Diagnostic value of ASVS for insulinoma localization: A systematic review and meta-analysis.

BACKGROUND: Previous studies on the diagnostic value of arterial calcium stimulation with hepatic venous sampling (ASVS) for the localization of insulinoma have reported inconsistent results. Here, we performed a meta-analysis of the relevant published studies.
METHODS: PubMed, Embase, Web of Science, the Cochrane Library, and Wanfang Data were searched for studies on the diagnostic value of ASVS in insulinoma localization published up to May 2019. We calculated the sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and receiver operating characteristic (ROC) curve of ASVS in the localization of insulinoma.
RESULTS: We included ten studies involving 337 patients in the study. The pooled sensitivity, specificity, PLR, and NLR were 0.93 (95% confidence interval [CI]: 0.83-0.97), 0.86 (95%CI: 0.75-0.93), 6.8(95%CI: 3.7-12.7), and 0.08 (95%CI: 0.03-0.19), respectively. The DOR was 84 (95%CI: 30-233), and the area under the ROC curve was 0.96 (95%CI: 0.94-0.97).The results of the heterogeneity of the studies (P = 0.00, I2 = 80.17) were calculated using forest plots of the DOR.
CONCLUSION: ASVS is of significant value in localization of insulinoma. If a qualitative diagnosis of insulinoma is definite and the imaging examination results are negative, ASVS should be performed to confirm the localization of insulinoma.

Introduction

Although insulinoma is the most common pancreatic cell tumor, it remains a rare disease with an annual incidence of 1/1,000,000 to 10/1,000,000 [1]. Insulinoma is characterized by the Whipple triad, with varying degrees of hypoglycemia, and severe conditions may be life-threatening. Insulinoma is usually treated with surgery [2,3]. Insulinomas are usually small in size, mostly <2 cm in diameter [4]. Intraoperative ultrasound has a very high positive detection rate, so some researchers believe that preoperative localization is unnecessary due to the possibility of intraoperative ultrasound localization of this tumor [5]. However, most researchers disagree with that opinion and believe that a definite preoperative location will help reduce surgical trauma, reduce the operation time, ensure a successful operation, and reduce surgeon and patient worries. In addition, definite preoperative localization and diagnosis can facilitate complete tumor resection and reduce the incidence of complications such as pancreatic fistula. Therefore, preoperative localization is highly recommended[6-9].

Methods for localizing insulinoma are generally divided into non-invasive and invasive tests. Computed tomography (CT), magnetic resonance imaging (MRI), and other non-invasive tests do not have high positive rates, i.e.31–57% [10,11], and the positive rate of digital subtraction angiography is 65–83% [11,12]. Endoscopic ultrasonography (EUS) is a mildly invasive test with a positive rate of 80–89% [13,14], depending greatly on the operator’s technique and experience. The above tests can detect insulinoma only morphologically, but arterial calcium stimulation with hepatic venous sampling (ASVS) can locate insulinoma functionally. ASVS is performed by selectively catheterizing the gastroduodenal artery, the superior mesenteric artery, and the proximal and distal splenic arteries; rapidly injecting calcium gluconate into these sites for stimulation; and collecting blood samples from the hepatic veins at different time points before and after the challenge. The ratios of the stimulation values to basic values are calculated, with the highest ratio treated as the peak ratio. The pancreatic region supplied by the artery with the highest peak ratio is considered the region where the tumor is located. The accuracy of localization does not depend on the tumor size, and even occult insulinoma can be detected. Therefore, localization of insulinoma by ASVS should be very accurate. However, there has been no meta-analysis of ASVS to date; accordingly, we performed the present meta-analysis to evaluate the diagnostic value of EUS for localization of insulinoma.

Methods

Data acquisition, search strategy, and inclusion and exclusion criteria

We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines[15]. PubMed, Embase, Web of Science, the Cochrane Library, and Wanfang Data were searched for studies on the value of ASVS in insulinoma localization and diagnosis published before May 2019. The following search terms were used: arterial calcium stimulation, insulinoma, localization, and pancreatic tumor. The search strategies were as follows: PubMed: (“arterial calcium stimulation” AND “insulinoma” [MeSH]); Embase: Emtree term–exploded = (insulinoma AND arterial calcium stimulation); Web of Science: TS = (insulinoma AND arterial calcium stimulation); the Cochrane Library and Wanfang: keyword = (insulinoma AND arterial calcium stimulation). Additional publications in the reference lists and citation sections of recovered articles were also searched. There were no restrictions on publication status or publication language.

Two authors of this study, Hao Wang and Ying Ba, independently searched the literature and included relevant research. To settle any disagreement, a third author (Qian Xing) joined the discussion to resolve the issue. The inclusion criteria for the study were as follows:(1) Studies reported on patients with clear diagnosis of hypoglycemia and suspected insulinoma. (2) The diagnosis of insulinoma was confirmed by postoperative pathology or by the combination of clinical manifestation (Whipple triad), laboratory tests (hyperinsulinemia) and surgery. (3) The research either showed true positives (TR), false positives (FP), false negatives (FN), and true negatives (TN), or contained data from which these values could be calculated. The exclusion criteria were: (1) incomplete data, which could not be extracted for a contingency table; (2) non-original clinical studies; (3) duplicate studies; and (4) animal studies.

Data extraction and quality evaluation

Two authors, Hao Wang and Ying Ba, independently extracted relevant information from the studies, including the authors’ names, publication year, country, study design, gold standard, apparatus, methods, true and false positives and negatives. For disagreement settlement, if necessary, a third author (Qian Xing) joined the discussion to resolve the issue. There were some studies in which patients with islet hyperplasia also had a positive response to ASVS; if a case of islet hyperplasia was involved, the three authors of this study would discuss and resolve the problem of whether to include the study in the analysis. The Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool was used for quality evaluation of each included study [16, 17]. The tool is composed of two parts: the risk of bias (four domains: patient selection, index test, reference standard, and flow and timing) and concerns regarding applicability (three domains: patient selection, index test, and reference standard). If the answers to all signaling questions for a domain were “yes,” the risk of bias was judged as “low.” If any signaling question in a domain was “no,” the risk of bias was judged as “high.” The term “unclear bias” was used only if insufficient information was supplied.

Statistical analysis

The included studies underwent quality evaluation using RevMan 5.3, followed by extracting the data from the included studies to calculate the true positive, false positive, false negative, and true negative values. Stata 14.0 software were used for statistical analysis. The bivariate effect model [18] was used to calculate the above data, followed by calculating positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and summary receiver operating characteristic (SROC) [19]. The heterogeneity between the included studies was calculated using the Q test and I2 test[20, 21]. For data with low heterogeneity (I2<50%), a fixed- effect model was used. A random-effect model was used for data with high heterogeneity (I2≥50%). Meta-regression analysis of the DOR was used to find the sources of heterogeneity to analyze factors that affected heterogeneity, including experimental design, race, publication year, and patient type [22]. We assessed potential publication bias using the funnel plots of Deeks [23]. All P-values were two-sided, with P<0.05 as the cut-off value for significance.

Results

Fig 1 shows the results of the study selection process. The initial electronic search identified 405 articles, of which 162 were excluded due to duplication. A further 210 articles were excluded due to irrelevance (articles were removed after the titles and abstracts had been read). A total of 33 potentially eligible studies remained; after reviewing the full text of the articles and browsing the results, 23 articles were excluded because of incomplete data, lack of gold standards, or incomplete description of the trial (articles were removed after the full manuscript had been read).

Fig 1

Flowchart for obtaining data for the present meta-analysis.

Eventually, ten studies involving a total of 337 patients were included in the present systematic review and meta-analysis [24-33]. Table 1 lists the characteristics of the included studies. These studies had been published form 1992 through 2010. Six studies were conducted in Europe [25,26,28,30,32,33], two studies were conducted in the USA [24,29], and the remaining two studies were conducted in China and New Zealand [27,31]. Five studies used a prospective design [24,25,26,28,31]; and five studies used a retrospective design [27,29,30,32,33]. Fig 2 shows the quality assessment results of the included studies.

Table 1

Characteristics of the studies included in the meta-analysis.

Author	Year	Country	Study design	Gold standard	Nesidioblastosis included	Calcium concentration(mEq/kg)	TP	FP	FN	TN
DoppmanJL[24]	1995	USA	Prospective	Clinic & surgery	No	0.025	22	3	3	22
OsheaD[25]	1996	UK	Prospective	Clinic & surgery	No	0.025,0.00625	5	0	1	1
DefreyneL[26]	1998	Belgium	Prospective	Clinic & surgery	No	0.025	9	2	0	7
JinZY[27]	2002	China	Retrospective	Pathology	Yes	0.025	12	0	1	3
WiesliP[28]	2004	Switzerland	Prospective	Pathology	No	0.025	14	0	0	5
GuettierJM[29]	2009	USA	Retrospective	Pathology	No	0.025	38	2	5	43
DruceMR[30]	2010	UK	Retrospective	Pathology	No	0.025	17	4	6	23
BraatvedtG[31]	2014	New Zealand	Prospective	Pathology	Yes	0.0025,0.0065	16	3	0	18
Morena J[32]	2016	France	Retrospective	Pathology	No	0.025	10	1	1	10
Moreno MP[33]	2016	Spain	Retrospective	Pathology	Yes	0.025	18	7	0	5

Fig 2

Quality assessments of the included studies.

Fig 3 presents the summarized results for sensitivity and specificity. The pooled sensitivity, specificity, PLR, and NLR were 0.93(95%confidence interval [CI]: 0.83–0.97), 0.86(95%CI: 0.75–0.93), 6.4(95%CI: 3.7–12.7), and 0.08(95%CI: 0.03–0.19), respectively. The pooled DOR of ASVS for insulinoma localization was 84(95%CI: 30–233, Fig 4). The SROC curve was 0.96(95%CI: 0.94–0.97, Fig 5). The results of the heterogeneity studies (P = 0.00, I2 = 80.17) were calculated using forests of the DOR, and threshold effects accounted for 59% of the sources of heterogeneity. Meta-regression analysis was conducted based on study design, publication year, enrolled population, ethnicity, calcium concentration, and patient type (i.e., with or without islet hyperplasia) (Fig 6). The results suggested that heterogeneity mainly derived from patient type. We determined the symmetry of the spots in the funnel plot, and Deeks’ asymmetry test showed no evidence of publication bias (P = 0.56; Fig 7).

Fig 3

Forest plots for sensitivity and specificity.

Fig 4

Forest plot for DOR.

Fig 5

Area under the ROC curve.

Fig 6

Meta-regression analysis for DOR.

Fig 7

Deeks’ plot for ASVS for localization of insulinoma.

Discussion

This article is the first meta-analysis to evaluate the diagnostic value of ASVS for insulinoma localization. Ten studies involving a total of 337 patients were included in the analysis. The sensitivity and specificity of ASVS for the localization of insulinoma were evaluated. The pooled sensitivity, specificity, and ROC were 0.93, 0.86, and 0.96, respectively, showing fairly good diagnostic efficiency. The high DOR suggested stronger discrimination ability for insulinoma localization. In addition, the area under the ROC curve was 0.96, indicating a high diagnostic accuracy rate. Therefore, ASVS is associated with high diagnostic value for preoperative localization of insulinomas, and ASVS can be combined with digital subtraction angiography and EUS to reduce the rate of misdiagnosis and improve the diagnostic value of preoperative localization of insulinoma.

Insulinoma is a functional tumor of the pancreas that can secrete insulin autonomously. ASVS does not locate insulinomas based on morphology, but does so functionally, which results in high sensitivity and specificity for the localization and diagnosis of the tumor. ASVS is highly suitable for the localization of such small but secretion-active tumors, and helps detect occult insulinomas [34]. For small and powerfully functional insulinomas, especially occult insulinomas, ASVS has higher accuracy for preoperative localization than other imaging examinations for preoperative localization. Therefore it is of great clinical value and makes it suitable as the gold standard for insulinoma localization. However, we distinguished insulinoma from islet cell hyperplasia in this article, which may have affected the specificity of our study. Insulinoma and islet cell hyperplasia differ in that neoplasms are absent from islet cell hyperplasia, but both secrete insulin, and surgery is indicated. Importantly, as we are using a meta-analysis/systematic review, we recognize that the results of the studies are highly dependent on the expertise and experience of the individual radiologists/institutions. Techniques may also have improved through the years, so not all the studies we included may be directly comparable.

ASVS may produce false positive results, The site suggested by ASVS may be inconsistent with the site confirmed by surgery, which may be attributed to vascular variation or mislocation resulting from persistent spasm after arterial intubation during surgery, leading to catheter withdrawal from the artery. If there are abnormal findings in routine examinations such as ultrasound, CT, and MRI, a corresponding arterial calcium stimulation in the suspected area can be performed first to reduce the possibilities of incorrect localization caused by calcium reflux due to arterial spasm. Different authors have used different calcium concentrations, and the effect of calcium concentration should also be further studied [35].

ASVS can locate an insulinoma regionally, but cannot locate its position precisely. Moreover, identifying a specific location is difficult if there are multiple insulinomas in the same region. If excessive insulin secretion is confirmed, but ASVS yields negative results in all areas of the pancreas, there may be an ectopic insulinoma.

Islet cell hyperplasia is usually difficult to detect on imaging examinations, while ASVS is very helpful for localization. The Mayo Clinic conducted a study to differentiate between insulinoma and islet hyperplasia by including 42 patients with insulinoma and 74 patients with islet hyperplasia and performing ASVS to observe insulin elevation after calcium gluconate. Of the 116 patients in that study, only one patient with islet hyperplasia had a non-significant increase in insulin. Insulin was elevated in the remaining 115 patients. In addition, the elevation of insulin in the patients with insulinoma was significantly higher than in the patients with islet hyperplasia. In identifying the two, maximum hepatic venous insulin concentration (mHVI) cutoffs of > 91.5 and > 263.5 IU/mL were 95 and 100% specific for insulinoma, respectively. A 19-fold increase in hepatic venous insulin concentration (rHVI) over baseline was 99% specific for insulinoma [36]. The Mayo Clinic study suggested that ASVS was quite effective in identifying insulinoma and islet hyperplasia. Pereira et al. reported a case of nodular hyperplasia in the head of the pancreas. After calcium stimulation in the superior mesenteric artery and gastroduodenal artery, the insulin levels in the blood increased by two- and seven-fold, respectively. These levels increased continuously, showing a response curve different from that of typical insulinoma [37]. In a case of mild islet cell hyperplasia in the tail and body of the pancreas, insulin secretion peaks appeared after calcium stimulation in the proximal and distal splenic artery, but they were less than twice the baseline values, The height of such peaks is considered related to the degree of hyperplasia [27]. Due to the limited number of cases, the effect of ASVS on the insulin secretion curve in islet cell hyperplasia requires further study.

While ASVS has its advantages in insulinoma localization, other methods for the localization of insulinoma also have advantages. SPECT/CT imaging is a very promising technique for insulinoma localization, and uses radionuclide-labeled glucagon-like peptide-1 receptor agonist (GLP-1RA) to bind to glucagon-like peptide-1 receptor (GLP-1R) for radionuclide imaging. Because there is high expression of GLP-1R in insulinomas, its binding to the GLP-1RA probe labeled by different radionuclides can identify the tumor location. Generally, analogues of Exendin-4 are used as the GLP-1RA probes, labeled by radionuclides such as 111In, 99Tcm, and 68Ga. Christ et al. performed preoperative SPECT/CT imaging with 111In-DOTA-Lys40-Exendin-4 in six patients suspected of insulinoma, and observed definite tumor lesions in all the cases, with lesion diameters of 9 to 18 mm. Five of the six cases were diagnosed with pancreatic insulinomas, and the remaining one with ectopic insulinoma, all of which were confirmed as benign by postoperative pathology [38]. Sowa-Staszczak et al. performed radionuclide imaging with 99Tcm-HYNIC-Lys40-Exendin-4 in 11 patients with persistent hyperinsulinemia and hypoglycemia (eight with benign insulinoma undetected by CT scans, two with malignant insulinoma, and one with islet cell hyperplasia). The radionuclide imaging successfully detected the lesions in all the cases with benign insulinoma, but failed in one case with malignant insulinoma [39]. A study showed that only 36% of malignant insulinomas express GLP-1R, resulting in a low detection rate of malignant insulinoma by GLP-1R imaging [40]. Luo et al. conducted a prospective study in which 68Ga-NOTA-Exendin-4 imaging detected 42 positive cases from 43 patients with insulinoma, with a sensitivity of 97.7% [41]. Therefore, the imaging of insulinoma using radionuclide-labeled GLP-1RA has high sensitivity for insulinoma diagnosis, and the specific binding of GLP-1RA to GLP-1R leads to a significant advantage in insulinoma localization, showing promise for use in preoperative and intraoperative localization of insulinoma, as well as its postoperative follow-up.

According to our meta-analysis, after a definite qualitative diagnosis of insulinoma, ASVS should be performed for localization. If an imaging examination yields negative results, ASVS may still be useful for insulinoma localization and for detecting occult insulinoma. This suggests that more patients with islet cell hyperplasia and non-insulinoma should be included in studies on the value of ASVS in insulinoma localization and diagnosis. Standards should be established for the dosage of calcium used for stimulation, and more studies should be conducted on the different manifestations of insulinoma and islet cell hyperplasia.

The strengths of this study are that we followed a standard protocol and used a comprehensive search strategy. We also calculated the bivariate random effects model and performed hierarchical SROC analyses. In addition, the pooled sample size was large so the present findings are more robust than any individual study. Lastly, heterogeneity was explored using meta-regression analysis. This indicated that the heterogeneity observed was due to different patient types.

The limitations of this study are as follows: First, data on the patients’ characteristics were not available, which might have affected the diagnostic value of ASVS. Second, we used summarized data, which restricted detailed analysis. Finally, the present study is based on published studies, and publication bias is an inevitable problem.

The present study is the first meta-analysis to determine the diagnostic value of ASVS for localization of insulinomas, and suggests that ASVS is associated with high diagnostic value for insulinoma localization. These findings require validation in further, large-scale prospective studies to evaluate the diagnostic value of ASVS in patients with specific characteristics.

PRISMA checklist.

(DOC)

Click here for additional data file.

Included studies.

(ZIP)

Click here for additional data file.

28 Jun 2019

PONE-D-19-14887

Diagnostic value of ASVS for insulinoma localization: A systematic review and meta-analysis

PLOS ONE

Dear Dr. Hao Wang,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

==============================

ACADEMIC EDITOR: Although it is of interest, the reviewers have raised a number of points which we believe major modifications are necessary to improve the manuscript, taking into account the reviewers' remarks.

==============================

We would appreciate receiving your revised manuscript by Aug 12 2019 11:59PM. When you are ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.

To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). This letter should be uploaded as separate file and labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'.

Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.

We look forward to receiving your revised manuscript.

Kind regards,

Wisit Cheungpasitporn, MD, FACP

University of Mississippi Medical Center

Twitter: @wisit661 Email: wcheungpasitporn@gmail.com

Academic Editor

PLOS ONE

Journal Requirements:

1. When submitting your revision, we need you to address these additional requirements.

Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

http://www.journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and http://www.journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. We noticed you have some minor occurrence of overlapping text with the following previous publication, which needs to be addressed: Wang, Hao, et al. "Diagnostic value of endoscopic ultrasound for insulinoma localization: A systematic review and meta-analysis." PloS one 13.10 (2018): e0206099. In your revision ensure you cite all your sources (including your own works), and quote or rephrase any duplicated text outside the methods section. Further consideration is dependent on these concerns being addressed.

3. Please provide an institutional email address for each author.

4. Thank you for stating the following financial disclosure: NO

Please provide an amended Funding Statement that declares *all* the funding or sources of support received during this specific study (whether external or internal to your organization) as detailed online in our guide for authors at http://journals.plos.org/plosone/s/submit-now.

Please state what role the funders took in the study.  If any authors received a salary from any of your funders, please state which authors and which funder. If the funders had no role, please state: "The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript."

Please include your amended statements within your cover letter; we will change the online submission form on your behalf.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Partly

Reviewer #3: Partly

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: I Don't Know

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: No

Reviewer #2: No

Reviewer #3: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: 1. Pathology diagnosis prior to year of 2000 likely are not accurate. Please perform sensitivity analysis excluding those 1990s studies.

2. Need to provide supplementary data on pathology in each study for the diagnosis of insulinoma.

3. Manuscript is very poor written in English. For example, "Chian" in table is not correct country. "Zealand" is not correct. There are also many errors throughout manuscripts.

Reviewer #2: This meta-analysis has not been registered online. Please add this point in the limitation.

Who are two independent investigators?

It will be better to show kappa for the selection and data extraction. Please show the data of kappa of agreement during the systematic searches. How disagreements were solved during the systematic search among two independent reviewers?

Search terms in PubMed and Embase are different. Please attach syntax used in each database as supplementary.

Please make the data for this review publicly available, possibly through the Open Science Framework (osf.io). Items to include: list of excluded studies, commands for statistical analysis, spreadsheets or data used for the meta-analyses, etc. Making data publicly available will promote the reproducibility of the review and is best practices for systematic reviews and meta-analyses.

Authors should discuss the reason of heterogeneity.

Please include I2 in the abstract.

It is “fixed-effects model and random-effects model”, not “fixed-effects model and random effect model”.

Revision of the English writing is strongly recommended. There are many grammar errors and misspells.

Reviewer #3: The review is concise and relatively easy to read. However, there are several important points which should be addressed.

I was unable to determine if all the relevant articles had been included for review. Two studies which could be included also would be

1. Placzkowski, Vella et al: JCEM 2009;94:1069 which describes trends in the use of success of the technique from the Mayo Clinic.

2.Thompson, Vella et al:JCEM 2015;100:4189

Also, the use of meta-analysis/ systematic review should also recognise that the results of the studies would also be highly dependent on the expertise and experience of the individual radiologist/ institution. Techniques presumably also have improved through the years- which should also be taken into account.

Mention should also be made of the potential role of GLP-RA labelled nuclear scans which in some hands appear to provide greater sensitivity and specificity than the more invasive tests.

I presume that the techniques used are sound otherwise.

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Please note that Supporting Information files do not need this step.

13 Aug 2019

1 We have read your model carefully and revised the article according to the model.

2 For the overlapping section, we have modified it.

3 Sorry, we have not institutional email address.

4 we have not any funding or sources of support.

1 We write this meta-analysis in strict accordance with the standard format of meta-analysis, search the relevant literature correctly, extract data, and draw data and conclusions through correct statistical analysis.

2 Our statistics are carried out in accordance with the normal diagnostic meta-analysis, strictly according to the input and output criteria into the relevant research. After extracting the data, according to TP FP FN TN, using STATA Software 14.0 for meta-analysis, using random effect model analysis.

3 We provide the full text of the study and present the data in tabular form. We have no restrictions on the sharing of documentary data.

4 English is not our mother tongue, but after we finish writing the article, we invite English experts to translate and polish it.

5 Reviewer #1: 1. As you said, pathology diagnosis prior to year of 2000 likely are not accurate. But we carefully read the three studies published 2000 years ago. These three studies were published in rigorous and regular clinical journals. The diagnosis of insulinoma is clear through clinical manifestations(Whipple's triad syndrome), biochemical tests(Hyperinsulinemia), surgery and so on. We believe that the diagnosis is reliable, so the data of these three studies are still retained.

2. We provided the pathological results of each study.

3. Thank you ,teacher. We know the manuscript is very poor written in English.But we did our best to improve it, and invite native language editors to translate and polish it in English.

Reviewer #2: Two independent investigators refer to Hao Wang and Ying Ba, Later, the article was also marked.

When we collect data, we have strict requirements for the operation process and set the Kappa standard.

Search syntax: PubMed indexed the collected data according to the medical thesaurus. Thesaurus retrieval can improve the efficiency of literature retrieval. MeSH network version is integrated in PubMed database. The application of MeSH Database can determine the standard search terms, view the annotations of word meanings, tree structure tables, view the sub-headings and extensions. PubMed search supports Boolean logic operations, AND, OR, NOT. It can be retrieved by AND, OR and NOT combined subject words and free words. Choosing appropriate subject words and free words retrieval can be more comprehensive and accurate. So we use the search strategy in PubMed: “arterial calcium stimulation” AND “insulinoma” [MeSH]

Embase provides an Independent Thesaurus Retrieval System (EMTREE). EMTREE thesaurus is one of the most powerful retrieval tools of Embase. EMTREE contains more than 54,000 preferred terms, more than 2.1 million synonyms and multi-level tree structure. The use of EMTREE keyword retrieval can improve the comprehensiveness and accuracy of literature retrieval.So we use the search strateg in Embase: Emtree term–exploded = (insulinoma AND arterial calcium stimulation)

During the systematic search when we meet disagreement, we negotiate. For example, Ying Ba want include a Chinese article about ASVS, but I don't think it's right because the article published in an informal magazine. I can't confirm its scientific nature. Later Ying Ba agreed with me.

We already discuss the reason of heterogeneity.

We already include I2 in the abstract.

English is not our first language, but after we finish writing the article, we invite English experts to translate and polish it.

Reviewer #3:Thank you for your comments. We actually notice the two article before.

We have read these two articles carefully and thought that these two articles are very helpful to study the diagnostic value of ASVS in localizing insulinoma, however, in "Placzkowski, Vella et al." 's article, ASVS has only mention positive diagnostic rate. There is no specific data, and there is no data of non-insulinoma control group, so we have not included in this study.

For Thompson, Vella et al, they studied the differential diagnosis of insulinoma and islet hyperplasia by ASVS. We also thought it's a very good study.However,we believe that there is a lack of data for the control group of non-insulinoma and non-islet hyperplasia. Because in the study of ASVS, besides the positive rate of ASVS in insulinoma and islet hyperplasia, the negative rate of non-insulinoma and islet hyperplasia is also important, In theory, both insulinoma and islet proliferation should have insulin secretion after calcium stimulation. So we have not included this study. However, in the discussion, we quoted Thompson, Vella 's article. Because this article is indeed a good study of ASVS in the differential diagnosis of insulinoma and islet hyperplasia.

As you suggest, We already mention the potential role of GLP-RA labelled nuclear scans which in some hands appear to provide greater sensitivity and specificity than the more invasive tests.

6 We agree to our identity to be public for this peer review

Submitted filename: rebuttal letter to reviewers.txt

Click here for additional data file.

2 Sep 2019

PONE-D-19-14887R1

Diagnostic value of ASVS for insulinoma localization: A systematic review and meta-analysis

PLOS ONE

Dear Hao Wang,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

==============================

ACADEMIC EDITOR: Our expert reviewers still have raised a number of points which we believe major modifications are necessary to improve the manuscript, taking into account the reviewers' remarks below.

==============================

We would appreciate receiving your revised manuscript by Oct 17 2019 11:59PM. When you are ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.

To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). This letter should be uploaded as separate file and labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'.

Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.

We look forward to receiving your revised manuscript.

Kind regards,

Wisit Cheungpasitporn, MD, FACP

Academic Editor

PLOS ONE

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

Reviewer #3: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Partly

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: I Don't Know

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: It appears that all comments have been appropriately responded to. I have no further comments and recommend publication.

Reviewer #2: Much improved manuscript from prior version. The paper, in its revised form, is suitable for publication

Reviewer #3: The authors have improved the manuscript with corrections to grammatical mistakes seen in the first submission. There is an attempt to discuss the findings in more detail and to answer the queries of the reviewers. However, there still needs to be acknowledgement of the wide range of expertise in the use of this investigation which would have significant implications on the results. GLP 1 receptor imaging needs to be included in the discussion in some detail as a noninvasive technique to locate the insulinoma. There is also a relative paucity of published studies overall with less positive experiences likely not submitted for publication.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Please note that Supporting Information files do not need this step.

21 Sep 2019

responds to academic editor

1. We have deposited my laboratory protocols in protocols.io. We get the DOI: dx.doi.org/10.17504/ protocols.io.7imhkc6.

2. We have no change to my financial disclosure.

3. We have upload the revision of my manuscript according to your direction.

Responds to the reviewers:

1. Thank you. We have addressed reviewers’ comments raised in a previous round of review.

2. The manuscript was written in accordance with normal criteria of standard diagnostic meta analysis. So We think it is technically sound, and the data do support the conclusions.

3. The manuscript comply with the Standard Writing of Meta-analysis. And We think statistical analysis been performed appropriately and rigorously.

4. All data underlying the findings described in the manuscript fully available without restriction. We already deposited the meta analysis and the relevant data and step to a public repository. We got the DOI: dx.doi.org/10.17504/ protocols.io.7imhkc6.

5. After we have finished the paper, we invited several mother tongue editor to polish the language.

6. Dear teacher,Thank you very much for your instruction. We also think that the wide range of expertise in the use of this investigation which would have significant implications on the results. For the role of GLP 1 receptor imaging in the localization of insulinoma, we also searched a lot of literature, and made a more detailed discussion.

7. Thanks for the peer review. We learnt a lot.

Submitted filename: response letter.docx

Click here for additional data file.

25 Oct 2019

Diagnostic value of ASVS for insulinoma localization: A systematic review and meta-analysis

PONE-D-19-14887R2

Dear Dr. Hao Wang,

We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.

Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication.

Shortly after the formal acceptance letter is sent, an invoice for payment will follow. To ensure an efficient production and billing process, please log into Editorial Manager at https://www.editorialmanager.com/pone/, click the "Update My Information" link at the top of the page, and update your user information. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, you must inform our press team as soon as possible and no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

With kind regards,

Wisit Cheungpasitporn, MD, FACP

Academic Editor

PLOS ONE

Additional Editor Comments:

I want to commend the authors on their superb efforts to revise the manuscript according to all reviewers’ suggestions. The quality of the manuscript has improved substantially.

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: It appears that all comments have been appropriately responded to. I have no further comments and recommend publication.

Reviewer #2: Very important research, much needed. The investigators have addressed all comments and concerns appropriately. I have no additional concerns.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

29 Oct 2019

PONE-D-19-14887R2

Diagnostic value of ASVS for insulinoma localization: A systematic review and meta-analysis

Dear Dr. Wang:

I am pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

For any other questions or concerns, please email plosone@plos.org.

Thank you for submitting your work to PLOS ONE.

With kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Wisit Cheungpasitporn

Academic Editor

PLOS ONE