Cancer-associated fibroblasts in hepatocellular carcinoma

The hepatic stellate cells in the liver are stimulated sustainably by chronic injury of the hepatocytes, activating myofibroblasts, which produce abundant collagen. Myofibroblasts are the major source of extracellular proteins during fibrogenesis, and may directly, or secreted products, contribute to carcinogenesis and tumor progression. Cancer-associated fibroblasts(CAFs) are one of the components of the tumor microenvironment that promote the proliferation and invasion of cancer cells by secreting various growth factors and cytokines. CAFs crosstalk with cancer cells stimulates tumor progression by creating a favorable microenvironment for progression, invasion, and metastasis through the epithelial-mesenchymal transition. Basic studies on CAFs have advanced, and the role of CAFs in tumors has been elucidated. In particular, for hepatocellular carcinoma, carcinogenesis from cirrhosis is a known fact, and participation of CAFs in carcinogenesis is supported. In this review, we discuss the current literature on the role of CAFs and CAF-related signaling in carcinogenesis, crosstalk with cancer cells, immunosuppressive effects, angiogenesis, therapeutic targets, and resistance to chemotherapy. The role of CAFs is important in cancer initiation and progression. CAF-targeted therapy may be effective for suppression not only of fibrosis but also cancer progression.

Portal vein thrombosis in liver cirrhosis

Portal vein thrombosis(PVT) is considered to be a frequent complication of liver cirrhosis. However, unlike PVT in patients without cirrhosis, very few data are available on the natural history and management of PVT in cirrhosis, despite its association with potentially life-threatening conditions, such as gastroesophageal bleeding and acute intestinal ischemia. Moreover, no consensus regarding PVT in cirrhosis exists. Suggested causes of PVT in cirrhosis include reduced portal blood flow velocity, multiple congenital or acquired thrombophilic factors, inherited or acquired conditions, and derangement of liver architecture. However, the understanding of PVT in cirrhosis is incomplete. In addition, information on the management of PVT in cirrhosis is inadequate. The aims of this review are to:(1) assemble data on the physiopathological mechanism, clinical findings, diagnosis and management of PVT in cirrhosis;(2) describe the principal factors most frequently involved in PVT development; and(3) summarize the recent knowledge concerning diagnostic and therapeutic procedures.

Management of thrombocytopenia due to liver cirrhosis:A review

Thrombocytopenia is a common complication in liver disease and can adversely affect the treatment of liver cirrhosis,limiting the ability to administer therapy and delaying planned surgical/diagnostic procedures because of an increased risk of bleeding.Multiple factors,including splenic sequestration,reduced activity of the hematopoietic growth factor thrombopoietin,bone marrow suppression by chronic hepatitis C virus infection and anti-cancer agents,and antiviral treatment with interferon-based therapy,can contribute to the development of thrombocytopenia in cirrhotic patients.Of these factors,the major mechanisms for thrombocytopenia in liver cirrhosis are(1)platelet sequestration in the spleen;and(2)decreased production of thrombopoietin in the liver.Several treatment options,including platelet transfusion,interventional partial splenic embolization,and surgical splenectomy,are now available for severe thrombocytopenia in cirrhotic patients.Although thrombopoietin agonists and targeted agents are alternative tools for noninvasively treating thrombocytopenia due to liver cirrhosis,their ability to improve thrombocytopenia in cirrhotic patients is under investigation in clinical trials.In this review,we propose a treatment approach to thrombocytopenia according to our novel concept of splenic volume,and we describe the current management of thrombocytopenia due to liver cirrhosis.

Prospective randomized controlled trial investigating the type of sutures used during hepatectomy

AIM: To determine whether absorbable sutures or non-absorbable sutures are better in preventing surgical site infection (SSI), in this paper we discuss the results of a randomized clinical trial which examined the type of sutures used during hepatectomy. METHODS: All hepatic resections performed from January 2007 to November 2008 at the Department of Surgery at Iizuka Hospital in Japan were included in this study. There were 125 patients randomly assigned to an absorbable sutures (Vicryl) group or non-absorbable sutures (Silk) group. RESULTS: SSI was observed in 13.6% (17/125) patients participating in this study, 11.3% in the Vicryl group and 15.8% in the Silk group. Incisional SSI including superficial and deep SSI, was observed in 8% of the Vicryl group and 9.5% of the Silk group. Organ/ space SSI was observed in 3.2% of the Vicryl group and 6.0% of the Silk group. There were no significant differences, but among the patients with SSI, the period for recovery was significantly shorter for the Vicryl group compared to the Silk group.CONCLUSION: The incidence of SSI in patients receiving absorbable sutures and silk sutures is not significantly different in this randomized controlled study; however, the period for recovery in patients with SSI was significantly shorter for absorbable sutures.

Prognosis of hepatocellular carcinoma accompanied by microscopic portal vein invasion

AIM:To investigate the prognostic factors in patients with hepatocellular carcinoma(HCC) accompanied by microscopic portal vein invasion(PVI).METHODS:Of the 267 patients with HCC undergoing hepatic resection at Aso Iizuka Hospital,71 had PVI.After excluding 16 patients with HCC that invaded the main trunk and the first and second branches of the portal vein,55 patients with microscopic PVI were enrolled.RESULTS:The patients with HCC accompanied by microscopic invasion were divided into two groups:solitary PVI(PVI-S:n = 44),and multiple PVIs(PVI-M:n = 11).The number of portal vein branches invaded by tumor thrombi was 5.4 ± 3.8(2-16) in patients with PVI-M.In cumulative survival,PVI-M was found to be a significantly poor prognostic factor(P = 0.0019);while PVI-M and non-anatomical resection were significantly poor prognostic factors in disease-free survival(P = 0.0213,and 0.0115,respectively).In patients with PVI-M,multiple intrahepatic recurrence was more common than in the patients with PVI-S(P = 0.0049).In patients with PVI-S,non-anatomical resection was a significantly poor prognostic factor in disease-free survival(P = 0.0370).Operative procedure was not a significant prognostic factor in patients with PVI-M.CONCLUSION:The presence of PVI-M was a poor prognostic factor in patients with HCC,accompanied by microscopic PVI.Anatomical resection is recommended in these patients with HCC.Patients with HCC and PVI-M may also be good candidates for adjuvant chemotherapy.

Image quality and diagnostic performance of free-breathing diffusion-weighted imaging for hepatocellular carcinoma

AIM To retrospectively evaluate the diagnostic performance of free-breathing diffusion-weighted imaging(FB-DWI) with modified imaging parameter settings for detecting hepatocellular carcinomas(HCCs).METHODS Fifty-one patients at risk for HCC were scanned with both FB-DWI and respiratory-triggered DWI with the navigator echo respiratory-triggering technique(RTDWI).Qualitatively,the sharpness of the liver contour,the image noise and the chemical shift artifacts on each DWI with b-values of 1000 s/mm2 were independently evaluated by three radiologists using 4-point scoring.Wecompared the image quality scores of each observer between the two DWI methods,using the Wilcoxon signed-rank test.Quantitatively,we compared the signal-to-noise ratios(SNRs) of the liver parenchyma and lesion-to-nonlesion contrast-to-noise ratios(CNRs) after measuring the signal intensity on each DWI with a b-factor of 1000 s/mm2.The average SNRs and CNRs between the two DWI methods were compared by the paired t-test.The detectability of HCC on each DWI was also analyzed by three radiologists.The detectability provided by the two DWI methods was compared using Mc Nemar's test.RESULTS For all observers,the averaged image quality scores of FB-DWI were:Sharpness of the liver contour [observer(Obs)-1,3.08 ± 0.81;Obs-2,2.98 ± 0.73;Obs-3,3.54 ± 0.75],those of the distortion(Obs-1,2.94 ± 0.50;Obs-2,2.71 ± 0.70;Obs-3,3.27 ± 0.53),and the chemical shift artifacts(Obs-1,3.38 ± 0.60;Obs-2,3.15 ± 1.07;Obs-3,3.21 ± 0.85).The averaged image quality scores of RTDWI were:Sharpness of the liver contour(Obs-1,2.33 ± 0.65;Obs-2,2.37 ± 0.74;Obs-3,2.75 ± 0.81),distortion(Obs-1,2.81 ± 0.56;Obs-2,2.25 ± 0.74;Obs-3,2.96 ± 0.71),and the chemical shift artifacts(Obs-1,2.92 ± 0.59;Obs-2,2.21 ± 0.85;Obs-3,2.77 ± 1.08).All image quality scores of FB-DWI were significantly higher than those of RT-DWI(P < 0.05).The average SNR of the normal liver parenchyma by FB-DWI(11.0 ± 4.8) was not significantly different from that shown by RT-DWI(11.0 ± 5.0);nor were the lesion-to-nonlesion CNRs significantly different(FB-DWI,21.4 ± 17.7;RT-DWI,20.1 ± 15.1).For all three observers,the detectability of FB-DWI(Obs-1,43.6%;Obs-2,53.6%;and Obs-3,45.0%) was significantly higher than that of RT-DWI(Obs-1,29.1%;Obs-2,43.6%;and Obs-3,34.5%)(P < 0.05).CONCLUSION FB-DWI showed better image quality and higher detectability of HCC compared to RT-DWI,without significantly reducing the SNRs of the liver parenchyma and lesionto-nonlesion CNRs.

Fibrosis in nonalcoholic fatty liver disease: Noninvasive assessment using computed tomography volumetry

AIM To evaluate the diagnostic performance of computed tomography(CT) volumetry for discriminating the fibrosis stage in patients with nonalcoholic fatty liver disease(NAFLD).METHODS A total of 38 NAFLD patients were enrolled. On the basis of CT imaging, the volumes of total, left lateral segment(LLS), left medial segment, caudate lobe, and right lobe(RL) of the liver were calculated with a dedicated liver application. The relationship between the volume percentage of each area and fibrosis stage was analyzed using Spearman's rank correlation coefficient. A receiver operating characteristic(ROC) curve analysis was performed to determine the accuracy of CT volumetry for discriminating fibrosis stage.RESULTS The volume percentages of the caudate lobe and the LLS significantly increased with the fibrosis stage(r = 0.815, P < 0.001; and r = 0.465, P = 0.003, respectively). Contrarily, the volume percentage of the RL significantly decreased with fibrosis stage(r =-0.563, P < 0.001). The volume percentage of the caudate lobe had the best diagnostic accuracy for staging fibrosis, and the area under the ROC curve values for discriminating fibrosis stage were as follows: ≥ F1, 0.896; ≥ F2, 0.929; ≥ F3, 0.955; and ≥ F4, 0.923. The best cut-off for advanced fibrosis(F3-F4) was 4.789%, 85.7% sensitivity and 94.1% specificity.CONCLUSION The volume percentage of the caudate lobe calculated by CT volumetry is a useful diagnostic parameter for staging fibrosis in NAFLD patients.

Late-onset non-islet cell tumor hypoglycemia: A case report

BACKGROUND Hypoglycemia due to non-insulin-producing tumors is referred to as non-islet cell tumor hypoglycemia(NICTH).As NICTH is a rare lesion,the natural course of NICTH is not well understood.We report a case of NICTH that was observed 30 years before the onset of hypoglycemia.CASE SUMMARY A 50-year-old man was diagnosed with an abnormal right chest shadow during a routine X-ray examination,but no further examination was undertaken because the lesion appeared benign.Thirty years after the tumor discovery,the patient was admitted to the hospital with symptoms of severe hypoglycemia,which was diagnosed as NICTH based on a complete examination.The tumor was resected and found to be a solitary fibrous mass(15.6 cm×13.7 cm×10.4 cm);thereafter,the patient’s blood glucose levels normalized and he completely recovered.CONCLUSION NICTH can have an acute onset,even if the tumor has been present and asymptomatic over a long time period.

Global standardization of laparoscopic liver resection and challenges for the future

Hepatobiliary Surgery and Nutrition recently published a review by X Cai that describes the current status and future of laparoscopic liver resection (LLR) in China. The advent of LLR has led to significant changes in the field of liver surgery, with numerous reports outlining how this procedure offers a better, less invasive approach for the treatment of liver disease. Two international consensus conferences regarding LLR—held in 2008 (Louisville, USA) and 2014 (Morioka, Japan)—highlighted the efficacy and safety of LLR, and discussed the surgical indications, technique, standardizations, and precautions that should be considered when performing LLR (1,2). Delegates deliberated whether open liver resection (OLR) should remain the current standard procedure for liver disease, and the importance of LLR within this arena. There was agreement that minor LLR offers sufficient safety and benefit to be considered standard practice, but major resection requires further investigation. The most recent guidelines from the European meeting on LLR, held in 2017 in Southampton, UK (3), integrate the available evidence and expert knowledge on LLR, taking into consideration relevant stakeholders' opinions and complying with international methodology standards across five domains (indications, patients and complex diseases, procedures, techniques, and implementation). The guidelines emphasize the importance of a team-oriented approach and the need to recruit experts in OLR and laparoscopic surgery within a specialist center.

It is time to abandon the Milan criteria

Hepatocellular carcinoma(HCC)is the fifth most common neoplasm worldwide and the third most common cause of cancer-related death.Liver transplantation(LT),which offers the theoretical advantage of removing both the tumor and the organ that are at risk of developing future malignancy,is an established therapy for HCC in patients with liver cirrhosis.A shortage of cadaveric organs for transplantation continues to impair our ability to provide LT despite progress in surgical techniques and immunosuppression.Therefore,it is important to allocate the deceased donor livers with excellent results,and to ensure reasonable outcome for living donors who need to undergo invasive surgery.