than that of the RR group but similar to that of the RFA group. CONCLUSION: RR/RFA provided better survival outcomes for rHCC patients with MVI-positive at first resection in selected BCLC stage 0-A. In selected BCLC stage B-C, TACE shared a similar efficacy with RR and RFA but a lower cost than RR.

The long noncoding RNA AK002107 negatively modulates miR-140-5p and targets TGFBR1 to induce epithelial-mesenchymal transition in hepatocellular carcinoma.

The abnormal expression of long noncoding RNAs (lncRNAs) is associated with human carcinoma. The present study aimed to investigate the mechanisms underlying the function of lncRNA AK002107 in the progression of hepatocellular carcinoma (HCC). The differential expression of lncRNAs between HCC and paired nontumor tissues was identified using microarrays, and the correlation between the expression of lncRNA AK002107 and the clinical prognosis of HCC was analyzed. We investigated the role of lncRNA AK002107 in HCC tumor biology in vitro using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT), colony formation, and Matrigel invasion assays and in vivo by assessing the growth of xenografted HCC tumors. The potential microRNAs that interact with lncRNA AK002107 were identified using online tools and were verified using PCR and luciferase reporter assay. The levels of TGFBR1, E-cadherin, and vimentin were determined using western blot assays. We then further investigated the correlation between expression of lncRNA AK002107 with miR-140-5p and TGFBR1 expression in HCC tissues. The expression of lncRNA AK002107 is frequently upregulated in HCC samples and cell lines. Patients with HCC who have elevated lncRNA AK002107 expression exhibit poorer overall survival and disease-free survival. Silencing lncRNA AK002107 expression significantly inhibited HCC cell proliferation, colony formation, and invasion both in vitro and in vivo. Furthermore, lncRNA AK002107 directly binds to miR-140-5p and significantly inhibits miR-140-5p expression. The functions of lncRNA AK002107 in cell growth and tumor invasion are mediated via miR-140-5p. lncRNA AK002107 upregulated TGFBR1 expression and then induced epithelial-mesenchymal transition (EMT) by inhibiting miR-140-5p expression. The expression of lncRNA AK002107 inversely correlated with miR-140-5p expression and positively correlated with TGFBR1 expression in HCC tissues. In summary, lncRNA AK002107 functions as an oncogene in tumors by inhibiting miR-140-5p, targeting TGFBR1, and then inducing EMT. The lncRNA AK002107/miR-140-5p/TGFBR1/EMT regulatory network may be a valuable target for the development of novel diagnostic and treatment methods for HCC.

Selective targeting of lysyl oxidase-like 2 (LOXL2) suppresses hepatic fibrosis progression and accelerates its reversal.

BACKGROUND/AIMS: We studied the role of lysyl oxidase-like 2 (LOXL2) in collagen crosslinking and hepatic progenitor cell (HPC) differentiation, and the therapeutic efficacy of a LOXL2-blocking monoclonal antibody on liver fibrosis progression/reversal in mice. METHODS: Anti-LOXL2 antibody, control antilysyl oxidase antibody or placebo was administered during thioacetamide (TAA)-induced fibrosis progression or during recovery. Therapeutic efficacy in biliary fibrosis was tested in BALB/c.Mdr2-/- and 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-fed mice. Collagen crosslinking, fibrosis progression and reversal were assessed histologically and biochemically. HPC differentiation was studied in primary EpCAM(+) liver cells in vitro. RESULTS: LOXL2 was virtually absent from healthy but strongly induced in fibrotic liver, with predominant localisation within fibrotic septa. Delayed anti-LOXL2 treatment of active TAA fibrosis significantly reduced collagen crosslinking and histological signs of bridging fibrosis, with a 53% reduction in morphometric collagen deposition. In established TAA fibrosis, LOXL2 inhibition promoted fibrosis reversal, with enhanced splitting and thinning of fibrotic septa, and a 45% decrease in collagen area at 4 weeks of recovery. In the Mdr2-/- and DDC-induced models of biliary fibrosis, anti-LOXL2 antibody similarly achieved significant antifibrotic efficacy and suppressed the ductular reaction, while hepatocyte replication increased. Blocking LOXL2 had a profound direct effect on primary EpCAM(+) HPC behaviour in vitro, promoting their differentiation towards hepatocytes, while inhibiting ductal cell lineage commitment. CONCLUSIONS: LOXL2 mediates collagen crosslinking and fibrotic matrix stabilisation during liver fibrosis, and independently promotes fibrogenic HPC differentiation. By blocking these two convergent profibrotic pathways, therapeutic LOXL2 inhibition attenuates both parenchymal and biliary fibrosis and promotes fibrosis reversal.

The ectonucleotidase ENTPD1/CD39 limits biliary injury and fibrosis in mouse models of sclerosing cholangitis.

The pathogenesis of primary sclerosing cholangitis (PSC) and the mechanistic link to inflammatory bowel disease remain ill-defined. Ectonucleoside triphosphate diphosphohydrolase-1 (ENTPD1)/clusters of differentiation (CD) 39, the dominant purinergic ecto-enzyme, modulates intestinal inflammation. Here, we have explored the role of CD39 in biliary injury and fibrosis. The impact of CD39 deletion on disease severity was studied in multidrug resistance protein 2 (Mdr2)-/- and 3,5-diethoxycarbonyl-1,4-dihydrocollidine mouse models of sclerosing cholangitis and biliary fibrosis. Antibody-mediated CD8+ T-cell depletion, selective gut decontamination, experimental colitis, and administration of stable adenosine triphosphate (ATP) agonist were performed. Retinoic acid-induced gut imprinting on T cells was studied in vitro. Over half of Mdr2-/-;CD39-/- double mutants, expected by Mendelian genetics, died in utero. Compared to Mdr2-/-;CD39+/+, surviving Mdr2-/-;CD39-/- mice demonstrated exacerbated liver injury, fibrosis, and ductular reaction. CD39 deficiency led to a selective increase in hepatic CD8+ T cells and integrin α4ß7, a T-cell gut-tropism receptor. CD8+ cell depletion in Mdr2-/-;CD39-/- mice diminished hepatobiliary injury and fibrosis. Treatment with antibiotics attenuated, whereas dextran sulfate sodium-induced colitis exacerbated, liver fibrosis in Mdr2-/- mice. Colonic administration of αß-ATP into CD39-sufficient Mdr2-/- mice triggered hepatic CD8+ cell influx and recapitulated the severe phenotype observed in Mdr2-/-;CD39-/- mice. In vitro, addition of ATP promoted the retinoic acid-induced imprinting of gut-homing integrin α4ß7 on naive CD8+ cells. CD39 expression was relatively low in human normal or PSC livers but abundantly present on immune cells of the colon and further up-regulated in samples of patients with inflammatory bowel disease. Conclusion: CD39 deletion promotes biliary injury and fibrosis through gut-imprinted CD8+ T cells. Pharmacological modulation of purinergic signaling may represent a promising approach for the treatment of PSC. (Hepatology Communications 2017;1:957-972).

Renal Function and All-Cause Mortality Risk Among Cancer Patients.

Renal dysfunction predicts all-cause mortality in general population. However, the prevalence of renal insufficiency and its relationship with mortality in cancer patients are unclear.We retrospectively studied 9465 patients with newly diagnosed cancer from January 2010 to December 2010. Renal insufficiency was defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m using the Chronic Kidney Disease Epidemiology Collaboration equation. The hazard ratio (HR) of all-cause mortality associated with baseline eGFR was assessed by Cox regression.Three thousand sixty-nine patients (32.4%) exhibited eGFR <90 mL/min/1.73 m and 3% had abnormal serum creatinine levels at the time of diagnosis. Over a median follow-up of 40.5 months, 2705 patients (28.6%) died. Compared with the reference group (eGFR ≥ 60 mL/min/1.73 m), an elevated all-cause mortality was observed among patients with eGFR < 60 mL/min/1.73 m stratified by cancer stage in the entire cohort, the corresponding hazard ratios were 1.87 (95% CI, 1.41-2.47) and 1.28 (95% CI, 1.01-1.62) for stage I to III and stage IV, respectively. However, this relationship was not observed after multivariate adjustment. Subgroup analysis found that eGFR < 60 mL/min/1.73 m independently predicted death among patients with hematologic (adjusted HR 2.93, 95% CI [1.36-6.31]) and gynecological cancer (adjusted HR 2.82, 95% CI [1.19-6.70]), but not in those with other cancer. Five hundred fifty-seven patients (6%) had proteinuria. When controlled for potential confounding factors, proteinuria was a risk factor for all-cause mortality among patients in the entire cohort, regardless of cancer stage and eGFR values. When patients were categorized by specific cancer type, the risk of all-cause death was only significant in patients with digestive system cancer (adjusted HR, 1.85 [1.48-2.32]).The prevalence of renal dysfunction was common in patients with newly diagnosed cancer. Patients with eGFR < 60 mL/min/1.73 m or proteinuria were associated with increased risk for all-cause mortality, this relation depended on cancer site.

Lysyl oxidase activity contributes to collagen stabilization during liver fibrosis progression and limits spontaneous fibrosis reversal in mice.

Collagen stabilization through irreversible cross-linking is thought to promote hepatic fibrosis progression and limit its reversibility. However, the mechanism of this process remains poorly defined. We studied the functional contribution of lysyl oxidase (LOX) to collagen stabilization and hepatic fibrosis progression/reversalin vivousing chronic administration of irreversible LOX inhibitor ß-aminopropionitrile (BAPN, or vehicle as control) in C57Bl/6J mice with carbon tetrachloride (CCl4)-induced fibrosis. Fibrotic matrix stability was directly assessed using a stepwise collagen extraction assay and fibrotic septae morphometry. Liver cells and fibrosis were studied by histologic, biochemical methods and quantitative real-time reverse-transcription PCR. During fibrosis progression, BAPN administration suppressed accumulation of cross-linked collagens, and fibrotic septae showed widening and collagen fibrils splitting, reminiscent of remodeling signs observed during fibrosis reversal. LOX inhibition attenuated hepatic stellate cell activation markers and promoted F4/80-positive scar-associated macrophage infiltration without an increase in liver injury. In reversal experiments, BAPN-treated fibrotic mice demonstrated accelerated fibrosis reversal after CCl4withdrawal. Our findings demonstrate for the first time that LOX contributes significantly to collagen stabilization in liver fibrosis, promotes fibrogenic activation of attenuated hepatic stellate cells, and limits fibrosis reversal. Our data support the concept of pharmacologic targeting of LOX pathway to inhibit liver fibrosis and promote its resolution.-Liu, S. B., Ikenaga, N., Peng, Z.-W., Sverdlov, D. Y., Greenstein, A., Smith, V., Schuppan, D., Popov, Y. Lysyl oxidase activity contributes to collagen stabilization during liver fibrosis progression and limits spontaneous fibrosis reversal in mice.

Integrin αvß6 critically regulates hepatic progenitor cell function and promotes ductular reaction, fibrosis, and tumorigenesis.

UNLABELLED: Integrin αvß6 is rapidly up-regulated on cells of epithelial lineage during tissue injury, where one of its primary functions is activation of latent transforming growth factor beta 1 (TGFß1). In human liver cirrhosis, αvß6 is overexpressed by cells comprising the ductular reaction, and its inhibition suppresses experimental biliary fibrosis in rodents. Here, we show that αvß6 is expressed on the actively proliferating subset of hepatic progenitor cells and is required for their progenitor function in vivo and in vitro through integrin αvß6-dependent TGFß1 activation. Freshly isolated αvß6(+) liver cells demonstrate clonogenic potential and differentiate into cholangiocytes and functional hepatocytes in vitro, whereas colony formation by epithelial cell adhesion molecule-positive progenitor cells is blocked by αvß6-neutralizing antibody and in integrin beta 6-deficient cells. Inhibition of progenitors by anti-αvß6 antibody is recapitulated by TGFß1 neutralization and rescued by addition of bioactive TGFß1. Genetic disruption or selective targeting of αvß6 with 3G9 antibody potently inhibits progenitor cell responses in mouse models of chronic biliary injury and protects from liver fibrosis and tumorigenesis, two conditions clinically associated with exacerbated ductular reaction. CONCLUSION: These results suggest that αvß6 is a promising target for chronic fibrotic liver diseases and associated cancers.

High expression of transforming acidic coiled coil-containing protein 3 strongly correlates with aggressive characteristics and poor prognosis of gastric cancer.

Transforming acidic coiled coil-containing protein 3 (TACC3) is well understood to regulate mitotic spindle dynamics and centrosome integrity during mitosis. TACC3 has been suggested to be deregulated in a variety of human malignancies and may be involved in the process of cancer progression. The aim of the present study was to determine the status of TACC3 expression in gastric cancer (GC) and to clarify its clinical/prognostic significance. In the present study, we applied quantitative PCR (qPCR) and western blotting to examine TACC3 mRNA/protein expression in paired GC tissues and matched adjacent non-malignant tissues. Immunohistochemistry (IHC) was performed on a large cohort of 186 postoperative GC samples. Chi-square test, Kaplan-Meier analysis and Cox regression modelling were used to analyse the data. Upregulated mRNA and protein expression levels of TACC3 were observed in the majority of the GC tissues based on qPCR and western blotting compared to the adjacent non-cancerous gastric tissues. Specific IHC staining for TACC3 was predominantly identified in the cytoplasm of the cancer cells. A high expression of TACC3 was detected in 102 of the 186 (54.8%) tissue samples and was significantly associated with the extracapsular extension of the tumour (P<0.001), tumour relapse (P<0.001) and shortened overall survival in GC (P<0.001). Further analysis demonstrated that the TACC3 expression level stratified the patient outcome in stage II (P=0.040), stage III (P<0.001), T3/4 (P<0.001), N positive (P<0.001) and poorly differentiated/undifferentiated tumour subgroups (P<0.001). The Cox regression analysis suggested that a high expression of TACC3 was an independent prognostic factor for GC patients. The measurement of TACC3 protein expression may be beneficial for predicting clinical outcomes for GC patients.

Prognostic nomogram for patients with unresectable hepatocellular carcinoma after transcatheter arterial chemoembolization.

BACKGROUND & AIMS: To establish an effective prognostic nomogram for patients with unresectable hepatocellular carcinoma (HCC) after transarterial chemoembolization (TACE). METHODS: The nomogram was constructed based on data obtained from a retrospective study on 2938 patients who received TACE as an initial therapy from 2000 to 2008. The predictive accuracy and discriminative ability of the nomogram were compared with seven current commonly used staging systems on HCC by using data obtained from a prospective study on a cohort of 647 patients treated from January 2011 to December 2011 at the same institution. Additional external validation was performed using a data set (n=221) from another institution. RESULTS: Portal vein invasion, tumor number, tumor capsule, alpha fetoprotein, aspartate aminotransferase, and indocyanine green retention at 15 min formed the basis of the nomogram. The concordance index (C-index) of the nomogram was 0.755, which was significantly better than the American Joint Committee on Cancer seventh edition (0.612), the Barcelona Clinic Liver Cancer system (0.692), the Okuda system (0.579), the Japan Integrated Staging system (0.637), Cancer of the Liver Italian Program system (0.683), the Chinese University Prognostic Index (0.637) and the Groupe d'Etude et de Traitement du Carcinome Hepatocellulaire (0.577) (p<0.001 for all). The calibration curve for predicting probability of survival showed a good agreement between the nomogram and actual observation. The findings were supported by the external validation cohort. The nomogram gave better discrimination than the seven staging systems. CONCLUSIONS: The proposed nomogram gave accurate prognostic prediction in patients with unresectable HCC after treatment with TACE.

Multidisciplinary treatment based on surgery leading to long-term survival of a patient with multiple asynchronous rare primary malignant neoplasms: A case report and literature review.

Patients that present with multiple primary malignant neoplasms are increasingly encountered, but the treatment of such patients presents specific challenges and long-term survival is rare. The present study reports the case of a 45-year-old female diagnosed with three rare, distinct primary malignant neoplasms, including epithelioid hemangioendothelioma (EHE) of the brain, Ewing's sarcoma of the lumbar 2 vertebra and a malignant solitary fibrous tumour (SFT) of the liver, at different time points. The patient underwent multidisciplinary treatment according to the diagnoses, including radial resection of all primary lesions, chemotherapy (consisting of vincristine, dactinomycin, cyclophosphamide and adriamycin) and radiotherapy, to treat Ewing's sarcoma and metastases of EHE and malignant SFT. Following these treatments, the patient survived for >14 years. Multidisciplinary treatment regimens based on surgery can lead to long-term survival of patients with multiple asynchronous rare primary malignant neoplasms. The present study reported that multidisciplinary treatment regimens based on surgery can lead to the long-term survival of patients with multiple asynchronous rare primary malignant neoplasms.

Transarterial chemoembolization vs. conservative treatment for unresectable infiltrating hepatocellular carcinoma: A retrospective comparative study.

This study was conducted to compare long-term survival between patients with unresectable infiltrating hepatocellular carcinoma (HCC) who were treated with transarterial chemoembolization (TACE) and those who received conservative treatment (best supportive care). Between January, 2007 and January, 2012, a total of 131 consecutive patients with unresectable infiltrating HCC underwent TACE in a cancer center (TACE group), while 156 similar consecutive HCC patients received conservative treatment in another cancer center (conservative treatment group). The diagnosis of unresectable infiltrating HCC was established by agreement between two radiologists coming from the two centers, who performed an independent review of all the cross-sectional imagings of the patients. The two groups were comparable regarding patient characteristics, preoperative liver function, tumor burden and general condition. In the TACE group, 52 patients received one session and 79 patients received more than one session of TACE (mean, 1.5 and range, 1-4 sessions). There was no reported TACE-related mortality. The 1-month mortality rate was 0.8 and 3.8% in the TACE and the conservative groups, respectively (P=0.134). The median survival for the TACE and conservative treatment groups was 7.0 and 3.0 months, respectively. The 6-, 12- and 24-month overall survival rates for the TACE and conservative treatment groups were 61.7, 18.5 and 2.3% vs. 22.7, 12.1 and 0%, respectively (P<0.001). On multivariate analysis, treatment allocation [odds ratio (OR)=1.777; 95% confidence interval (CI): 1.499-2.107; P<0.001] and portal vein tumor thrombosis (OR=1.721; 95% CI: 1.504-1.907; P<0.001) were independent predictors of overall survival. In conclusion, TACE was found to be a safe and feasible treatment option for patients with unresectable infiltrating HCC and it conferred survival benefit over conservative treatment.

Extrahepatic platelet-derived growth factor-ß, delivered by platelets, promotes activation of hepatic stellate cells and biliary fibrosis in mice.

BACKGROUND & AIMS: Platelet-derived growth factor-ß (PDGFB) is a mitogen for hepatic stellate cells (HSCs). We studied the cellular sources of PDGFB and the effects of a high-affinity monoclonal antibody against PDGFB (MOR8457) in mouse models of biliary fibrosis. METHODS: Cellular sources of PDGFB were identified using quantitative reverse-transcription polymerase chain reaction, biochemical, and immunohistologic methods. Mice with advanced biliary fibrosis, MDR2(Abcb4)-null mice, and C57Bl/6 (control) mice were placed on 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-supplemented diets and were given weekly intraperitoneal injections of MOR8457. Platelets were depleted from MDR2-null mice by injection of an antibody against CD41, or inhibited with diets containing low-dose aspirin. Liver tissues were collected and analyzed by quantitative reverse-transcription PCR and histologic and biochemical analyses. RESULTS: Levels of PDGFB protein, but not messenger RNA, were increased in fibrotic livers of MDR2-null mice, compared with control mice. Platelet clusters were detected in the hepatic endothelium, in close proximity to HSCs, and were identified as a source of PDGFB protein in MDR2-null mice. Levels of the PDGFB were increased in serum samples from patients with early stages of liver fibrosis of various etiologies (F1-2, n = 16; P < .05), compared with nonfibrotic liver tissue (F0, n = 12). Depletion of platelets from MDR2-null mice normalized hepatic levels of PDGFB within 48 hours, reducing levels of a marker of HSC activation (α-smooth muscle actin) and expression of genes that promote fibrosis. Diets supplemented with low-dose aspirin reduced circulating serum and hepatic levels of PDGFB and significantly reduced progression of fibrosis in MDR2-null mice over 1 year. MOR8457 produced a dose-dependent decrease in liver fibrosis in MDR2-null mice, reducing collagen deposition by 45% and expression of fibrosis-associated genes by 50%, compared with mice given a control antibody. In vitro, platelets activated freshly isolated HSCs (induction of α-smooth muscle actin and fibrosis-associated genes) via a PDGFB-dependent mechanism. MOR8457 also reduced liver fibrosis in mice placed on DDC-supplemented diets. CONCLUSIONS: Platelets produce PDGFB to activate HSC and promote fibrosis in MDR2-null mice and mice on DDC-supplemented diets. Antiplatelet therapy or selective inhibition of PDGFB might reduce biliary fibrosis in patients with liver disease.

XPC gene polymorphisms contribute to bladder cancer susceptibility: a meta-analysis.

Numerous studies have investigated the association between three polymorphisms (Lys939Gln, Ala499Val and PAT-/+) of Xeroderma pigmentosum group C (XPC) gene and bladder cancer susceptibility; however, the findings are inconclusive. In order to acquire a more precise estimation of the relationship, we performed a meta-analysis based on 10 studies including 3,934 cases and 4,269 controls for Lys939Gln, five studies including 2,113 cases and 2,249 controls for Ala499Val, and seven studies including 2,834 cases and 3,048 controls for PAT-/+ polymorphism. We searched publications from EMBASE, MEDLINE, and Chinese Biomedical. We calculated pooled odds ratio (OR) and 95% confidence interval (CI) by using either fixed-effects or random-effects model according to the between-study heterogeneity. We found that all studied polymorphisms were individually associated with increased overall cancer risks, as shown by ORs (95% CIs) below: the Lys939Gln (Gln/Gln vs. Lys/Lys: OR = 1.39, 95% CI = 1.08-1.79; recessive model: OR = 1.42, 95% CI = 1.11-1.83; and allele comparing: OR = 1.12, 95% CI = 1.003-1.24), the Ala499Val (Val/Val vs. Ala/Ala: OR = 1.82, 95% CI = 1.19-2.79; recessive model: OR = 1.70, 95% CI = 1.18-2.46; and allele comparing: OR = 1.23, 95% CI = 1.01-1.50), and the PAT-/+ (+/+ vs. -/-: OR = 1.36, 95% CI = 1.03-1.79 and recessive model: OR = 1.34, 95% CI = 1.06-1.70). Furthermore, stratification analyses demonstrated an increased risk for Asian populations as to the Lys939Gln and PAT-/+ whereas for Caucasian populations as to the Ala499Val polymorphism in the homozygous and recessive models. Despite some limitations, this meta-analysis suggests that XPC polymorphisms are associated with bladder cancer risk, but this association warrants further validation in well-designed studies with large sample sizes.