The role of salivary orosomucoid 1 as an early diagnostic and prognostic biomarker of hepatocellular carcinoma related to Hepatitis B: A systematic review

Edward Kurnia Setiawan Limijadi; Ardiyana Ar; Nurul Azizah Dian Rahmawati; I Nyoman Sebastian Sudiasa; Kevin Christian Tjandra

doi:10.12688/f1000research.132034.1

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Systematic Review

The role of salivary orosomucoid 1 as an early diagnostic and prognostic biomarker of hepatocellular carcinoma related to Hepatitis B: A systematic review

[version 1; peer review: 1 approved with reservations]

Edward Kurnia Setiawan Limijadi¹, Ardiyana Ar², Nurul Azizah Dian Rahmawati², I Nyoman Sebastian Sudiasa², Kevin Christian Tjandra ²

Edward Kurnia Setiawan Limijadi¹, Ardiyana Ar², [...] Nurul Azizah Dian Rahmawati², I Nyoman Sebastian Sudiasa², Kevin Christian Tjandra ²

PUBLISHED 14 Apr 2023

Author details Author details

¹ Department of Clinical Pathology, Faculty of Medicine, Universitas Diponegoro, Semarang, Central Java, 50275, Indonesia
² Department of Medicine, Faculty of Medicine, Universitas Diponegoro, Semarang, Central Java, 50275, Indonesia

Edward Kurnia Setiawan Limijadi
Roles: Conceptualization, Funding Acquisition, Investigation, Methodology, Validation, Writing – Original Draft Preparation, Writing – Review & Editing

Ardiyana Ar
Roles: Investigation, Methodology, Resources, Writing – Original Draft Preparation, Writing – Review & Editing

Nurul Azizah Dian Rahmawati
Roles: Investigation, Methodology, Resources, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing

I Nyoman Sebastian Sudiasa
Roles: Investigation, Methodology, Resources, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing

Kevin Christian Tjandra
Roles: Conceptualization, Investigation, Methodology, Resources, Supervision, Validation, Writing – Original Draft Preparation, Writing – Review & Editing

OPEN PEER REVIEW

REVIEWER STATUS

This article is included in the Oncology gateway.

Abstract

Background: Salivary orosomucoid 1 (ORM1) is highly increased in hepatocellular carcinoma related to hepatitis B. Thus, this study aims to investigate the role of salivary ORM1 as an early diagnostic and prognostic biomarker of HCC related to hepatitis B.
Methods: The sources included were original articles published from 2013 until 2023 (last date searched, January 2023) from ProQuest, Google Scholar, Springer, and ScienceDirect. The inclusion criteria were original research articles (observational cohort or diagnostic studies). Other article reviews, meta-analyses, non-comparative research, and in silico, in vitro and in vivo studies, technical reports, editor responses, conference abstracts, non-English, non-full-text, and irrelevant articles that were not related to either salivary ORM1, or hepatocellular carcinoma, hepatitis B, or kidney failure were excluded. Then, the ROBINS-I took was used to assess bias . The result was constructed with PICOS criteria within the table created in the google spreadsheet. This systematic review followed the PRISMA guidelines.
Results: We included five diagnostic studies with 533 samples conducted in China and Japan. Even though limited original studies with homogenous PICO was a limitation, the evidence output of this study can still be well presented. Salivary ORM1 may be useful to detect early cancer diagnosis as rapidly increased levels of ORM1 can be observed in the early stages of HCC (four times higher than usual) and the biomarker has a sensitivity of 81.67% and a specificity of 77.5%. This biomarker is also able to detect the prognosis of individuals with the disease with or without chemotherapy because the higher the level of ORM1, the more liver damage occurs that leads to a poorer prognosis.
Conclusions: Salivary ORM1 is a potential early diagnostic biomarker of HCC related to hepatitis B and a biomarker of the disease prognosis.
Registration: Open Science Framework (OSF) (March 16, 2023).

Keywords

Salivary Orosomucoid 1, Hepatocellular Carcinoma, Early Diagnostic, Prognostic, Biomarker

Corresponding author: Kevin Christian Tjandra

Competing interests: No competing interests were disclosed.

Grant information: The author(s) declared that no grants were involved in supporting this work.

Copyright: © 2023 Limijadi EKS et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

How to cite: Limijadi EKS, Ar A, Rahmawati NAD et al. The role of salivary orosomucoid 1 as an early diagnostic and prognostic biomarker of hepatocellular carcinoma related to Hepatitis B: A systematic review [version 1; peer review: 1 approved with reservations]. F1000Research 2023, 12:401 (https://doi.org/10.12688/f1000research.132034.1) First published: 14 Apr 2023, 12:401 (https://doi.org/10.12688/f1000research.132034.1) Latest published: 06 Jun 2023, 12:401 (https://doi.org/10.12688/f1000research.132034.2)

Introduction

Salivary orosomucoid 1 (ORM1) or alpha-1-acid glycoprotein (AGP) is an acute phase protein of about 1-3% of all plasma proteins. ORM1 is normally produced by hepatocyte cells but can also be produced and found in extrahepatic tissues such as endothelial cells and some tumor cells.¹ ORM1 is expressed in inflammatory injuries, infections, and stress conditions.² ORM1 is predominantly synthesized in the liver so liver disease, especially hepatocellular carcinoma (HCC) induced by hepatitis B can affect changes in its concentration or expression more in saliva as well as serum. The expression pattern of ORM1 shows a rapid increase in saliva and serum at the beginning of HCC induced by hepatitis B because a characteristic of this disease is that liver cell destruction happens from very early stages.²^,³ Even though ORM1 is not only used to detect HCC related to hepatitis B, HCC related to hepatitis B is the only disease that has a specific behavior as mentioned above.²^,⁴

Orosomucoid is produced by hepatocyte cells and it increases when there is inflammation in the body, especially the liver as the place of production. When inflammation occurs, hepatocyte cells will secrete ORM1 as an inflammatory expression agent that can be detected through saliva, urine, and serum.¹ HCC related to hepatitis B is associated with a massive inflammatory response that leads to the production of a huge amount of ORM1. It indicates that ORM1 is suitable for early diagnosis of HCC related to hepatitis B.² Malignant cells in hepatocytes can affect the function of the liver in the body. The liver is the place of albumin synthesis in the human body, and if HCC is detected, it will be followed by hypoalbuminemia in laboratory tests.⁵ So hypoalbuminemia is one of the early diagnostic parameters that can be assessed besides ORM1.

Modalities of early detection of HCC are usually looking at biomarkers. Alpha-fetoprotein (AFP) is one of the biomarkers that is often used in detecting the presence of hepatic cancer. However, AFP has the disadvantage of having low specificity and cannot detect early-stage hepatic cancer compared to ORM1.⁶

Saliva is a molecule rich in protein, DNA, RNA, and microorganisms, and can be considered a library of biomarkers. Cancer biomarkers present in the blood can also be found in saliva, and changes in their concentration can be used as biomarkers to detect cancer early and monitor response to treatment management. Saliva is a biomarker that is non-invasive, simple and does not require professional medical personnel, and has the ability to last longer than blood and urine. Screening methods using saliva can be used to detect the incidence of cancer.²

Gani et al. (2015) found ORM1 to have significantly higher expression in the saliva of patients with HCC compared to the non-HCC group (p < 0.001) and ORM1 expression in saliva liver cancer was significantly higher than adjacent normal tissue (p < 0.001).⁷ ORM1 expression differs in each response to a disease condition, be it infection, drug sensitivity or cancer. However, its role in HCC remains largely unknown. Therefore, ORM1 may become an enhanced diagnostic tool for HCC. In addition, in a study by Higuchi et al. (2020) it was found that ORM1 was expressed differently in HCC tumors and non-tumor tissues using a combination of in vitro, in silico, and clinical sample immunohistochemistry methods. Thus, ORM1 can be considered as a potential target for the development of future therapies against HCC.⁸

This article aims to fulfil two objectives. First, we try to investigate the role of salivary ORM1 as an early diagnostic biomarker of HCC related to hepatitis B, including sensitivity and specificity. Second, we try to identify the general prognosis of the patient with HCC induced by hepatitis B, i.e., whether the outcome will be favorable or unfavorable, using levels of salivary ORM1 as a biomarker.

Methods

This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).⁹ This review was registered with Open Science Framework (OSF) (March 16, 2023).

Eligibility criteria

We included original articles published in 2013 until 2023 (last date searched January 2023). The study comprised original research articles or research reports that used observational cohort or diagnostic studies as the inclusion criteria. Scientific posters, study protocols, narrative reviews, systematic reviews, meta-analyses, non-comparative research, in silico studies, in vitro studies, in vivo studies, technical reports, editor responses, and conference abstracts were all disqualified. Additionally, non-English, non-full-text, and irrelevant articles that were not related to either salivary ORM1, or HCC, or hepatitis B, or kidney failure were also excluded. The eligibility criteria for articles were as follows: i) Population, adults with cancer or hepatitis B or kidney failure; ii) Intervention, measuring salivary ORM1; iii) Comparison, healthy patient (control); and iv) Outcomes, level of ORM1.

Outcome measure

ORM1 is the parameter assessed as the outcome measure in this systematic review. This parameter is synthesized by hepatocytes and has a normal plasma concentration between 0.6–1.2 mg/mL (1–3% plasma protein). ORM1 can be found in several types of fluid, including saliva, urine, and plasma. Since it’s produced by hepatocytes, the level of this parameter can increase in conditions that affect hepatocytes’ activity and damage its product (albumin), such as hepatitis, cancer, and kidney failure.

Index test

Studies that provided the data of evaluations of ORM1 are included in this systematic review.

Reference standard

Reference standards are professional research using observational cohorts or diagnostic studies to assess the transition of ORM1 serum levels.

Data sources and search

Research for this study were gathered through ProQuest (RRID:SCR_006093), Google Scholar (RRID:SCR_008878), Springer, and Science Direct database searches. Boolean operators were utilized among the keywords. In Table 1, the keywords used in each database are displayed.

Table 1. Keywords used for the literature search.

Database	Keywords
ProQuest	salivary orosomucoid 1 AND (hepatitis b OR hepatocellular carcinoma); salivary orosomucoid 1 AND mechanism of action; salivary orosomucoid 1 AND biomarker
Google Scholar
Springer
Science Direct

The filters used for each database included year (from 2013 until January 2023), type of documents from ProQuest was filtered by scholarly journal, any type of article was used in Google Scholar, content type article was used as the Springer database filter, and research article type was used for Science Direct database filter. The last date the databases were searched was 10 January 2023. The database search gave a total result of 2,482 studies (324 ProQuest, 1,683 Google Scholar, 221 Springer, and 254 Science Direct). Once the aforementioned filters were added, 712 studies were then imported to the Mendeley Group Reference Manager in the authors’ library before the selection process.

Selection process

After using the search terms listed in Table 1, four independent reviewers (KCT, AA, NADR, and INSS) and one validator (EKSL) merged the results from four databases. They then screened the abstracts and full text to eliminate the irrelevant articles and keep the relevant articles and expelled non-cohort and non-diagnostic articles. From this process, 655 studies were excluded, then the 57 studies left were checked for whether the full text could be retrieved. As a result, only 17 full text articles could be retrieved. Following this, 12 articles were excluded due to duplication, as found using the title, year of publication, and DOIs. A total of five included studied were assessed for eligibility using the Risk Of Bias In Non-randomized Studies - of Interventions (ROBINS-I) tool. From this procedure, all the five included studies passed the assessment bias check. The research selection processes were recorded in the PRISMA flow chart.

Data collection process

After the final screening, the pertinent information from the studies was retrieved and entered into a Google Spreadsheet. Data were recorded and validated by all five authors into columns as follows: i) First, author and year; ii) second, country; iii) third, study design; iv) fourth, sample size; v) fifth, gender; vi) sixth, mean age; vii) seventh, intervention name; viii) eighth, intervention length; ix) ninth, comparison; and x) tenth, outcome consisting of ORM1 expression levels.

Data items

The main outcome of interest was the concentration of ORM1, sensitivity, and specificity in detecting HCC related to hepatitis B. Expression of ORM1 related genes, correlation between ORM1 and prognosis or other medical conditions were decided as secondary outcomes.

Study risk of bias assessment (qualitative synthesis)

The ROBINS-I tool was used by five independent reviewers (KCT, AA, NADR, INSS, and EKSL) to evaluate each study that was included in this analysis. Later, the disagreements were discussed and settled between the reviewers, and we decided to exclude article with critical overall bias from ROBINS-I assessment.

Reporting bias assessment

According to the ROBINS-I assessment bias conducted by KCT, AA, NADR, INSS, and EKSL, All the five included articles did not show any critical overall bias as mentioned in Figure 1 so we did not remove any articles.

Figure 1. Risk of bias assessment result.

Results

Study selection

Overall, 2,482 studies were produced by doing a literature search using four databases: ProQuest, Google Scholar, Springer, and ScienceDirect. In order to exclude non-cohort studies, automation techniques from each database were employed, which led to the exclusion of 1,770 publications. A total of 655 irrelevant topic articles were removed after authors evaluated every last article from the title and abstract for relevance. Then, 40 non-retrieved articles were excluded due to the inability to access the full text document. In total, 12 duplicate study papers were then removed. The complete texts of five articles were then obtained. Last but not least, the author determined the eligibility of each study and all five articles passed the eligibility criteria. Five papers were included in this systematic review. Our study selection process is presented in the PRISMA diagram flow chart in Figure 2.

Figure 2. PRISMA 2020 flow diagram.

Study characteristics

In total, 533 people participated in the five studies included in this systematic review. Three studies were conducted in China such as Dalian city, while two studies were conducted in Japan, including Maebasi City, and Sapporo City. The complete study characteristics, including the PICO of each study, are stated in Table 2.

Table 2. Summary of the studies included in this systematic review.

No.	Author; Year	Title	Location	Study design	Population		Intervention & Comparison		Outcomes
No.	Author; Year	Title	Location	Study design	Sample size, n	Mean age, years (Mean ± SD)	Intervention	Comparison	Outcomes
1	Yazawa et al., 2016.¹⁰	Fucosylated glycans in alpha-1 acid glycoprotein for monitoring treatment outcomes and prognosis of patients with cancer	Japan	Cohort	30 cancer patients (9 gastric, 8 colon, 5 lung, 4 esophagus, 2 liver, 1 rectum, 1 pancreas), and 21 healthy patients	N/A	AGP levels in serum samples were measured by ELISA, then AGP was purified from 0.5 ml serum, then used for preparation of labeled N-glycans followed by spectrophotometric analysis.	Cancer patients vs. healthy patients	FUCAGP in cancer patients (Mean ± SD) = 32.25 ± 6.89; FUCAGP in healthy patients (Mean ± SD) = 20.70 ± 6.61; P<0.05	Serum AGP concentration in cancer patients (Mean ± SD) = 2507.33 ± 1093.14; Serum AGP concentration in healthy patients (Mean ± SD) = 1119.75 ± 456.65.14; P<0.05	In post-operative period the FUCAGP and AGP levels showed no significant difference in association with their prognostic status, even though elevated levels were found in cancer patients compared with healthy patients.	Notes: quantitative changes in AGP is associated with inflammation, pregnancy, estrogen treatment, cancer, liver disease and autoimmune diseases (RA).
2	Gu et al., 2022.¹¹	ORM1 as a biomarker of increased vascular invasion and decreased sorafenib sensitivity in hepatocellular carcinoma	China	Cohort	15 pairs of HCC samples with adjacent non-tumor tissues and 5 HCC samples with microvascular invasion were collected from patients who underwent surgical resection.	N/A	Cells were cultured and total RNA was isolated and the quality and concentration were evaluated with spectrophotometer. Cell proliferation was evaluated with cell counting kit, and immunohistochemistry was used to evaluate ORM1 expression in HCC and adjacent non-tumor samples.	GSE45114 & GSE45267 dataset (cancer & tumor) vs. noncancer and nontumor dataset	919 DEGs were identified, 354 were upregulated and remaining downregulated, functional analysis using gene ontology and gene set enrichment analysis analyses showed DEGs were associated with immune response, cell adhesion, and cell metabolism associated with carcinogenesis.	Expression of ORM1 was significantly downregulated in HCC in both datasets compared to non-tumor. IHC was later used with results indicating ORM1 was downregulated in HCC compared to noncancer, although ORM1 had higher levels in stroma of HCC tissues.	ORM1 was significantly upregulated in the microvascular invasion samples (P=0.042)	ORM1 expression levels did not correlate with overall survival, or distant, or lymphatic metastasis, but strongly correlated with the tumor stage and grade of HCC.	Correlation between ORM1 expression and sorafenib resistance in HCC: GSE93595 showed lower in resistant but there was no significant difference (p=0.333), GSE 75620 showed ORM1 was higher in sorafenib-treated cell but there was no significant difference (p=0.421) between short-term treated and long-term resistant cells.	CCK-8 assay revealed that ORM1 could promote tumor growth, and its knock-down could suppress cancer cell growth.
3	Higuchi et al., 2020.⁸	Orosomucoid 1 is involved in the development of chronic allograft rejection after kidney transplantation	Japan	Cohort	17 CAAMR, 30 IFTA, 25 CNI-T, 17 Normal	46.0 (CAAMR), 44.5 (IFTA), 43 (CNI=T), 38 (Normal)	Serum and urine samples collected from kidney transplant patients. Then, samples were centrifuged and the supernatant of the urine and blood were analyzed.	CAAMR vs. interstitial IFTA vs. CNI-T vs. normal	Serum Creatinine mg/dl (CAAMR, IFTA, CNI-T, Normal) = 1.47, 1.14, 1.15, 1.05. P<0.05 for CNI-T and normal vs. CAAMR	CRP mg/dl (CAAMR, IFTA, CNI-T, Normal) = 0.02, 0.03, 0.03, 0.03 with P > 0.05	Urinary TP/Creatinine g/g Cre (CAAMR, IFTA, CNI-T, Normal) = 0.53, 0.05, 0.03, 0.02. with P < 0.05 for CNI-T and IFTA, N VS CAAMR.
4	He et al., 2022.²	Salivary orosomucoid 1 as a biomarker of hepatitis B associated hepatocellular carcinoma	China	Cohort	Discovery Cohort: 10 HCC, 10 LC, 10 CHB, 10 NC, Validation Cohort: 80 HCC, 40 LC, 40 CHB, 40 NC	HCC: 52.47 ± 8.65, LC: 51.93 ± 12.18, CHB: 47.88 ± 9.36, NC: 48.2 ± 10.76	Saliva were collected and mixed in each groups then underwent through protein extraction and labeled with iTRAQ marker reagent. Samples later went to peptide fractionation, high performance liquid chromatography, mass spectrometry detection, target protein determination, and analyzed with western blot, immunohistochemistry, ELISA, and statistical analyses.	HCC patients vs. LC patients vs. CHB) patients vs. NC	Serum ALT IU/ml (HCC, LC, CHB, NC) = 54,5 ± 13.533, 35 ± 11,1212, 428.5 ± 10.2466, 25 ± 11.41. P>0.05 for HCC vs. LC, P<0.05 for HCC vs. CHB, HCC vs. NC.	Serum ALT IU/ml (HCC, LC, CHB, NC) = 81.95 ± 20.558, 49 ± 15,1011, 190 ± 17.2134, 25.5 ± 13.38. P>0.05 for HCC vs. LC, P<0.05 for HCC vs. CHB, HCC vs. NC.	Serum AFP ug/L (HCC, LC, CHB, NC) = 301.7 ± 1.51,8890, 11.78 ± 1.63,358.4, 13.52 ± 1.55,600.6, NA. P<0.05 for HCC vs. LC, HCC vs. CHB	HBV-DNA log IU/ml (HCC, LC, CHB, NC) = 3.11 ± 1.7,7.43, 1.7 ± 1.7,7.21, 5.24 ± 1.7,9.52, NA. P<0.05 for HCC vs. LC, HCC vs. CHB	HBeAg (Positive/negative) (n) (HCC, LC, CHB, NC) = 23/57, 9/31, 21/19, 0/40. P>0.05for HCC vs. LC, P<0.05 for HCC vs. CHB, HCC vs. NC.	Early HCC (n)/advanced HCC (n) (HCC) = 40/40	The AUC of salivary ORM1 was 0.8499 (95% CI: 0.7724–0.9075), with a sensitivity of 77.5%, a specificity of 81.67%, when the cut-off point was set to 1,277 ng/ml; the AUC of salivary AFP+ORM1 combination was 0.9207 (95% CI: 0.8825–0.9590), with a sensitivity of 95%, a specificity of 74.17%. Salivary ORMI may be a potential biomarker for diagnosis or screening of HCC, and performed much better when combined with salivary AFP.
5	Li et al., 2016.¹	The increased excretion of urinary orosomucoid 1 as a useful biomarker for bladder cancer	China	Cohort	112 patients with bladder cancer and 21 cases with benign bladder damage	2- Dimensional Electrophoresis: Healthy controls (67.64 ± 8.34), Bladder cancer (69.23 ± 14.11); Western blotting: Healthy controls (63.12 ± 7.54), Bladder cancer (67.89 ± 17.21); ELISA: Healthy controls (65.33 ± 10.57), Benign Damage (61.27 ± 9.77), Bladder Cancer (64.85 ± 18.85).	Urine samples were collected and underwent through 2-DE analysis, Spectrometric analysis, and western blot analysis.	Bladder cancer vs. NC (2-De and Western Blot), bladder cancer vs. benign damage vs. NC (ELISA)	urinary ORM1 was significantly (P<0.05) upregulated in bladder cancer cases than that of the control group.	the urinary ORM1 was markedly elevated in bladder cancer patients than in controls and benign cases (7,172.23±3,049.67 vs. 2,243.16±969.01, 2,493.48±830.37 ng/ml, P<0.0001). After division of the patients into groups by tumor classification, the urinary ORM1 concentrations were 5,313.35±1341.39, 5,892.76±1,943.94 and 1,0376.49±2,677.76 ng/mg for bladder cancer with low grade non-invasive papillary urothelial carcinoma, high grade noninvasive papillary urothelial carcinoma and infiltrating urothelial carcinoma.	Spearman rank correlation = 0.712 (P<0.0001). There was no significant association between the urinary ORM1 expression and other clinical features of bladder cancer, except ORM1 content was associated with urinary inflammation (OR: 1.841, 95% CI: 1.123–2.565, P=0.024) and the classification of tumor pathology in bladder cancer (OR: 2.432, 95% CI:1.253–3.589, P<0.001).	ROC curve analysis showed cut-off value of 3,912.97 ng/mg corresponding to 91.96% sensitivity and 94.34% specificity with AUC 0.965 (95%CI: 0.923–0.987) for utility of urinary ORM1 in early diagnosis and surveillance of bladder cancer. Also, a cut-off value with 7,351.28 ng/mg corresponding to 91.89% sensitivity and 90.67% specificity. The AUC was 0.921 (95% CI 0.853–0.963) for utilization of ORM1 to distinguish infiltrating urothelial carcinoma from bladder cancer.

Risk of bias in studies

With the use of the ROBINS-I risk-of-bias tool for observational studies, the quality of each study was rigorously evaluated. No bias was indicated in five of the studies. Figure 1 provides a summary of the bias risk assessment.

Study result summaries

The journal selection method that has been carried out produced five studies that were used in the systematic review process. The five studies were conducted by Yazawa et al. (2016),¹⁰ Gu et al. (2022),¹¹ Higuchi et al. (2020),⁸ He et al. (2022)² and Li et al. (2016).¹ Brief profiles of the five studies are shown in Table 2.

Discussion

Statement of principal findings

This systematic review confirms the evidence of salivary ORM1 as a possible early diagnostic and prognostic biomarker for HCC related to hepatitis B. From the studies included, we can generally find how ORM1 has a role in the early stage of HCC induced by hepatitis B and could be a potential early stage biomarker and determine the correlation of ORM1 level related to patient prognosis.

Strength and limitations of the study

The methodical approach to the identification, selection, and extraction of data using a causality framework that offers a framework for the assessment of varied sources of evidence and a substantial number of review questions are the study’s strengths. To our knowledge, this is the first systematic review that assesses the levels of ORM1 in patients with cancer along with the diagnostic and prognostic evidence. The main limitation of the traditional systematic review was high workload and time necessary to maintain it. Another disadvantage was the time required to settle inter-reviewer variations in the interpretation of qualifying requirements. This might have led to subjectivity in judgments about inclusion in the review. Although a second reviewer examined all extractions, changes in the review team might cause inconsistency. We utilized case definitions as given by authors in individual articles, as we did in the baseline review.

Even though this systematic review can qualitatively analyze the evidence of the included studies, the limited number of original studies with homogenous PICO is our limitation. In the future with more original related studies, it will be possible to conduct quantitative analyses.

Overview of orosomucoid 1

Orosomucoid is a component of plasma protein that has numerous roles in body physiology, including capillary barrier regulation, metabolism, and the immune system.¹² ORM1 or alpha-1-acid glycoprotein (AGP) is a class of proteins with carbohydrate content up to 45% and protein pI 2.8-3.8, which often appears during the acute phase of the disease.⁶ ORM is formed by the liver and finally secreted throughout the body with a normal value of 0.4–1.2 mg/ml plasma in the human body. If the amount increases, it can be a sign of an unusual condition in the body, such as pregnancy, drug use, or certain diseases. The alpha (1)-acid glycoprotein glycan structure is shown in Figure 3.¹⁰

Figure 3. Symbolic representation of alpha (1)-acid glycoprotein glycan structure.

This figure is reproduced from Yazawa et al., 2016.¹⁰

The human ORM is located on the long arm of chromosome 9 in the AGP-A, AGP-B, and AGP-B′ clusters.¹¹^,¹³ α-1 acid glycoprotein (AGP) or ORM is a class of plasma glycoproteins consisting of many N-linked glycan branches and a total molecular weight of 41–43 kD.¹⁰ The ORM structure consists of 201 polypeptide chain residues, of which 22 residues distinguish ORM1 and ORM2. Structural analysis of ORM1 shows a combination of N-linked glycan chains associated with neutral hexagons, fructose, sialic acid, hexosamine (N-acetylglucosamine), mannose, and galactose.⁴ Theoretically, each of the five N-linked glycans can join branches with different degrees, express other glycan chains, and form more than 105 other glycoforms of ORMs.

As aforementioned, if ORM1 is produced in hepatocyte cells in the liver, it will then be distributed to the peripheral circulation, even in saliva, and it will increase its value if the tissue is inflamed or malignant.⁴ Serum is the gold standard in the detection of ORM levels, but the potential of saliva and urine for a similar role is currently being developed. It has been investigated whether there are differences between those three media, and which results showed that the correlation between the reference method and assay of ORM1 serum was 0.97 (p < 0.001). Meanwhile, the saliva also gave a similar result as serum, that is 0.97 (p < 0.001) higher than in media that showed 0.93 (p < 0.001).¹²

Function and production of salivary ORM1

ORM1 is synthesized by hepatocytes and parenchymal cells of the liver. Orosomucoid synthesis is upregulated by inflammatory cytokines and then released into the blood where it is distributed in body fluids, such as saliva, urine, plasma, and mucus.¹⁴^–¹⁶ ORM1 expression is regulated by TGF-β and mediated by the TGF-β/Smad signaling pathway.² ORM1 concentration can elevate 1–10 times during pathological conditions depending on the severity of the disease. Inflammation level and degree of injury are also factors that can increase the concentration of ORM1. ORM gene expression in liver cells is related to inflammatory mediators, such as glucocorticoids, cytokines, interleukins, and TNF-alpha. Hepatocytes and the liver are the primary sources of ORM synthesis.¹⁷^–²⁰

ORM1 has various biological functions, including being a biomarker for disease, immunomodulatory effects, and roles in important drug-binding processes, transporting proteins in the serum with albumin and lipoproteins, maintaining capillary barrier function, and various metabolisms. ORM1 serum and saliva concentration can change due to stressful stimuli, such as physical trauma, bacterial infection, and unspecific inflammatory stimuli.⁴ Due to its immunomodulatory effects, Higuchi et al., stated that ORM1 can be used as a possible therapeutic molecular target. ORM1 concentration was found to be significantly higher after kidney transplant due to cytokine mediated NFxB and STAT3 activation in primary kidney tubular cells.⁸ ORM1 could also be used as a potential biomarker for cancers in the pancreas, bladder, and liver cancer by determining the level of ORM1 in the serum of body fluids, saliva, urine, and blood.¹⁰ Damage in the hepatocytes due to liver cancer may cause a change of ORM1 serum levels. He et al., showed that salivary ORM1 is significantly increased in HCC related to hepatitis B virus.² Gu et al., also stated that the expression levels of ORM1 were strongly correlated with the tumor stage and grade of HCC.¹¹ From these studies, we can conclude that even if salivary ORM1 is significant in several other cases, the highest increased level compared to normal controls happened in HCC related to hepatitis B, which is 4.02 times higher than the normal level.²^,⁸^,¹⁰

Mechanism of action in cancer

ORM1 functions as a transport protein in the bloodstream. ORM1 plays an important role in modulating immune system activity during acute phase inflammation.²⁰ A previous study showed that serum ORM levels are increased in inflammatory and lymphoproliferative disorders and cancers such as liver, lung, breast, and ovarian cancer.¹ ORM1 has a down-regulating effect on the inflammatory cascade, thereby protecting against tissue damage due to excessive inflammation and malignancy.

ORM1 increases in types of cancer such as invasive breast carcinoma and colon adenocarcinoma. ORM1 is also differentially expressed between tumoral and non-tumor tissues. ORM1 expression was found to be higher in embolic cancer than in surrounding tumor cells, indicating that ORM1 expression is associated with vascular invasion thereby reducing the overall prognosis of patients with HCC.¹¹

ORM1 is predominantly synthesized in the liver, therefore liver disease has more influence on its expression, ORM1 can be induced by injury in the liver and can activate the liver cell cycle to achieve liver regeneration. He et al., reported that ORM1 expression was highly correlated with tumor growth according to tumor grade and stage.² This is consistent with the finding that salivary ORM1 increased significantly in patients with advanced liver cancer compared to patients with early-stage liver cancer, that is advanced HCC ORM level is 9.39 times higher than the normal level, while early-stage HCC is only 4.02 times higher than the normal level.² Elevated salivary ORM1 may be a risk factor for poor prognosis in patients with HCC.

As shown in the study conducted by He et al. (2022) salivary ORM1 and AFP are significantly higher in other liver diseases. In the same study, it was found that ORM1 had significantly higher expression in the saliva of patients with HCC compared to the non-HCC group (p < 0.001) and ORM1 expression in liver cancer tissue was significantly higher than in adjacent normal tissues.² There are different levels of salivary AFP expression and salivary ORM1 expression in total HCC, liver cirrhosis (LC), chronic hepatitis B (CHB), and normal control (NC) groups. On the same finding, salivary ORM1 showed good specificity and sensitivity for detecting HCC, especially in HCC associated with hepatitis B.⁷ The sensitivity and specificity of salivary ORM1 reached 81.67% and 77.5%.

Role as early diagnostic biomarker in hepatitis B associated with hepatocellular carcinoma

As an acute-phase protein, AGP has been studied for its potential physiological significance, and both quantitative and qualitative changes to the molecule’s glycan structure have been examined in relation to inflammation and malignancy of the liver.²^,²¹^–²³ The comparison value of liver disease related to hepatitis B shows in a sequence of normal liver, LC, CHB, early HCC, HCC, and advanced HCC is 429, 657, 1,073, 1,723, 2,143 and 4,029 ng/ml, respectively.²

The first rapidly increased level of ORM1 shown in early HCC (four times higher than normal) indicates that ORM1 can detect HCC in the early stage with high sensitivity and specificity. This early diagnostic biomarker has a sensitivity of 77.5% and a specificity of 81.67%.²

According to the study conducted by Yazawa et al. (2016) the reason ORM1 can be used as an early diagnostic biomarker is that it is exclusively synthesized in the liver by the encoded FUT6 gene, then this enzyme acts as a catalyzer for many reactions related to L-fucose addition to the receptor in order to protect liver cells from damage caused by HCC related to hepatitis B.¹⁰ Moreover, this biomarker is also able to detect the prognosis of the disease with or without chemotherapy, this is because the higher the level of ORM1, the more liver damage occurs that leads to a poor prognosis.¹²

A combination of salivary ORM1 and AFP is specific and sensitive in detecting HCC as written in a study conducted by He et al. (2022). Thus, salivary ORM1, α 1,3 fucosyltransferase, and AFP are going to be a sensitive and specific combination in detecting HCC related hepatitis B as well as prognosis, microvascular invasion (MVI), and sorafenib drug sensitivity. This method of using salivary ORM1, α 1,3 fucosyltransferase, and AFP is also a promising and less invasive method, so it has a high potential to be commercialized.²

Conclusions and recommendations

Salivary ORM1 is a potential early diagnostic biomarker of HCC related to hepatitis B, as well as a biomarker of disease prognosis. This biomarker has a sensitivity of 81.67% and a specificity of 77.5%.

In order to increase the sensitivity and specificity of ORM1 as an early diagnostic biomarker, a combination of other biomarkers may be a good topic for further research and application. The sensitivity and specificity of combined salivary AFP and salivary ORM1 tend to be 95% and 74.17%, respectively. In order to overcome the lack of specificity of the aforementioned biomarker combination, hypoalbuminemia detection from albumin assessment as an additional sign of poor liver function is suggested. Therefore, the combination of salivary ORM1, salivary AFP and albumin assessment may be able to provide high sensitivity and specificity in detecting HCC related to hepatitis B.

Data availability

Underlying data

All data underlying the results are available as part of the article and no additional source data are required.

Reporting guidelines

Mendeley Data: PRISMA checklist for ‘The role of salivary orosomucoid 1 as an early diagnostic and prognostic biomarker of hepatocellular carcinoma related to Hepatitis B: A systematic review’. https://doi.org/10.17632/ykr5jtj6sx.1.⁹

Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).

References

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Version 2

VERSION 2 PUBLISHED 14 Apr 2023

Author details Author details

Edward Kurnia Setiawan Limijadi
Roles: Conceptualization, Funding Acquisition, Investigation, Methodology, Validation, Writing – Original Draft Preparation, Writing – Review & Editing

Ardiyana Ar
Roles: Investigation, Methodology, Resources, Writing – Original Draft Preparation, Writing – Review & Editing

Nurul Azizah Dian Rahmawati
Roles: Investigation, Methodology, Resources, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing

I Nyoman Sebastian Sudiasa
Roles: Investigation, Methodology, Resources, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing

Kevin Christian Tjandra
Roles: Conceptualization, Investigation, Methodology, Resources, Supervision, Validation, Writing – Original Draft Preparation, Writing – Review & Editing

Competing interests

No competing interests were disclosed.

Grant information

The author(s) declared that no grants were involved in supporting this work.

Article Versions (2)

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Published: 06 Jun 2023, 12:401

https://doi.org/10.12688/f1000research.132034.2

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Published: 14 Apr 2023, 12:401

https://doi.org/10.12688/f1000research.132034.1

© 2023 Limijadi EKS et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Limijadi EKS, Ar A, Rahmawati NAD et al. The role of salivary orosomucoid 1 as an early diagnostic and prognostic biomarker of hepatocellular carcinoma related to Hepatitis B: A systematic review [version 1; peer review: 1 approved with reservations]. F1000Research 2023, 12:401 (https://doi.org/10.12688/f1000research.132034.1)

NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article.

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Open Peer Review

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PUBLISHED 14 Apr 2023

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Reviewer Report 28 Apr 2023

Maria Komariah, Department of Fundamental Nursing, Faculty of Nursing, Universitas Padjadjaran, Bandung, West Java, Indonesia

Sidik Maulana, Faculty of Nursing, Universitas Padjadjaran, Bandung, West Java, Indonesia

Approved with Reservations

https://doi.org/10.5256/f1000research.144930.r169865

The abstract could benefit from a sentence that highlights the main objective or question of the systematic review. For example, "This systematic review aimed to investigate the diagnostic and prognostic value of salivary orosomucoid 1 (ORM1) in patients with hepatocellular carcinoma related to hepatitis B."
It would be helpful to include the number of databases searched in the methods section, as this is an important aspect of a systematic review.
The sentence "This biomarker is also able to detect the prognosis of individuals with the disease with or without chemotherapy because the higher the level of ORM1, the more liver damage occurs that leads to a poorer prognosis" could use further clarification. It is not clear how ORM1 levels relate to prognosis, and the sentence could benefit from further explanation or references to support the claims made.

Introduction
Your introduction section provides a clear and informative overview of salivary orosomucoid 1 (ORM1) and its potential role in the diagnosis and prognosis of hepatocellular carcinoma (HCC) related to hepatitis B. However, here are a few areas that could be improved:

The introduction could benefit from a concise and clear statement of the research question or objective. For example, "The objective of this systematic review is to investigate the diagnostic and prognostic value of salivary orosomucoid 1 (ORM1) in patients with hepatocellular carcinoma related to hepatitis B, including its sensitivity and specificity as an early diagnostic biomarker, and its potential prognostic value."
Some of the sentences could be simplified, such as "ORM1 is expressed in inflammatory injuries, infections, and stress conditions," which could be shortened to "ORM1 is produced in response to inflammation, infections, and stress."
Try to avoid repeating information. For example, the discussion of the advantages of saliva as a biomarker could be consolidated into a single paragraph or sentence.
The introduction could benefit from a more concise and focused overview of the current state of knowledge regarding ORM1 and HCC related to hepatitis B. You could consider trimming some of the less essential or tangential details to keep the focus on the main topic of the review.

Methods
Your methods section appears to be quite comprehensive, but here are a few areas that could use some clarification or improvement:

In the Eligibility criteria section, you mention that non-comparative research was disqualified, but it's not clear what this means. Can you provide more information about what you mean by "non-comparative research"?
In the Selection process section, it would be helpful to provide more information about why the 655 excluded studies were removed, and whether any specific criteria were used for exclusion (beyond the abstract screening and full-text retrieval).
In the Data collection process section, it would be helpful to provide more details about how disagreements between reviewers were resolved, and whether any inter-rater reliability statistics were calculated.
Regarding the risk of bias assessment, it would be helpful to include a brief overview of the domains assessed by the ROBINS-I tool, and how each domain was scored for each study.
In the Reporting bias assessment section, it would be helpful to clarify whether any reporting bias was identified in the included studies, or whether this section simply reflects the results of the risk of bias assessment.

Results and discussion
Overall, the results and discussion section is well-written and provides a clear summary of the main findings in the systematic review. The section is well-organized and provides adequate information about the salivary ORM1 biomarker, its function, and production. The discussion of the limitations of the study is also thorough and provides insight into the potential sources of bias.
In terms of strengths, the discussion highlights the methodical approach of the review process and the assessment of varied sources of evidence. The discussion also emphasizes the novel contribution of the study as the first systematic review to assess the levels of ORM1 in patients with cancer along with diagnostic and prognostic evidence.

The section provides a comprehensive overview of ORM1 as a biomarker, specifically its function and production. The discussion of the mechanism of action in cancer provides clear explanations of how salivary ORM1 could be a potential biomarker for cancers in the pancreas, bladder, and liver cancer.

Regarding the role of salivary ORM1 as an early diagnostic biomarker in hepatitis B associated with hepatocellular carcinoma, the discussion provides a clear summary of the study's findings, including the sensitivity and specificity of the biomarker. Additionally, the section highlights the potential of using a combination of salivary ORM1, α 1,3 fucosyltransferase, and AFP for detecting HCC related to hepatitis B and for assessing prognosis, microvascular invasion, and sorafenib drug sensitivity.

Conclusion
Clear

Are the rationale for, and objectives of, the Systematic Review clearly stated?

Partly
Are sufficient details of the methods and analysis provided to allow replication by others?

Yes
Is the statistical analysis and its interpretation appropriate?

Not applicable
Are the conclusions drawn adequately supported by the results presented in the review?

Yes

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: Nursing, cancer, general medicine, systematic review, and meta-analysis

We confirm that we have read this submission and believe that we have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however we have significant reservations, as outlined above.

CITE

Report a concern

Author Response 06 Jun 2023

Kevin Christian Tjandra, Department of Medicine, Faculty of Medicine, Universitas Diponegoro, Semarang, 50275, Indonesia

06 Jun 2023

Author Response

This systematic review provides a comprehensive overview of the current literature regarding the use of salivary ORM1 as a biomarker for HCC related to hepatitis B. The authors provide a ... Continue reading This systematic review provides a comprehensive overview of the current literature regarding the use of salivary ORM1 as a biomarker for HCC related to hepatitis B. The authors provide a clear summary of the results of the studies included in the review and make well-supported recommendations for further research. The strengths of the article lie in the clarity of the writing, the thoroughness of the literature search, and the validity and reliability of the data analysis.

Title and abstract
Overall, I think the title and abstract provide a clear and concise overview of the systematic review. However, there are a few areas that could be improved:

Query 1
The abstract could benefit from a sentence that highlights the main objective or question of the systematic review. For example, "This systematic review aimed to investigate the diagnostic and prognostic value of salivary orosomucoid 1 (ORM1) in patients with hepatocellular carcinoma related to hepatitis B."

Response 1
The suggestion has been added in the background of the abstract
“Salivary orosomucoid 1 (ORM1) is highly increased in hepatocellular carcinoma related to hepatitis B. Thus, this systematic review aimed to investigate the diagnostic and prognostic value of salivary orosomucoid 1 (ORM1) in patients with hepatocellular carcinoma related to hepatitis B”

Query 2
It would be helpful to include the number of databases searched in the methods section, as this is an important aspect of a systematic review.

Response 2
This suggestion has been added to the method of the abstract

Query 3
The sentence "This biomarker is also able to detect the prognosis of individuals with the disease with or without chemotherapy because the higher the level of ORM1, the more liver damage occurs that leads to a poorer prognosis" could use further clarification. It is not clear how ORM1 levels relate to prognosis, and the sentence could benefit from further explanation or references to support the claims made.

Response 3
The corresponding sentence has been clarified to show the correlation between salivary ORM1 and prognosis of the prognosis. The reference from He et al is available in the discussion to support the claim of the sentence
“We included five diagnostic studies with 533 samples conducted in China and Japan. Even though limited original studies with homogenous PICO was a limitation, the evidence output of this study can still be well presented. Salivary ORM1 may be useful to detect early cancer diagnosis as rapidly increased levels of ORM1 can be observed in the early stages of HCC (four times higher than usual) and the biomarker has a sensitivity of 81.67% and a specificity of 77.5%. This biomarker is also able to detect the prognosis of individuals with the disease with or without chemotherapy. It is because level of salivary ORM1 related to liver damage, the higher the level of ORM1, the more liver damage occurs that leads to a poorer prognosis.”

Introduction
Your introduction section provides a clear and informative overview of salivary orosomucoid 1 (ORM1) and its potential role in the diagnosis and prognosis of hepatocellular carcinoma (HCC) related to hepatitis B. However, here are a few areas that could be improved:

Query 4
The introduction could benefit from a concise and clear statement of the research question or objective. For example, "The objective of this systematic review is to investigate the diagnostic and prognostic value of salivary orosomucoid 1 (ORM1) in patients with hepatocellular carcinoma related to hepatitis B, including its sensitivity and specificity as an early diagnostic biomarker, and its potential prognostic value."

Response 4
The suggestion has been added to the last paragraph of the Introduction part

Query 5
Some of the sentences could be simplified, such as "ORM1 is expressed in inflammatory injuries, infections, and stress conditions," which could be shortened to "ORM1 is produced in response to inflammation, infections, and stress."

Response 5
The Suggestion has been resolved to simplified several sentence in the introduction

Query 6
Try to avoid repeating information. For example, the discussion of the advantages of saliva as a biomarker could be consolidated into a single paragraph or sentence.

Response 6
The repeating information has been revised

Query 7
The introduction could benefit from a more concise and focused overview of the current state of knowledge regarding ORM1 and HCC related to hepatitis B. You could consider trimming some of the less essential or tangential details to keep the focus on the main topic of the review.

Response 7
The introduction has been revised to be more focus on research question and remove less essential information.

Methods
Your methods section appears to be quite comprehensive, but here are a few areas that could use some clarification or improvement:

Query 8
In the Eligibility criteria section, you mention that non-comparative research was disqualified, but it's not clear what this means. Can you provide more information about what you mean by "non-comparative research"?

Response 8
Non-comparative research means that the research with no treatment or control group. This information has been added to the eligibility criteria subsection

Query 9
In the Selection process section, it would be helpful to provide more information about why the 655 excluded studies were removed, and whether any specific criteria were used for exclusion (beyond the abstract screening and full-text retrieval).

Response 9
The more information why the 655 articles were removed has been updated “lack of relevant information related to the research question (diagnostic and prognostic value of salivary orosomucoid 1 (ORM1) in patients with hepatocellular carcinoma related to hepatitis B) and the study design do not meet the inclusion criteria (cohort and diagnostic study)”
We also want to confirm that we did not use any specific criteria for the exclusion, we only screened the article based on abstract and full text screening, and full text retrieval to assess whether the articles meet the inclusion or exclusion criteria.

Query 10
In the Data collection process section, it would be helpful to provide more details about how disagreements between reviewers were resolved, and whether any inter-rater reliability statistics were calculated.

Response 10
The disagreements were resolved by comprehensive discussions. Inter-rater reliability statics were not calculated in this study

Query 11
Regarding the risk of bias assessment, it would be helpful to include a brief overview of the domains assessed by the ROBINS-I tool, and how each domain was scored for each study.

Response 11
The brief overview and assessment criteria has been updated to the relevant subsection

Query 12
In the Reporting bias assessment section, it would be helpful to clarify whether any reporting bias was identified in the included studies, or whether this section simply reflects the results of the risk of bias assessment.

Response 12
We clarify that this section simply reflects the results of the risk of bias assessment.

Results and discussion
Overall, the results and discussion section is well-written and provides a clear summary of the main findings in the systematic review. The section is well-organized and provides adequate information about the salivary ORM1 biomarker, its function, and production. The discussion of the limitations of the study is also thorough and provides insight into the potential sources of bias.
In terms of strengths, the discussion highlights the methodical approach of the review process and the assessment of varied sources of evidence. The discussion also emphasizes the novel contribution of the study as the first systematic review to assess the levels of ORM1 in patients with cancer along with diagnostic and prognostic evidence.

The section provides a comprehensive overview of ORM1 as a biomarker, specifically its function and production. The discussion of the mechanism of action in cancer provides clear explanations of how salivary ORM1 could be a potential biomarker for cancers in the pancreas, bladder, and liver cancer.

Regarding the role of salivary ORM1 as an early diagnostic biomarker in hepatitis B associated with hepatocellular carcinoma, the discussion provides a clear summary of the study's findings, including the sensitivity and specificity of the biomarker. Additionally, the section highlights the potential of using a combination of salivary ORM1, α 1,3 fucosyltransferase, and AFP for detecting HCC related to hepatitis B and for assessing prognosis, microvascular invasion, and sorafenib drug sensitivity.

This systematic review provides a comprehensive overview of the current literature regarding the use of salivary ORM1 as a biomarker for HCC related to hepatitis B. The authors provide a clear summary of the results of the studies included in the review and make well-supported recommendations for further research. The strengths of the article lie in the clarity of the writing, the thoroughness of the literature search, and the validity and reliability of the data analysis.

Title and abstract
Overall, I think the title and abstract provide a clear and concise overview of the systematic review. However, there are a few areas that could be improved:

Query 1
The abstract could benefit from a sentence that highlights the main objective or question of the systematic review. For example, "This systematic review aimed to investigate the diagnostic and prognostic value of salivary orosomucoid 1 (ORM1) in patients with hepatocellular carcinoma related to hepatitis B."

Response 1
The suggestion has been added in the background of the abstract
“Salivary orosomucoid 1 (ORM1) is highly increased in hepatocellular carcinoma related to hepatitis B. Thus, this systematic review aimed to investigate the diagnostic and prognostic value of salivary orosomucoid 1 (ORM1) in patients with hepatocellular carcinoma related to hepatitis B”

Query 2
It would be helpful to include the number of databases searched in the methods section, as this is an important aspect of a systematic review.

Response 2
This suggestion has been added to the method of the abstract

Query 3
The sentence "This biomarker is also able to detect the prognosis of individuals with the disease with or without chemotherapy because the higher the level of ORM1, the more liver damage occurs that leads to a poorer prognosis" could use further clarification. It is not clear how ORM1 levels relate to prognosis, and the sentence could benefit from further explanation or references to support the claims made.

Response 3
The corresponding sentence has been clarified to show the correlation between salivary ORM1 and prognosis of the prognosis. The reference from He et al is available in the discussion to support the claim of the sentence
“We included five diagnostic studies with 533 samples conducted in China and Japan. Even though limited original studies with homogenous PICO was a limitation, the evidence output of this study can still be well presented. Salivary ORM1 may be useful to detect early cancer diagnosis as rapidly increased levels of ORM1 can be observed in the early stages of HCC (four times higher than usual) and the biomarker has a sensitivity of 81.67% and a specificity of 77.5%. This biomarker is also able to detect the prognosis of individuals with the disease with or without chemotherapy. It is because level of salivary ORM1 related to liver damage, the higher the level of ORM1, the more liver damage occurs that leads to a poorer prognosis.”

Introduction
Your introduction section provides a clear and informative overview of salivary orosomucoid 1 (ORM1) and its potential role in the diagnosis and prognosis of hepatocellular carcinoma (HCC) related to hepatitis B. However, here are a few areas that could be improved:

Query 4
The introduction could benefit from a concise and clear statement of the research question or objective. For example, "The objective of this systematic review is to investigate the diagnostic and prognostic value of salivary orosomucoid 1 (ORM1) in patients with hepatocellular carcinoma related to hepatitis B, including its sensitivity and specificity as an early diagnostic biomarker, and its potential prognostic value."

Response 4
The suggestion has been added to the last paragraph of the Introduction part

Query 5
Some of the sentences could be simplified, such as "ORM1 is expressed in inflammatory injuries, infections, and stress conditions," which could be shortened to "ORM1 is produced in response to inflammation, infections, and stress."

Response 5
The Suggestion has been resolved to simplified several sentence in the introduction

Query 6
Try to avoid repeating information. For example, the discussion of the advantages of saliva as a biomarker could be consolidated into a single paragraph or sentence.

Response 6
The repeating information has been revised

Query 7
The introduction could benefit from a more concise and focused overview of the current state of knowledge regarding ORM1 and HCC related to hepatitis B. You could consider trimming some of the less essential or tangential details to keep the focus on the main topic of the review.

Response 7
The introduction has been revised to be more focus on research question and remove less essential information.

Methods
Your methods section appears to be quite comprehensive, but here are a few areas that could use some clarification or improvement:

Query 8
In the Eligibility criteria section, you mention that non-comparative research was disqualified, but it's not clear what this means. Can you provide more information about what you mean by "non-comparative research"?

Response 8
Non-comparative research means that the research with no treatment or control group. This information has been added to the eligibility criteria subsection

Query 9
In the Selection process section, it would be helpful to provide more information about why the 655 excluded studies were removed, and whether any specific criteria were used for exclusion (beyond the abstract screening and full-text retrieval).

Response 9
The more information why the 655 articles were removed has been updated “lack of relevant information related to the research question (diagnostic and prognostic value of salivary orosomucoid 1 (ORM1) in patients with hepatocellular carcinoma related to hepatitis B) and the study design do not meet the inclusion criteria (cohort and diagnostic study)”
We also want to confirm that we did not use any specific criteria for the exclusion, we only screened the article based on abstract and full text screening, and full text retrieval to assess whether the articles meet the inclusion or exclusion criteria.

Query 10
In the Data collection process section, it would be helpful to provide more details about how disagreements between reviewers were resolved, and whether any inter-rater reliability statistics were calculated.

Response 10
The disagreements were resolved by comprehensive discussions. Inter-rater reliability statics were not calculated in this study

Query 11
Regarding the risk of bias assessment, it would be helpful to include a brief overview of the domains assessed by the ROBINS-I tool, and how each domain was scored for each study.

Response 11
The brief overview and assessment criteria has been updated to the relevant subsection

Query 12
In the Reporting bias assessment section, it would be helpful to clarify whether any reporting bias was identified in the included studies, or whether this section simply reflects the results of the risk of bias assessment.

Response 12
We clarify that this section simply reflects the results of the risk of bias assessment.

Results and discussion
Overall, the results and discussion section is well-written and provides a clear summary of the main findings in the systematic review. The section is well-organized and provides adequate information about the salivary ORM1 biomarker, its function, and production. The discussion of the limitations of the study is also thorough and provides insight into the potential sources of bias.
In terms of strengths, the discussion highlights the methodical approach of the review process and the assessment of varied sources of evidence. The discussion also emphasizes the novel contribution of the study as the first systematic review to assess the levels of ORM1 in patients with cancer along with diagnostic and prognostic evidence.

The section provides a comprehensive overview of ORM1 as a biomarker, specifically its function and production. The discussion of the mechanism of action in cancer provides clear explanations of how salivary ORM1 could be a potential biomarker for cancers in the pancreas, bladder, and liver cancer.

Regarding the role of salivary ORM1 as an early diagnostic biomarker in hepatitis B associated with hepatocellular carcinoma, the discussion provides a clear summary of the study's findings, including the sensitivity and specificity of the biomarker. Additionally, the section highlights the potential of using a combination of salivary ORM1, α 1,3 fucosyltransferase, and AFP for detecting HCC related to hepatitis B and for assessing prognosis, microvascular invasion, and sorafenib drug sensitivity.

Competing Interests: No competing interests were disclosed. Close
Report a concern
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COMMENTS ON THIS REPORT

Author Response 06 Jun 2023

Kevin Christian Tjandra, Department of Medicine, Faculty of Medicine, Universitas Diponegoro, Semarang, 50275, Indonesia

06 Jun 2023

Author Response

This systematic review provides a comprehensive overview of the current literature regarding the use of salivary ORM1 as a biomarker for HCC related to hepatitis B. The authors provide a ... Continue reading This systematic review provides a comprehensive overview of the current literature regarding the use of salivary ORM1 as a biomarker for HCC related to hepatitis B. The authors provide a clear summary of the results of the studies included in the review and make well-supported recommendations for further research. The strengths of the article lie in the clarity of the writing, the thoroughness of the literature search, and the validity and reliability of the data analysis.

Title and abstract
Overall, I think the title and abstract provide a clear and concise overview of the systematic review. However, there are a few areas that could be improved:

Query 1
The abstract could benefit from a sentence that highlights the main objective or question of the systematic review. For example, "This systematic review aimed to investigate the diagnostic and prognostic value of salivary orosomucoid 1 (ORM1) in patients with hepatocellular carcinoma related to hepatitis B."

Response 1
The suggestion has been added in the background of the abstract
“Salivary orosomucoid 1 (ORM1) is highly increased in hepatocellular carcinoma related to hepatitis B. Thus, this systematic review aimed to investigate the diagnostic and prognostic value of salivary orosomucoid 1 (ORM1) in patients with hepatocellular carcinoma related to hepatitis B”

Query 2
It would be helpful to include the number of databases searched in the methods section, as this is an important aspect of a systematic review.

Response 2
This suggestion has been added to the method of the abstract

Query 3
The sentence "This biomarker is also able to detect the prognosis of individuals with the disease with or without chemotherapy because the higher the level of ORM1, the more liver damage occurs that leads to a poorer prognosis" could use further clarification. It is not clear how ORM1 levels relate to prognosis, and the sentence could benefit from further explanation or references to support the claims made.

Response 3
The corresponding sentence has been clarified to show the correlation between salivary ORM1 and prognosis of the prognosis. The reference from He et al is available in the discussion to support the claim of the sentence
“We included five diagnostic studies with 533 samples conducted in China and Japan. Even though limited original studies with homogenous PICO was a limitation, the evidence output of this study can still be well presented. Salivary ORM1 may be useful to detect early cancer diagnosis as rapidly increased levels of ORM1 can be observed in the early stages of HCC (four times higher than usual) and the biomarker has a sensitivity of 81.67% and a specificity of 77.5%. This biomarker is also able to detect the prognosis of individuals with the disease with or without chemotherapy. It is because level of salivary ORM1 related to liver damage, the higher the level of ORM1, the more liver damage occurs that leads to a poorer prognosis.”

Introduction
Your introduction section provides a clear and informative overview of salivary orosomucoid 1 (ORM1) and its potential role in the diagnosis and prognosis of hepatocellular carcinoma (HCC) related to hepatitis B. However, here are a few areas that could be improved:

Query 4
The introduction could benefit from a concise and clear statement of the research question or objective. For example, "The objective of this systematic review is to investigate the diagnostic and prognostic value of salivary orosomucoid 1 (ORM1) in patients with hepatocellular carcinoma related to hepatitis B, including its sensitivity and specificity as an early diagnostic biomarker, and its potential prognostic value."

Response 4
The suggestion has been added to the last paragraph of the Introduction part

Query 5
Some of the sentences could be simplified, such as "ORM1 is expressed in inflammatory injuries, infections, and stress conditions," which could be shortened to "ORM1 is produced in response to inflammation, infections, and stress."

Response 5
The Suggestion has been resolved to simplified several sentence in the introduction

Query 6
Try to avoid repeating information. For example, the discussion of the advantages of saliva as a biomarker could be consolidated into a single paragraph or sentence.

Response 6
The repeating information has been revised

Query 7
The introduction could benefit from a more concise and focused overview of the current state of knowledge regarding ORM1 and HCC related to hepatitis B. You could consider trimming some of the less essential or tangential details to keep the focus on the main topic of the review.

Response 7
The introduction has been revised to be more focus on research question and remove less essential information.

Methods
Your methods section appears to be quite comprehensive, but here are a few areas that could use some clarification or improvement:

Query 8
In the Eligibility criteria section, you mention that non-comparative research was disqualified, but it's not clear what this means. Can you provide more information about what you mean by "non-comparative research"?

Response 8
Non-comparative research means that the research with no treatment or control group. This information has been added to the eligibility criteria subsection

Query 9
In the Selection process section, it would be helpful to provide more information about why the 655 excluded studies were removed, and whether any specific criteria were used for exclusion (beyond the abstract screening and full-text retrieval).

Response 9
The more information why the 655 articles were removed has been updated “lack of relevant information related to the research question (diagnostic and prognostic value of salivary orosomucoid 1 (ORM1) in patients with hepatocellular carcinoma related to hepatitis B) and the study design do not meet the inclusion criteria (cohort and diagnostic study)”
We also want to confirm that we did not use any specific criteria for the exclusion, we only screened the article based on abstract and full text screening, and full text retrieval to assess whether the articles meet the inclusion or exclusion criteria.

Query 10
In the Data collection process section, it would be helpful to provide more details about how disagreements between reviewers were resolved, and whether any inter-rater reliability statistics were calculated.

Response 10
The disagreements were resolved by comprehensive discussions. Inter-rater reliability statics were not calculated in this study

Query 11
Regarding the risk of bias assessment, it would be helpful to include a brief overview of the domains assessed by the ROBINS-I tool, and how each domain was scored for each study.

Response 11
The brief overview and assessment criteria has been updated to the relevant subsection

Query 12
In the Reporting bias assessment section, it would be helpful to clarify whether any reporting bias was identified in the included studies, or whether this section simply reflects the results of the risk of bias assessment.

Response 12
We clarify that this section simply reflects the results of the risk of bias assessment.

Results and discussion
Overall, the results and discussion section is well-written and provides a clear summary of the main findings in the systematic review. The section is well-organized and provides adequate information about the salivary ORM1 biomarker, its function, and production. The discussion of the limitations of the study is also thorough and provides insight into the potential sources of bias.
In terms of strengths, the discussion highlights the methodical approach of the review process and the assessment of varied sources of evidence. The discussion also emphasizes the novel contribution of the study as the first systematic review to assess the levels of ORM1 in patients with cancer along with diagnostic and prognostic evidence.

The section provides a comprehensive overview of ORM1 as a biomarker, specifically its function and production. The discussion of the mechanism of action in cancer provides clear explanations of how salivary ORM1 could be a potential biomarker for cancers in the pancreas, bladder, and liver cancer.

Regarding the role of salivary ORM1 as an early diagnostic biomarker in hepatitis B associated with hepatocellular carcinoma, the discussion provides a clear summary of the study's findings, including the sensitivity and specificity of the biomarker. Additionally, the section highlights the potential of using a combination of salivary ORM1, α 1,3 fucosyltransferase, and AFP for detecting HCC related to hepatitis B and for assessing prognosis, microvascular invasion, and sorafenib drug sensitivity.

This systematic review provides a comprehensive overview of the current literature regarding the use of salivary ORM1 as a biomarker for HCC related to hepatitis B. The authors provide a clear summary of the results of the studies included in the review and make well-supported recommendations for further research. The strengths of the article lie in the clarity of the writing, the thoroughness of the literature search, and the validity and reliability of the data analysis.

Title and abstract
Overall, I think the title and abstract provide a clear and concise overview of the systematic review. However, there are a few areas that could be improved:

Query 1
The abstract could benefit from a sentence that highlights the main objective or question of the systematic review. For example, "This systematic review aimed to investigate the diagnostic and prognostic value of salivary orosomucoid 1 (ORM1) in patients with hepatocellular carcinoma related to hepatitis B."

Response 1
The suggestion has been added in the background of the abstract
“Salivary orosomucoid 1 (ORM1) is highly increased in hepatocellular carcinoma related to hepatitis B. Thus, this systematic review aimed to investigate the diagnostic and prognostic value of salivary orosomucoid 1 (ORM1) in patients with hepatocellular carcinoma related to hepatitis B”

Query 2
It would be helpful to include the number of databases searched in the methods section, as this is an important aspect of a systematic review.

Response 2
This suggestion has been added to the method of the abstract

Query 3
The sentence "This biomarker is also able to detect the prognosis of individuals with the disease with or without chemotherapy because the higher the level of ORM1, the more liver damage occurs that leads to a poorer prognosis" could use further clarification. It is not clear how ORM1 levels relate to prognosis, and the sentence could benefit from further explanation or references to support the claims made.

Response 3
The corresponding sentence has been clarified to show the correlation between salivary ORM1 and prognosis of the prognosis. The reference from He et al is available in the discussion to support the claim of the sentence
“We included five diagnostic studies with 533 samples conducted in China and Japan. Even though limited original studies with homogenous PICO was a limitation, the evidence output of this study can still be well presented. Salivary ORM1 may be useful to detect early cancer diagnosis as rapidly increased levels of ORM1 can be observed in the early stages of HCC (four times higher than usual) and the biomarker has a sensitivity of 81.67% and a specificity of 77.5%. This biomarker is also able to detect the prognosis of individuals with the disease with or without chemotherapy. It is because level of salivary ORM1 related to liver damage, the higher the level of ORM1, the more liver damage occurs that leads to a poorer prognosis.”

Introduction
Your introduction section provides a clear and informative overview of salivary orosomucoid 1 (ORM1) and its potential role in the diagnosis and prognosis of hepatocellular carcinoma (HCC) related to hepatitis B. However, here are a few areas that could be improved:

Query 4
The introduction could benefit from a concise and clear statement of the research question or objective. For example, "The objective of this systematic review is to investigate the diagnostic and prognostic value of salivary orosomucoid 1 (ORM1) in patients with hepatocellular carcinoma related to hepatitis B, including its sensitivity and specificity as an early diagnostic biomarker, and its potential prognostic value."

Response 4
The suggestion has been added to the last paragraph of the Introduction part

Query 5
Some of the sentences could be simplified, such as "ORM1 is expressed in inflammatory injuries, infections, and stress conditions," which could be shortened to "ORM1 is produced in response to inflammation, infections, and stress."

Response 5
The Suggestion has been resolved to simplified several sentence in the introduction

Query 6
Try to avoid repeating information. For example, the discussion of the advantages of saliva as a biomarker could be consolidated into a single paragraph or sentence.

Response 6
The repeating information has been revised

Query 7
The introduction could benefit from a more concise and focused overview of the current state of knowledge regarding ORM1 and HCC related to hepatitis B. You could consider trimming some of the less essential or tangential details to keep the focus on the main topic of the review.

Response 7
The introduction has been revised to be more focus on research question and remove less essential information.

Methods
Your methods section appears to be quite comprehensive, but here are a few areas that could use some clarification or improvement:

Query 8
In the Eligibility criteria section, you mention that non-comparative research was disqualified, but it's not clear what this means. Can you provide more information about what you mean by "non-comparative research"?

Response 8
Non-comparative research means that the research with no treatment or control group. This information has been added to the eligibility criteria subsection

Query 9
In the Selection process section, it would be helpful to provide more information about why the 655 excluded studies were removed, and whether any specific criteria were used for exclusion (beyond the abstract screening and full-text retrieval).

Response 9
The more information why the 655 articles were removed has been updated “lack of relevant information related to the research question (diagnostic and prognostic value of salivary orosomucoid 1 (ORM1) in patients with hepatocellular carcinoma related to hepatitis B) and the study design do not meet the inclusion criteria (cohort and diagnostic study)”
We also want to confirm that we did not use any specific criteria for the exclusion, we only screened the article based on abstract and full text screening, and full text retrieval to assess whether the articles meet the inclusion or exclusion criteria.

Query 10
In the Data collection process section, it would be helpful to provide more details about how disagreements between reviewers were resolved, and whether any inter-rater reliability statistics were calculated.

Response 10
The disagreements were resolved by comprehensive discussions. Inter-rater reliability statics were not calculated in this study

Query 11
Regarding the risk of bias assessment, it would be helpful to include a brief overview of the domains assessed by the ROBINS-I tool, and how each domain was scored for each study.

Response 11
The brief overview and assessment criteria has been updated to the relevant subsection

Query 12
In the Reporting bias assessment section, it would be helpful to clarify whether any reporting bias was identified in the included studies, or whether this section simply reflects the results of the risk of bias assessment.

Response 12
We clarify that this section simply reflects the results of the risk of bias assessment.

Results and discussion
Overall, the results and discussion section is well-written and provides a clear summary of the main findings in the systematic review. The section is well-organized and provides adequate information about the salivary ORM1 biomarker, its function, and production. The discussion of the limitations of the study is also thorough and provides insight into the potential sources of bias.
In terms of strengths, the discussion highlights the methodical approach of the review process and the assessment of varied sources of evidence. The discussion also emphasizes the novel contribution of the study as the first systematic review to assess the levels of ORM1 in patients with cancer along with diagnostic and prognostic evidence.

The section provides a comprehensive overview of ORM1 as a biomarker, specifically its function and production. The discussion of the mechanism of action in cancer provides clear explanations of how salivary ORM1 could be a potential biomarker for cancers in the pancreas, bladder, and liver cancer.

Regarding the role of salivary ORM1 as an early diagnostic biomarker in hepatitis B associated with hepatocellular carcinoma, the discussion provides a clear summary of the study's findings, including the sensitivity and specificity of the biomarker. Additionally, the section highlights the potential of using a combination of salivary ORM1, α 1,3 fucosyltransferase, and AFP for detecting HCC related to hepatitis B and for assessing prognosis, microvascular invasion, and sorafenib drug sensitivity.

Competing Interests: No competing interests were disclosed. Close
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Version 2

VERSION 2 PUBLISHED 14 Apr 2023

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	1	2
Version 2 (revision) 06 Jun 23	read	read
Version 1 14 Apr 23	read

Maria Komariah, Universitas Padjadjaran, Bandung, Indonesia

Sidik Maulana, Universitas Padjadjaran, Bandung, Indonesia
Antonio Giovanni Solimando, Guido Baccelli Unit of Internal Medicine, Aldo Moro University of Bari, Bari, Italy

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Reviewer Report

4 Views

17 May 2024 | for Version 2

Antonio Giovanni Solimando, Department of Precision and Regenerative Medicine and Ionian Area—(DiMePRe-J), School of Medicine, Guido Baccelli Unit of Internal Medicine, Aldo Moro University of Bari, Bari, Italy

4 Views Cite this report Responses(0)

Not Approved

Background: The authors conducted a systematic review to explore the diagnostic and prognostic value of salivary orosomucoid 1 (ORM1) in patients with hepatocellular carcinoma (HCC) related to hepatitis B. This is important because previous research has shown that ORM1 levels are significantly elevated in HCC patients with hepatitis B.
Methods: The authors searched four databases (ProQuest, Google Scholar, Springer, and ScienceDirect) for original articles published between 2013 and January 2023. They focused on observational cohort or diagnostic studies that met specific inclusion criteria. Various exclusion criteria were applied to ensure the relevance of the selected articles. The authors assessed bias using the ROBINS-I tool and organized the results using the PICOS criteria in a Google spreadsheet. The systematic review adhered to the PRISMA guidelines.
Results: The authors identified five diagnostic studies conducted in China and Japan, which collectively involved 533 samples. However, they noted a limitation in terms of the limited number of original studies with homogenous PICOS criteria. Nevertheless, the evidence presented in this study was considered substantial. The findings suggested that salivary ORM1 could be a valuable tool for early cancer detection, as its levels rapidly increase in the early stages of HCC, reaching four times the usual levels. The biomarker exhibited a sensitivity of 81.67% and a specificity of 77.5%. Furthermore, salivary ORM1 was found to be indicative of prognosis in HCC patients, regardless of whether they received chemotherapy. Higher levels of ORM1 were associated with greater liver damage and a poorer prognosis.
Conclusions: Based on the systematic review, the authors concluded that salivary ORM1 has the potential to serve as an early diagnostic biomarker for HCC associated with hepatitis B. Additionally, it can be used as a prognostic biomarker for the disease. The study was registered on the Open Science Framework (OSF) on March 16, 2023.
Limitations:

Study Design Limitation: The systematic review focused on observational cohort and diagnostic studies, excluding other study designs such as randomized controlled trials (RCTs). By excluding RCTs, which are considered the gold standard for evaluating diagnostic and prognostic tests, the review may have missed important evidence on the diagnostic and prognostic value of salivary ORM1. RCTs provide a higher level of evidence for assessing the accuracy and effectiveness of interventions. Including RCTs in the review would have strengthened the overall evidence base and provided a more robust evaluation of the diagnostic and prognostic value of salivary ORM1.
Search Strategy and Database Selection: Although the authors searched multiple databases, including ProQuest, Google Scholar, Springer, and ScienceDirect, there is a possibility that some relevant articles may have been missed. The search strategy may not have captured all relevant studies due to the specific keywords and databases used. To enhance the comprehensiveness of the search, the authors could have considered including additional databases, such as PubMed or Embase, to ensure a more thorough coverage of the literature. Moreover, the exclusion of non-full-text articles may have led to the exclusion of potentially relevant information, as abstracts or summaries often contain valuable data.
Heterogeneity and Generalizability: The systematic review included a limited number of original studies with homogenous PICOS criteria, which may limit the generalizability of the findings. The studies included in the review were conducted in China and Japan, which could introduce geographical and ethnic biases. Additionally, the review focused on patients with hepatocellular carcinoma related to hepatitis B, which may limit the applicability of the findings to other populations or subtypes of liver cancer. Including studies from diverse populations and different etiologies of liver cancer would have provided a broader perspective on the diagnostic and prognostic value of salivary ORM1.

Suggestions:

Expanded Study Designs: To provide a more comprehensive assessment of the diagnostic and prognostic value of salivary ORM1, the authors could consider including other study designs, such as randomized controlled trials (RCTs), in future reviews. RCTs provide a higher level of evidence and allow for a more rigorous evaluation of the accuracy and effectiveness of diagnostic tests. Including RCTs would enhance the overall quality and reliability of the evidence synthesis.
Comprehensive Search Strategy: To ensure a more comprehensive search, the authors could consider expanding the search strategy by including additional databases, such as PubMed or Embase. This would help capture a wider range of relevant articles and minimize the risk of missing key studies. Additionally, considering alternative search methods, such as hand-searching reference lists of relevant articles or contacting experts in the field, could further enhance the completeness of the literature search.
Inclusion of Non-English Studies: To reduce language bias and capture relevant research conducted in languages other than English, the authors should consider including non-English articles in future reviews. This would provide a more diverse and inclusive representation of the available evidence and increase the generalizability of the findings.
Addressing Heterogeneity: To improve the generalizability of the findings, future reviews could aim to include studies from different geographical locations and diverse populations, encompassing various etiologies of liver cancer. This would allow for a more comprehensive understanding of the diagnostic and prognostic value of salivary ORM1 across different patient populations.
Meta-analysis and Subgroup Analysis: If feasible, the authors could consider conducting a meta-analysis to quantitatively synthesize the results of the included studies. This would provide a pooled estimate of the diagnostic accuracy or prognostic value of salivary ORM1. Additionally, subgroup analysis based on different patient characteristics, such as disease stage or treatment status, could help identify potential sources of heterogeneity and explore the impact of these factors on the diagnostic and prognostic performance of salivary ORM1.A systematic review on the second-line treatment in hepatocellular carcinoma (HCC) and immune checkpoint inhibitor (ICI) anti-angiogenesis therapy aims to evaluate the efficacy and safety of this treatment approach. The review will search relevant databases for studies that investigate ICI anti-angiogenesis therapy as a second-line treatment in HCC patients. The included studies will be analyzed to determine outcomes such as overall survival, progression-free survival, response rates, and adverse events. The review will provide a comprehensive synthesis of the findings and discuss their clinical implications. Limitations, potential biases, and areas for further research will also be addressed. Ultimately, the review aims to inform clinical practice and identify the need for future research in this area. Please refer to Solimando AG, et. al. 2022 (Ref 2) and similar and expand the introduction and discussion sections.

Are the rationale for, and objectives of, the Systematic Review clearly stated?

Yes
Are sufficient details of the methods and analysis provided to allow replication by others?

Yes
Is the statistical analysis and its interpretation appropriate?

Yes
Are the conclusions drawn adequately supported by the results presented in the review?

Yes
If this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.)

Yes

References

1. Rimassa L, Wörns MA: Navigating the new landscape of second-line treatment in advanced hepatocellular carcinoma.Liver Int. 2020; 40 (8): 1800-1811 PubMed Abstract | Publisher Full Text
2. Solimando AG, Susca N, Argentiero A, Brunetti O, et al.: Second-line treatments for Advanced Hepatocellular Carcinoma: A Systematic Review and Bayesian Network Meta-analysis.Clin Exp Med. 2022; 22 (1): 65-74 PubMed Abstract | Publisher Full Text

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

Cancer. Miceroenvironment. Myeloma.

I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above.

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Reviewer Report

3 Views

08 Jun 2023 | for Version 2

Maria Komariah, Department of Fundamental Nursing, Faculty of Nursing, Universitas Padjadjaran, Bandung, West Java, Indonesia

3 Views Cite this report Responses(0)

Approved

The authors have done a good job to revise the manuscript rendering it appropriate for indexing.

Competing Interests

No competing interests were disclosed.

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

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Reviewer Report

13 Views

28 Apr 2023 | for Version 1

Maria Komariah, Department of Fundamental Nursing, Faculty of Nursing, Universitas Padjadjaran, Bandung, West Java, Indonesia

Sidik Maulana, Faculty of Nursing, Universitas Padjadjaran, Bandung, West Java, Indonesia

13 Views Cite this report Responses(1)

Approved With Reservations

The abstract could benefit from a sentence that highlights the main objective or question of the systematic review. For example, "This systematic review aimed to investigate the diagnostic and prognostic value of salivary orosomucoid 1 (ORM1) in patients with hepatocellular carcinoma related to hepatitis B."
It would be helpful to include the number of databases searched in the methods section, as this is an important aspect of a systematic review.
The sentence "This biomarker is also able to detect the prognosis of individuals with the disease with or without chemotherapy because the higher the level of ORM1, the more liver damage occurs that leads to a poorer prognosis" could use further clarification. It is not clear how ORM1 levels relate to prognosis, and the sentence could benefit from further explanation or references to support the claims made.

The introduction could benefit from a concise and clear statement of the research question or objective. For example, "The objective of this systematic review is to investigate the diagnostic and prognostic value of salivary orosomucoid 1 (ORM1) in patients with hepatocellular carcinoma related to hepatitis B, including its sensitivity and specificity as an early diagnostic biomarker, and its potential prognostic value."
Some of the sentences could be simplified, such as "ORM1 is expressed in inflammatory injuries, infections, and stress conditions," which could be shortened to "ORM1 is produced in response to inflammation, infections, and stress."
Try to avoid repeating information. For example, the discussion of the advantages of saliva as a biomarker could be consolidated into a single paragraph or sentence.
The introduction could benefit from a more concise and focused overview of the current state of knowledge regarding ORM1 and HCC related to hepatitis B. You could consider trimming some of the less essential or tangential details to keep the focus on the main topic of the review.

Methods
Your methods section appears to be quite comprehensive, but here are a few areas that could use some clarification or improvement:

In the Eligibility criteria section, you mention that non-comparative research was disqualified, but it's not clear what this means. Can you provide more information about what you mean by "non-comparative research"?
In the Selection process section, it would be helpful to provide more information about why the 655 excluded studies were removed, and whether any specific criteria were used for exclusion (beyond the abstract screening and full-text retrieval).
In the Data collection process section, it would be helpful to provide more details about how disagreements between reviewers were resolved, and whether any inter-rater reliability statistics were calculated.
Regarding the risk of bias assessment, it would be helpful to include a brief overview of the domains assessed by the ROBINS-I tool, and how each domain was scored for each study.
In the Reporting bias assessment section, it would be helpful to clarify whether any reporting bias was identified in the included studies, or whether this section simply reflects the results of the risk of bias assessment.

Are the rationale for, and objectives of, the Systematic Review clearly stated?

Partly
Are sufficient details of the methods and analysis provided to allow replication by others?

Yes
Is the statistical analysis and its interpretation appropriate?

Not applicable
Are the conclusions drawn adequately supported by the results presented in the review?

Yes

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

Nursing, cancer, general medicine, systematic review, and meta-analysis

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Responses (1)

Author Response

06 Jun 2023

Kevin Christian Tjandra, Department of Medicine, Faculty of Medicine, Universitas Diponegoro, Semarang, 50275, Indonesia

This systematic review provides a comprehensive overview of the current literature regarding the use of salivary ORM1 as a biomarker for HCC related to hepatitis B. The authors provide a clear summary of the results of the studies included in the review and make well-supported recommendations for further research. The strengths of the article lie in the clarity of the writing, the thoroughness of the literature search, and the validity and reliability of the data analysis.

Title and abstract
Overall, I think the title and abstract provide a clear and concise overview of the systematic review. However, there are a few areas that could be improved:

Query 1
The abstract could benefit from a sentence that highlights the main objective or question of the systematic review. For example, "This systematic review aimed to investigate the diagnostic and prognostic value of salivary orosomucoid 1 (ORM1) in patients with hepatocellular carcinoma related to hepatitis B."

Response 1
The suggestion has been added in the background of the abstract
“Salivary orosomucoid 1 (ORM1) is highly increased in hepatocellular carcinoma related to hepatitis B. Thus, this systematic review aimed to investigate the diagnostic and prognostic value of salivary orosomucoid 1 (ORM1) in patients with hepatocellular carcinoma related to hepatitis B”

Query 2
It would be helpful to include the number of databases searched in the methods section, as this is an important aspect of a systematic review.

Response 2
This suggestion has been added to the method of the abstract

Query 3
The sentence "This biomarker is also able to detect the prognosis of individuals with the disease with or without chemotherapy because the higher the level of ORM1, the more liver damage occurs that leads to a poorer prognosis" could use further clarification. It is not clear how ORM1 levels relate to prognosis, and the sentence could benefit from further explanation or references to support the claims made.

Response 3
The corresponding sentence has been clarified to show the correlation between salivary ORM1 and prognosis of the prognosis. The reference from He et al is available in the discussion to support the claim of the sentence
“We included five diagnostic studies with 533 samples conducted in China and Japan. Even though limited original studies with homogenous PICO was a limitation, the evidence output of this study can still be well presented. Salivary ORM1 may be useful to detect early cancer diagnosis as rapidly increased levels of ORM1 can be observed in the early stages of HCC (four times higher than usual) and the biomarker has a sensitivity of 81.67% and a specificity of 77.5%. This biomarker is also able to detect the prognosis of individuals with the disease with or without chemotherapy. It is because level of salivary ORM1 related to liver damage, the higher the level of ORM1, the more liver damage occurs that leads to a poorer prognosis.”

Introduction
Your introduction section provides a clear and informative overview of salivary orosomucoid 1 (ORM1) and its potential role in the diagnosis and prognosis of hepatocellular carcinoma (HCC) related to hepatitis B. However, here are a few areas that could be improved:

Query 4
The introduction could benefit from a concise and clear statement of the research question or objective. For example, "The objective of this systematic review is to investigate the diagnostic and prognostic value of salivary orosomucoid 1 (ORM1) in patients with hepatocellular carcinoma related to hepatitis B, including its sensitivity and specificity as an early diagnostic biomarker, and its potential prognostic value."

Response 4
The suggestion has been added to the last paragraph of the Introduction part

Query 5
Some of the sentences could be simplified, such as "ORM1 is expressed in inflammatory injuries, infections, and stress conditions," which could be shortened to "ORM1 is produced in response to inflammation, infections, and stress."

Response 5
The Suggestion has been resolved to simplified several sentence in the introduction

Query 6
Try to avoid repeating information. For example, the discussion of the advantages of saliva as a biomarker could be consolidated into a single paragraph or sentence.

Response 6
The repeating information has been revised

Query 7
The introduction could benefit from a more concise and focused overview of the current state of knowledge regarding ORM1 and HCC related to hepatitis B. You could consider trimming some of the less essential or tangential details to keep the focus on the main topic of the review.

Response 7
The introduction has been revised to be more focus on research question and remove less essential information.

Methods
Your methods section appears to be quite comprehensive, but here are a few areas that could use some clarification or improvement:

Query 8
In the Eligibility criteria section, you mention that non-comparative research was disqualified, but it's not clear what this means. Can you provide more information about what you mean by "non-comparative research"?

Response 8
Non-comparative research means that the research with no treatment or control group. This information has been added to the eligibility criteria subsection

Query 9
In the Selection process section, it would be helpful to provide more information about why the 655 excluded studies were removed, and whether any specific criteria were used for exclusion (beyond the abstract screening and full-text retrieval).

Response 9
The more information why the 655 articles were removed has been updated “lack of relevant information related to the research question (diagnostic and prognostic value of salivary orosomucoid 1 (ORM1) in patients with hepatocellular carcinoma related to hepatitis B) and the study design do not meet the inclusion criteria (cohort and diagnostic study)”
We also want to confirm that we did not use any specific criteria for the exclusion, we only screened the article based on abstract and full text screening, and full text retrieval to assess whether the articles meet the inclusion or exclusion criteria.

Query 10
In the Data collection process section, it would be helpful to provide more details about how disagreements between reviewers were resolved, and whether any inter-rater reliability statistics were calculated.

Response 10
The disagreements were resolved by comprehensive discussions. Inter-rater reliability statics were not calculated in this study

Query 11
Regarding the risk of bias assessment, it would be helpful to include a brief overview of the domains assessed by the ROBINS-I tool, and how each domain was scored for each study.

Response 11
The brief overview and assessment criteria has been updated to the relevant subsection

Query 12
In the Reporting bias assessment section, it would be helpful to clarify whether any reporting bias was identified in the included studies, or whether this section simply reflects the results of the risk of bias assessment.

Response 12
We clarify that this section simply reflects the results of the risk of bias assessment.

Results and discussion
Overall, the results and discussion section is well-written and provides a clear summary of the main findings in the systematic review. The section is well-organized and provides adequate information about the salivary ORM1 biomarker, its function, and production. The discussion of the limitations of the study is also thorough and provides insight into the potential sources of bias.
In terms of strengths, the discussion highlights the methodical approach of the review process and the assessment of varied sources of evidence. The discussion also emphasizes the novel contribution of the study as the first systematic review to assess the levels of ORM1 in patients with cancer along with diagnostic and prognostic evidence.

The section provides a comprehensive overview of ORM1 as a biomarker, specifically its function and production. The discussion of the mechanism of action in cancer provides clear explanations of how salivary ORM1 could be a potential biomarker for cancers in the pancreas, bladder, and liver cancer.

Regarding the role of salivary ORM1 as an early diagnostic biomarker in hepatitis B associated with hepatocellular carcinoma, the discussion provides a clear summary of the study's findings, including the sensitivity and specificity of the biomarker. Additionally, the section highlights the potential of using a combination of salivary ORM1, α 1,3 fucosyltransferase, and AFP for detecting HCC related to hepatitis B and for assessing prognosis, microvascular invasion, and sorafenib drug sensitivity.

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Competing Interests

No competing interests were disclosed.

Alongside their report, reviewers assign a status to the article:

Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested

Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.

Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions

[1] 1. Li F, Yu Z, Chen P, et al.: The increased excretion of urinary orosomucoid 1 as a useful biomarker for bladder cancer. Am. J. Cancer Res. 2016 Jan 15; 6(2): 331–340. PubMed Abstract | Free Full Text

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The role of salivary orosomucoid 1 as an early diagnostic and prognostic biomarker of hepatocellular carcinoma related to Hepatitis B: A systematic review

Abstract

Keywords

Introduction

Methods

Eligibility criteria

Data sources and search

Table 1. Keywords used for the literature search.

Selection process

Data collection process

Data items

Study risk of bias assessment (qualitative synthesis)

Reporting bias assessment

Figure 1. Risk of bias assessment result.

Results

Study selection

Figure 2. PRISMA 2020 flow diagram.

Study characteristics

Table 2. Summary of the studies included in this systematic review.

Risk of bias in studies

Study result summaries

Discussion

Statement of principal findings

Strength and limitations of the study

Overview of orosomucoid 1

Figure 3. Symbolic representation of alpha (1)-acid glycoprotein glycan structure.

Function and production of salivary ORM1

Mechanism of action in cancer

Role as early diagnostic biomarker in hepatitis B associated with hepatocellular carcinoma

Conclusions and recommendations

Data availability

Underlying data

Reporting guidelines

References

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