Hong-Gui Qin

Preoperative Ratio of Neutrophils to Lymphocytes Predicts Postresection Survival in Selected Patients With Early or Intermediate Stage Hepatocellular Carcinoma.

Abstract This study aims to clarify the prognostic value of the preoperative neutrophil-to-lymphocyte ratio (NLR) for patients with hepatocellular carcinoma (HCC) after potentially curative hepatic resection (HR). The prognostic value of the NLR for HCC patients has not been definitely reviewed by large studies, especially for those with different Barcelona Clinic Liver Cancer (BCLC) stages. A consecutive sample of 963 HCC patients who underwent potentially curative HR was classified as having low or high NLR using a cut-off value of 2.81. Overall survival (OS) and tumor recurrence were compared for patients with low or high NLR across the total population, as well as in subgroups of patients in BCLC stages 0/A, B, or C. Clinicopathological parameters, including NLR, were evaluated to identify risk factors of OS and tumor recurrence after potentially curative hepatic resection. Multivariate analyses were performed using the Cox proportional hazards model or subdistribution hazard regression model. Multivariate analyses showed that NLR (>2.81), tumor number (>3), incomplete capsule, serum albumin (⩽35 g/L), alanine transaminase activity (>40 U/L), and macrovascular invasion were risk factors for low OS, whereas NLR (>2.81), tumor size (>5 cm), alpha fetal protein concentration (>400 ng/L), and macrovascular invasion were risk factors for low tumor recurrence. NLR > 2.81 was significantly associated with poor OS and tumor recurrence in the total patient population (both P < 0.001), as well as in the subgroups of patients in BCLC stages 0/A or B (all P < 0.05). Moreover, those with high NLR were associated with low OS (P = 0.027), and also with slightly higher tumor recurrence than those with low NLR for the subgroups in BCLC stage B (P = 0.058). Neither association, however, was observed among patients with BCLC stage C disease. NLR may be an independent predictor of low OS and tumor recurrence after potentially curative HR in HCC patients in BCLC stages 0/A or B.

Expression of P62 in hepatocellular carcinoma involving hepatitis B virus infection and aflatoxin B1 exposure

This study aims to clarify the relationship and mechanism between expression of autophagy‐related protein P62 and prognosis of patients with hepatocellular carcinoma (HCC) involving chronic hepatitis B virus (HBV) infection and aflatoxin B1 (AFB1) exposure. HCC patients who underwent resection were divided into three groups: HBV(+)/AFB1(+) (n = 26), HBV(+)/AFB1(−) (n = 68), and HBV(−)/AFB1(−) (n = 14). The groups were compared in terms of mRNA and protein levels of P62, disease‐free survival (DFS), and overall survival (OS) and the expression of NRF2, Nqo1, and AKR7A3 in P62 high‐expression and low‐expression group. HBV(+)/AFB1(+) group has lower DFS and OS, and higher P62 expression than in the other two groups. P62 expression generally correlated with elevated NRF2 and Nqo1 expression, and reduced AKR7A3 expression. Patients expressing high levels of P62 showed significantly lower DFS and OS rates than patients expressing low levels. HCC involving HBV infection and AFB1 exposure is associated with relatively high risk of tumor recurrence, and this poor prognosis may relate to high P62 expression. High P62 expression activates the NRF2 pathway, promotes tumor recurrence. The downregulation of AKR7A3 also reduced liver detoxification of aflatoxin B1.

Randomized Clinical Trial Comparing Efficacy of Simo Decoction and Acupuncture or Chewing Gum Alone on Postoperative Ileus in Patients With Hepatocellular Carcinoma After Hepatectomy.

AbstractTo compare the efficacy of simo decoction (SMD) combined with acupuncture at the tsusanli acupoint or chewing gum alone for treating postoperative ileus in patients with hepatocellular carcinoma (HCC) after hepatectomy.In postoperative ileus, a frequent complication following hepatectomy, bowel function recovery is delayed, which increases length of hospital stay. Studies suggest that chewing gum may reduce postoperative ileus; SMD and acupuncture at the tsusanli acupoint have long been used in China to promote bowel movement.Patients with primary HCC undergoing hepatectomy between January 2015 and August 2015 were randomized to receive SMD and acupuncture (n = 55) or chewing gum (n = 53) or no intervention (n = 54) starting on postoperative day 1 and continuing for 6 consecutive days or until flatus. Primary endpoints were occurrence of postoperative ileus and length of hospital stay; secondary endpoints were surgical complications.Groups treated with SMD and acupuncture or with chewing gum experienced significantly shorter time to first peristalsis, flatus, and defecation than the no-intervention group (all P < 0.05). Hospital stay was significantly shorter in the combined SMD and acupuncture group (mean 14.0 d, SD 4.9) than in the no-intervention group (mean 16.5 d, SD 6.8; P = 0.014), while length of stay was similar between the chewing gum group (mean 14.7, SD 6.2) and the no-intervention group (P = 0.147). Incidence of grades I and II complications was slightly lower in both intervention groups than in the no-intervention group.The combination of SMD and acupuncture may reduce incidence of postoperative ileus and shorten hospital stay in HCC patients after hepatectomy. Chewing gum may also reduce incidence of ileus but does not appear to affect hospital stay. (Clinicaltrials.gov registration number: NCT02438436.)

High expression of AKR1B10 predicts low risk of early tumor recurrence in patients with hepatitis B virus-related hepatocellular carcinoma.

To clarify the relationship between aldo-keto reductase family 1 member B10 (AKR1B10) expression and early hepatocellular carcinoma (HCC) recurrence, this study detected AKR1B10 expression in tumor and adjacent non-tumor tissues from 110 patients with hepatitis B virus (HBV)-related HCC underwent liver resection and analyzed its correlations with clinicopathological characteristics and prognosis of these patients. Detected by quantitative reverse transcription polymerase chain reaction, AKR1B10 mRNA expression showed significantly higher in HCC tissues than in adjacent non-tumor tissues, with a low level in normal liver tissues. Similar results was confirmed at the protein level using immunohistochemistry and Western blotting. High AKR1B10 expression was negatively correlated with serum alpha-fetoprotein level and positively correlated with HBV-DNA level. Patients with high AKR1B10 expression had significantly higher disease-free survival than those with low expression within 2 years after liver resection. Multivariate analysis also confirmed high AKR1B10 expression to be a predictor of low risk of early HCC recurrence. In addition, high AKR1B10 expression was found to be a favorable factor of overall survival. These results suggest that AKR1B10 is involved in HBV-related hepatocarcinogenesis, but its high expression could predict low risk of early tumor recurrence in patients with HBV-related HCC after liver resection.

Does the elevation of serum carbohydrate antigen 19-9 level predict poor overall survival in patients with hepatocellular carcinoma?

To the Editor: Carbohydrate antigen (CA) 19-9 is the most widely used biomarker for diagnosing pancreatic cancer, and pretreatment serum levels correlate with overall survival of patients [1]. Serum levels of CA 19-9 have also been proved to be associated with prognosis in several other gastrointestinal cancers, including gastric cancer, cholangiocarcinoma, and gallbladder cancer [2–4]. A recent study by Zhang and coworkers in Tumor Biology proposes to extend the prognostic usefulness of CA 19-9 to hepatocellular carcinoma (HCC) [5]. Their retrospective study of 97 patients with resectable HCC showed, by both KaplanMeier and multivariate analyses, that elevated serum CA 19-9 levels were significantly associated with poor overall survival. Although we commend the authors for applying this biomarker to the challenging problem of predicting prognosis of patients with HCC, we believe that several important issues need to be clarified before their conclusions can be accepted. In this study, the inclusion criteria were indistinct. Prognosis in HCC strongly depends on treatment history, which in turn depends on the course and complications of the disease, so it is important to know whether the patients in the study by Zhang et al. had primary HCC and whether they received other treatments before resection. Since cholangiocarcinoma can be misdiagnosed as HCC in the absence of histopathologic evidence, it is important to know whether the patients were diagnosed based on histopathology. Zhang et al. need to be able to exclude the possibility that the observed relationship between CA 19-9 levels and overall survival in HCC was not confounded by the known relationship between elevated CA 19-9 levels and poor survival in cholangiocarcinoma [3]. The multivariate analysis conducted by Zhang et al. to identify independent predictors of overall survival in patients with HCC did not take into account possible confounding by liver comorbidity. Approximately 80–90 % of patients with HCC have coexisting cirrhosis or other chronic liver disease [6], which can significantly influence overall survival independently of the tumor [7]. In addition, poor liver function has been linked to elevated levels of CA 19-9 [8]. Thus, the overall survival observed by Zhang et al. may be influenced by poor liver function, which should be controlled for through appropriate analyses. In addition to reporting overall survival, Zhang et al. should compare disease-free survival between patients with elevated and normal CA 19-9 levels. Tumor recurrence is the main cause of poor overall survival in patients with HCC [6, 7], so analyzing disease-free survival may indicate whether elevated CA 19-9 levels affect risk of recurrence. This may then help explain why elevated CA 19-9 levels are associated with lower overall survival. The work by Zhang et al. raises interesting questions about the prognostic usefulness of CA 19-9 levels in HCC, but their conclusions require more thorough analysis before they can be accepted. Larger, well-designed studies are needed to verify and extend their findings.

Comprehensive treatments for hepatocellular carcinoma with tumor thrombus in major portal vein.

AIM To evaluate the efficacy of transcatheter arterial chemoembolisation (TACE) compared with surgical intervention and sorafenib for treatment of hepatocellular carcinoma (HCC) in patients with tumor thrombus extending to the main portal vein. METHODS From 2009 to 2013, a total of 418 HCC patients with tumor thrombus extending to the main portal vein were enrolled in this study and divided into four groups. These groups underwent different treatments as follows: TACE (n = 307), surgical intervention (n = 54), sorafenib (n = 15) and palliative treatment (n = 42). Overall survival rates were determined by Kaplan-Meier method, and differences between the groups were identified through log-rank analysis. Coxs proportional hazard model was used to identify the risk factors for survival. RESULTS The mean survival periods for patients in the TACE, surgical intervention, sorafenib and palliative treatment groups were 10.39, 4.13, 5.54 and 2.82 mo, respectively. For the TACE group, the 3-, 6-, 12- and 24-mo survival rates were 94.1%, 85.9%, 51.5% and 0.0%, respectively. The corresponding rates were 60.3%, 22.2%, 0.0% and 0.0% for the surgical intervention group and 50.9%, 29.5%, 0.0% and 0.0% for the sorafenib group. Evidently, the results in the TACE group were significantly higher than those in the other groups (P < 0.0001). Furthermore, no significant difference among survival rates was observed between TACE with/without sorafenib (10.22 mo vs 10.52 mo, P = 0.615). No significant difference in survival rates was also found among the surgical intervention, sorafenib and palliative treatment groups (P > 0.05). These values significantly increased after TACE with/without sorafenib compared with other treatments (P < 0.05). CONCLUSION For HCC patients with tumor thrombus extending to the main portal vein, TACE can yield a higher survival rate than surgical intervention or sorafenib treatment.

Letter: risk factors and impacts of psychological morbidity in young people with inflammatory bowel disease.

*Gastrointestinal Surgery, University of Helsinki, Helsinki University Hospital, Helsinki, Finland. Unit of Primary Health Care, Helsinki University, Helsinki University Hospital, Helsinki, Finland. Primary Health Care Unit, Department of General Practice, Kuopio University, Kuopio, Finland. Research Department, The Social Insurance Institution of Finland, Turku, Finland. Helsinki University Clinic of Gastroenterology, University of Helsinki, Helsinki, Finland. E-mail: hanna.malmi@helsinki.fi

Association of blood transfusion during resection for hepatocellular carcinoma with postoperative recurrence and overall survival: A cautionary comment

To the Editor: As researchers at a large tertiary liver care center with a longstanding interest in periand post-resection prognosis of patients with hepatocellular carcinoma (HCC) [1], we were pleased that Yang and coworkers [2] took on the controversial question of whether perioperative blood transfusion (PBT) during curative liver resection for HCC affects risk of recurrence and overall survival. Their results prior to propensity score matching indicated that, indeed, PBT was associated with significantly higher risk of recurrence-free survival and significantly lower overall survival. However, these significant associations disappeared after patients were paired based on propensity scores calculated over numerous liverand tumor-related variables, including Child-Pugh grade, cirrhosis, portal hypertension, serum alpha fetoprotein, tumor size and number, and presence of microor macroscopic vascular invasion. Those authors concluded that it is primarily liverand/or tumor-related variables, much more than PBT-related factors, which mediate the observed association of PBT with increased recurrence and decreased survival. While we applaud the authors for tackling this controversial question, we caution that the preponderance of evidence in the medical literature suggests that PBT exerts a significant detrimental effect on clinical outcomes in patients with HCC [3], colorectal cancer [4,5], and ampullary cancer [6]. For example, a study published in 2015 that adjusted for clinicopathological biases using inverse probability of treatment weighting demonstrated a link between PBT and higher risk of HCC recurrence after resection [7]. Indeed, Yang and coworkers’ own data are consistent with the idea that PBT contributes substantially to post-resection outcomes. Their PBT group had substantially higher overall morbidity (34.6% vs. 27.4%, p = 0.089), lower overall survival (42.5% vs. 50.1% at 3 years, p = 0.063), and lower recurrence-free survival (32.3% vs. 37.3% at 3 years, p = 0.113). Although these differences did not achieve statistical significance, the substantial size of the study population (234 non-PBT patients, 234 PBT patients) suggests that they are real and merit further study. Future studies are needed that systematically examine PBT-specific factors and their possible effects on post-resection outcomes. One plausible hypothesis is that allogeneic PBT immunosuppresses the patient by altering the balance between proand anti-inflammatory processes [8]. The recent results of Yang and coworkers do not lessen the need to examine this and other hypotheses that may link PBT with undesirable surgical outcomes.

Possible associations between ascites and vascular invasion in patients with hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a common malignancy, and its incidence is expected to increase in many countries in coming decades [1]. The main risk factors for the development of HCC are chronic infection with hepatitis B virus (HBV) or hepatitis C virus (HCV) as well as alcoholic cirrhosis [2]. Though prognosis for patients with HCC is generally poor, hepatic resection (HR) can be an effective curative treatment, and its indications have been expanding in recent years [3, 4]. HR can be reasonably safe and effective even for patients with 2–3 tumors with maximum diameter >3 cm, patients with >3 tumors regardless of size, and patients with macrovascular invasion [5, 6]. However, the recurrence rate of HCC is as high as 74 % for patients with intermediate and advanced HCC after HR [7]. Many factors influence patient prognosis and risk of HCC recurrence after HR; these factors can be due to the characteristics of the HCC itself as well as to the characteristics of the remnant liver. Identifying these risk factors is important for decreasing the recurrence rate and improving overall survival. A recent issue of Tumour Biology contains an interesting retrospective study by Chen and coworkers based on 336 patients with HBV-related cirrhotic HCC, of which histopathology data were available for 153 [8]. Multivariate analyses revealed that factors predicting macrovascular invasion (n= 336) included tumor size >5 cm, metastases, presence of ascites, and α-fetoprotein >1000 ng/mL. Factors predicting microvascular invasion, based on subgroup analysis of 128 patients, were high-grade tumor differentiation, presence of ascites, and α-fetoprotein >1000 ng/mL. The presence of ascites and α-fetoprotein >1000 ng/mL were both risk factors of macroand microvascular invasion. While this study provides some important information about risk factors of recurrence rate for patients with HCC, it fails to examine any of the most clinically relevant and valuable outcomes of recurrence rate and overall or disease-free survival. It is essential to compare survival curves between patients with and without macroor microvascular invasion, ascites, or α-fetoprotein >1000 ng/mL in order to know whether these characteristics, which statistically may qualify as Brisk factors,^ actually predict risk of clinically relevant outcomes of recurrence and survival. This is important not just for clinical relevance but also for the credibility of the analysis: if the risk factors identified by Chen et al. are truly associated with microor macroinvasion, they should independently predict adverse outcomes such as recurrence or shorter survival. In the absence of more clinically relevant outcome data, the conclusions of Chen and coworkers should be regarded as preliminary. The study presents additional issues that highlight the need to consider its results preliminary. In 54 % of their study population, cirrhosis was diagnosed based only on imaging without histopathology. It is possible that these 54 % patients had more severe cirrhosis. In addition, the researchers diagnosed ascites based on ultrasonography and categorized the condition as Bnone,^ Bmild-to-moderate,^ or “severe.” In practice, it is difficult to detect ascites when the volume is less than Ling Deng, Hong-Gui Qin and Chun Yang contributed equally to this work.