Baseline neutrophil-lymphocyte ratio and platelet-lymphocyte ratio appear predictive of immune treatment related toxicity in hepatocellular carcinoma

BACKGROUND A well-recognized class effect of immune checkpoint inhibitors(ICI)is immune-related adverse events(IrAEs)ranging from low grade toxicities to life-threatening end organ damage requiring permanent discontinuation of ICI.Deaths are reported in<5%of patients treated with ICI.There are,however,no reliable markers to predict the onset and severity of IrAEs.We tested the association between neutrophil-lymphocyte ratio(NLR)and platelet-lymphocyte ratio(PLR)at baseline with development of clinically significant IrAEs(grade≥2)in hepatocellular carcinoma(HCC)patients treated with ICI.AIM To test the association between NLR and PLR at baseline with development of clinically significant IrAEs(grade≥2)in HCC patients treated with ICI.METHODS Data was extracted from an international database from a consortium of 11 tertiary-care referral centers.NLR=absolute neutrophil count/absolute lymphocyte count(ALC)and PLR=platelet count/ALC.Cutoff of 5 was used for NLR and 300 for PLR based on literature.We also tested the association between RESULTS Data was collected from 361 patients treated between 2016-2020 across the United States(67%),Asia(14%)and Europe(19%).Most patients received Nivolumab(n=255,71%).One hundred sixty-seven(46%)patients developed at least one IrAE,highest grade 1 in 80(48%),grade≥2 in 87(52%)patients.In a univariable regression model PLR>300 was significantly associated with a lower incidence of grade≥2 IrAEs(OR=0.40;P=0.044).Similarly,a trend was observed between NLR>5 and lower incidence of grade≥2 IrAEs(OR=0.58;P=0.097).Multivariate analyses confirmed PLR>300 as an independent predictive marker of grade≥2 IrAEs(OR=0.26;P=0.011),in addition to treatment with programmed cell death ligand 1(PD-1)/cytotoxic T lymphocyte-associated protein-4(OR=2.57;P=0.037)and PD-1/tyrosine kinase inhibitor(OR=3.39;P=0.01)combinations.Antibiotic use was not associated with IrAE incidence(OR=1.02;P=0.954).Patients treated with steroids had a>2-fold higher incidence of grade≥2 IrAEs(OR=2.74;P<0.001),although 74%were prescribed steroids for the treatment of IrAEs.CONCLUSION Given that high baseline NLR and PLR are associated with a decreased incidence of IrAEs,lower baseline NLR and PLR may be predictive biomarkers for the appearance of IrAEs in HCC treated with ICI.This finding is in keeping with several studies in solid tumors that have shown that baseline NLR and PLR appear predictive of IrAEs.

Therapeutic response assessment of RFA for HCC:Contrast-enhanced US,CT and MRI

Radiofrequency ablation (RFA) is commonly applied for the treatment of hepatocellular carcinoma (HCC) because of the facile procedure, and the safety and effectiveness for the treatment of this type of tumor. On the other hand, it is believed that HCC cells should spread predominantly through the blood flow of the portal vein, which could lead to the formation of intrahepatic micrometastases. Therefore, monitoring tumor response after the treatment is quite important and accurate assessment of treatment response is critical to obtain the most favorable outcome after the RFA. Indeed, several reports suggested that even small HCCs of &#x02264; 3 cm in diameter might carry intrahepatic micrometastases and/or microvascular invasion. From this point of view, for preventing local recurrences, RFA should be performed ablating a main tumor as well as its surrounding non-tumorous liver tissue where micrometastases and microvascular invasion might exist. Recent advancement of imaging modalities such as contrast-enhanced ultrasonic, computed tomography, and magnetic resonance imaging are playing an important role on assessing the therapeutic effects of RFA. The local recurrence rate tends to be low in HCC patients who were proven to have adequate ablation margin after RFA; namely, not only disappearance of vascular enhancement of main tumor, but also an adequate ablation margin. Therefore, contrast enhancement gives important findings for the diagnosis of recurrent HCCs on each imaging. However, hyperemia of non-tumorous liver surrounding the ablated lesion, which could be attributed to an inflammation after RFA, may well obscure the findings of local recurrence of HCCs after RFA. Therefore, we need to carefully address to these imaging findings given the fact that diagnostic difficulties of local recurrence of HCC. Here, we give an overview of the current status of the imaging assessment of HCC response to RFA.

Antiviral therapy for chronic hepatitis B: Combination of nucleoside analogs and interferon

The ideal goal of chronic hepatitis B(CHB) treatment should be suppression of emergence of hepatocellular carcinoma through the disappearance of hepatitis B s antigen(HBs Ag) rather than the control of serum hepatitis B virus-DNA level. For this purpose, various types of combination therapies using nucleoside analogs(NAs) and interferon(IFN) have been conducted. The therapeutic effects of combination of two different kinds of agents are better than those of the monotherapy using NAs or IFN alone, probably because different pharmaceutical properties might act in a coordinated manner. Recently, combination therapies with NAs and IFN and sequential therapies with NAs administration followed by IFN therapy have been routinely employed. We previously reported that combination therapy using entecavir(ETV) and pegylated(PEG)-IFN showed antiviral effects in 71% of CHB patients; the effect of this combination was better than that using lamivudine(LAM) and PEG-IFN. This is partially explained by the better antiviral effects of ETV than those of LAM. In our analysis, the cohort of CHB consisted of the patients who showed a flare-up of hepatitis before antiviral therapy, and their baseline HBs Ag levels were relatively low. Therefore, in addition to the combination of the agents, the appropriate selection of patients is critical to achieve a good viral response.

Endoscopic ultrasound-guided gallbladder drainage for acute cholecystitis: Long-term outcomes after removal of a self-expandable metal stent

AIM To assess the long-term outcomes of this procedure after removal of self-expandable metal stent(SEMS). The efficacy and safety of endoscopic ultrasoundguided gallbladder drainage(EUS-GBD) with SEMS were also assessed.METHODS Between January 2010 and April 2015, 12 patients with acute calculous cholecystitis, who were deemed unsuitable for cholecystectomy, underwent EUSGBD with a SEMS. EUS-GBD was performed under the guidance of EUS and fluoroscopy, by puncturing the gallbladder with a needle, inserting a guidewire, dilating the puncture hole, and placing a SEMS. TheSEMS was removed and/or replaced with a 7-Fr plastic pigtail stent after cholecystitis improved. The technical and clinical success rates, adverse event rate, and recurrence rate were all measured.RESULTS The rates of technical success, clinical success, and adverse events were 100%, 100%, and 0%, respectively. After cholecystitis improved, the SEMS was removed without replacement in eight patients, whereas it was replaced with a 7-Fr pigtail stent in four patients. Recurrence was seen in one patient(8.3%) who did not receive a replacement pigtail stent. The median follow-up period after EUS-GBD was 304 d(78-1492).CONCLUSION EUS-GBD with a SEMS is a possible alternative treatment for acute cholecystitis. Long-term outcomes after removal of the SEMS were excellent. Removal of the SEMS at 4-wk after SEMS placement and improvement of symptoms might avoid migration of the stent and recurrence of cholecystitis due to food impaction.

Risk factors for local recurrence and appropriate surveillance interval after endoscopic resection

BACKGROUND Risk factors for local recurrence after polypectomy, endoscopic mucosal resection(EMR), and endoscopic submucosal dissection(ESD) have not been identified.Additionally, the appropriate interval for endoscopic surveillance of colorectal tumors at high-risk of local recurrence has not been established.AIM To clarify the clinicopathological characteristics of recurrent lesions after endoscopic colorectal tumor resection and determine the appropriate interval.METHODS Three hundred and sixty patients(1412 colorectal tumors) who underwent polypectomy, EMR, or ESD and received endoscopic surveillance subsequently for more than one year to detect local recurrence were enrolled in this study. The clinicopathological factors associated with local recurrence were determined via univariate and multivariate analyses.RESULTS Local recurrence was observed in 31 of 360(8.6%) patients [31 of 1412(2.2%)lesions] after colorectal tumor resection. Piecemeal resection, tumor size of more than 2 cm, and the presence of villous components were associated with colorectal tumor recurrence after endoscopic resection. Of these three factors, the piecemeal resection procedure was identified as an independent risk factor for recurrence. Colorectal tumors resected into more than five pieces were associated with a high risk of recurrence since the average period from resection torecurrence in these cases was approximately 3 mo. The period to recurrence in cases resected into more than 5 pieces was much shorter than that in those resected into less than 4 pieces(3.8 ± 1.9 mo vs 7.9 ± 5.0 mo, P < 0.05).CONCLUSION Local recurrence of endoscopically treated colorectal tumors depends upon the outcome of first endoscopic procedure. Piecemeal resection was the only significant risk factor associated with local recurrence after endoscopic resection.

Evaluation of anti-migration properties of biliary covered self-expandable metal stents

AIM: To assess anti-migration potential of six biliary covered self-expandable metal stents(C-SEMSs) by using a newly designed phantom model. METHODS: In the phantom model, the stent was placed in differently sized holes in a silicone wall and retracted with a retraction robot. Resistance force to migration(RFM) was measured by a force gauge on the stent end. Radial force(RF) was measured with a RF measurement machine. Measured flare structure variables were the outer diameter, height, and taper angle of the flare(ODF, HF, and TAF, respectively). Correlations between RFM and RF or flare variables were analyzed using a linear correlated model.RESULTS: Out of the six stents, five stents were braided, the other was laser-cut. The RF and RFM of each stent were expressed as the average of five replicate measurements. For all six stents, RFM and RF decreased as the hole diameter increased. For all six stents, RFM and RF correlated strongly when the stent had not fully expanded. This correlation was not observed in the five braided stents excluding the laser cut stent. For all six stents, there was a strong correlation between RFM and TAF when the stent fully expanded. For the five braided stents, RFM after full stent expansion correlated strongly with all three stent flare structure variables(ODF, HF, and TAF). The laser-cut C-SEMS had higher RFMs than the braided C-SEMSs regardless of expansion state.CONCLUSION: RF was an important anti-migration property when the C-SEMS did not fully expand. Once fully expanded, stent flare structure variables plays an important role in anti-migration.

Castor oil as booster for colon capsule endoscopy preparation reduction: A prospective pilot study and patient questionnaire

BACKGROUND Preparation for colon capsule endoscopy(CCE)requires a large liquid laxative volume for capsule excretion,which compromises the procedure's tolerability.AIM To assess the safety and utility of castor oil-boosted bowel preparation.METHODS This prospective cohort study including 20 patients(age range,16-80 years;six men and 14 women)suspected of having colorectal disease was conducted at Kindai University Hospital from September 2017 to August 2019.All patients underwent CCE because of the following inclusion criteria:previous incomplete colonoscopy in other facility(n=20),history of abdominal surgery(n=7),or organ abnormalities such as multiple diverticulum(n=4)and adhesion after surgery(n=6).The exclusion criteria were as follows:Dysphagia,history of allergic reactions to the drugs used in this study(magnesium citrate,polyethylene glycol,metoclopramide,and castor oil),possibility of pregnancy,possibility of bowel obstruction or stenosis based on symptoms,or scheduled magnetic resonance imaging within 2 wk after CCE.The primary outcome was the capsule excretion rate within the battery life,as evaluated by the total large bowel observation rate,large bowel transit time,and bowel creasing level using a fivegrade scale in different colorectal segments.The secondary outcomes were complications,colorectal lesion detection rates,and patients’tolerability.RESULTS The castor oil-based regimen was implemented in 17 patients.Three patients cancelled CCE because they could tolerate castor oil,but not liquid laxatives.The capsule excretion rate within the battery life was 88%(15/17).The mean large bowel transit time was 236 min.Approximately 70%of patients had satisfactory colon cleansing levels.CCE detected colon polyps(14/17,82%)and colonic diverticulum(4/12,33%).The sensitivity,specificity,and diagnostic accuracy rates for detecting colorectal polyps(size≥6 mm)were 76.9%,75.0%,and 76.4%,respectively.The sensitivity,specificity,and diagnostic accuracy rates for detection of diverticulum were 100%each.Twelve patients(71%)rated CCE as more than“good”,confirming the new regimen’s tolerability.No serious adverse events occurred during this study.CONCLUSION The castor oil-based regimen could reduce bowel preparation dose and improve CCE tolerability.

The role of FGFR inhibitors in the treatment of intrahepatic cholangiocarcinoma-unveiling the future challenges in drug therapy

Intrahepatic cholangiocarcinoma(iCCA)is a rare malignancy,constituting approximately 3-5%of hepatic tumors,with an increasing incidence in recent years(1).Early stage iCCA typically presents asymptomatically,often resulting in its detection at advanced stages.Surgical resection remains the primary therapeutic approach for iCCA;however,a substantial proportion of patients are precluded from surgery due to disease progression,necessitating a reliance on pharmaceutical interventions(2).

Clinical implications of the dual blockade of the PD-1/PD-L1 and vascular endothelial growth factor axes in the treatment of hepatocellular carcinoma

Currently,liver cancer is the fourth most common cause of cancer mortality worldwide.The overwhelming majority of liver cancers are hepatocellular carcinomas(HCC),developing on the background of chronic liver diseases,including chronic hepatitis B,chronic hepatitis C,and non-alcoholic steatohepatitis(1).Despite the recent progress in the treatment of HCC,it remains largely refractory,with a high recurrence rate even after therapeutic intervention(2).Numerous agents,including tyrosine-kinase inhibitors(TKIs),antibodies blocking the vascular endothelial growth factor(VEGF)/VEGF receptor(VEGFR)axis,and immune checkpoint inhibitors,are now available for the treatment of advanced stage HCC(3).However,their antitumor responses are still unsatisfactory.

Verrucous antral gastritis in relation to Helicobacter pylori infection,nutrition,and gastric atrophy

Background:There have been few studies in the English literature regarding verrucous gastritis(VG).The present study investigated the clinical and endoscopic features of verrucous antral gastritis,especially focusing on Helicobacter pylori infection,nutrition,and gastric atrophy.Methods:We performed a retrospective study of patients who underwent routine endoscopy with indigo carmine chromoendoscopy and a comparative study was conducted between VG-positive and VG-negative groups.VG was subdivided into classical and numerous types based on the number and distribution of verrucous lesions.Demographic,clinical,and endoscopic data including body mass index(BMI),serum albumin and cholesterol,gastric atrophy,reflux oesophagitis,Barrett’s oesophagus,and H.pylori status were collected.Univariate and multivariable analyses were performed to identify factors associated with VG.Results:We analysed the data of 621 patients undergoing routine endoscopy and found that VG(n=352)was significantly associated with increased BMI(1.12[1.05-1.18],P<0.01),reflux esophagitis(1.96[1.10-3.28],P<0.01),and H.pylori negativity with or without a history of eradication(9.94[6.00-16.47]and 6.12[3.51-10.68],P<0.001,respectively).Numerous-type(n=163)VG was associated with both closed-and open-type gastric atrophy(9.9[4.04-21.37]and 8.10[3.41-19.24],P<0.001,respectively).There were no statistical differences between groups regarding age,sex,total cholesterol,albumin,and bile-colored gastric juice.Conclusions:Verrucous antral gastritis was related to increased BMI,reflux esophagitis,and H.pylori negativity.Numerous-type verrucous lesions were associated with gastric atrophy.These indicate that VG may be a physiological phenomenon due to high gastric acidity,mechanical overload,and vulnerability of background mucosa.

Cancer immunotherapy for hepatocellular carcinoma

Most hepatocellular carcinomas (HCCs) arise on a background of chronically inflamed liver, and thus are considered typical immunogenic cancers. Although there have been advances in treatment options for HCC, many patients still struggle with a limited chance of survival requiring further innovative approach. Especially for the advanced HCC, many other molecular targeted therapies had been evaluated without success. Based on the immunological mechanisms thought to be acting during HCC development, the effects of diverse immunomodulatory regimens such as therapeutic vaccination, immune checkpoint inhibitors, and adoptive cellular immunotherapy have been investigated. Notably, many strategies have been developed in adoptive cellular immunotherapy, including dendritic cells, cytotoxic T cells, natural killer cells, cytokine-induced killer (CIK) cells, and genetically engineered T cells. In recent clinical trials, adjuvant CIK cell immunotherapy increased progression free survival after curative treatment of HCC. Most recently, new immunomodulatory agents were introduced for oncological treatment, eventually leading to the clinical breakthrough of checkpoint inhibitors targeting cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed cell death-1 (PD-1). To date, very promising published evidence with checkpoint inhibitors in HCC has been reported in the clinical trials with anti-CTLA-4 agent tremelimumab and a large phase II trial with anti-PD-1 agent nivolumab. Further investigations of immuno-oncology potentially popularized the applications of immunotherapy in the various stages of HCCs, and thus immune-based therapies are the promising innovative approach for patients with HCC. Hopefully, the immuno-oncology will bring about a paradigm shift of anti-cancer treatment for HCC.

Promising anticancer therapy: combination of immune checkpoint inhibitors and molecular-targeted agents

Hepatocellular carcinoma(HCC)is the fourth leading cause of cancer death worldwide,and prognosis remains unsatisfactory when the disease is diagnosed at an advanced stage.Sorafenib resistance is one of the main obstacles to the treatment of advanced HCC.Several studies have proposed that the activation of escape pathways from RAF/MEK/ERK/STAT3 might result in sorafenib resistance(1-3).Leung et al.showed that HCC cells with higher SHP2 expression was associated with a lower sensitivity towards sorafenib treatment(4).Consistently,SHP2 inhibitor SHP099 abrogated sorafenib resistance in cancer cells by blocking RAS/MEK/ERK and AKT signaling pathways(4).Unlike other tyrosine phosphatases,SHP2 functions as a positive regulator of proliferative signals.