UMIN-CTR Clinical Trial

Basic information
Public title	Immunohistochemical markers to differentiate primary adenocarcinoma and squamous cell carcinoma of the lung: diagnostic test accuracy meta-analysis
Acronym	Immunohistochemical markers to differentiate primary adenocarcinoma and squamous cell carcinoma of the lung: diagnostic test accuracy meta-analysis
Scientific Title	Immunohistochemical markers to differentiate primary adenocarcinoma and squamous cell carcinoma of the lung: diagnostic test accuracy meta-analysis
Scientific Title:Acronym	Immunohistochemical markers to differentiate primary adenocarcinoma and squamous cell carcinoma of the lung: diagnostic test accuracy meta-analysis
Region	Japan

Condition
Condition	NSCLC
Classification by specialty	Pneumology Chest surgery
Classification by malignancy	Malignancy
Genomic information	NO

Objectives
Narrative objectives1	Sensitivity and specificity are key metrics to understand the diagnostic test accuracy of immunohistochemical stain technique. Without knowing the sensitivity and specificity of each marker, pathologist cannot select appropriate immunohistochemical markers. In addition, these data are required to judge the pathological subtype of NSCLC when multiple markers indicate discrepant results. Numerous studies were conducted to reveal the diagnostic test accuracy of immunohistochemical markers. However, these articles reported highly diverse results. To our knowledge, a meta-analysis assessing diagnostic value of TTF--1 for metastases of pulmonary adenocarcinoma and a meta-analysis elucidating combined TTF-1 and Napsin A were published. However, no systematic review evaluated diagnostic test accuracy of each marker to distinguish adenocarcinoma and squamous cell carcinoma of lungs. Aim of the current systematic review and meta-analysis is to summarize data from the previous studies regarding diagnostic test accuracy of immunohistochemical markers that are used for distinguishing primary adenocarcinoma and squamous cell lung cancer of the lungs.
Basic objectives2	Others
Basic objectives -Others	Aim of the current systematic review and meta-analysis is to summarize data from the previous studies regarding diagnostic test accuracy of immunohistochemical markers that are used for distinguishing primary adenocarcinoma and squamous cell lung cancer of the lungs.
Trial characteristics_1
Trial characteristics_2
Developmental phase

Assessment
Primary outcomes	Sensitivity, specificity, area under curve (AUC), and diagnostic odds ratio will be evaluated. If two or more of cutoffs are applied in an original article, all of weak, moderate, and strong positive will be collectively considered positive. To diagnose adenocarcinoma, both adenocarcinoma and adenosquamous carcinoma will be counted since adenosquamous carcinoma has adenocarcinoma component while large cell carcinoma and NSCLC not otherwise specified will not be counted as adenocarcinoma. Similar algorithm will be applied to diagnose squamous cell carcinoma. If data for multiple clones, e.g. 8G7G3/1, SPT24, and SP141 clones of TTF-1, are available, the data of 8G7G3/1 will be selected for our analysis because 8G7G3/1 clone has been known to provide the best diagnostic odds ratio among the three clones. Subgroup analysis focusing on each clone will be also done.
Key secondary outcomes

Base
Study type	Others,meta-analysis etc

Study design
Basic design
Randomization
Randomization unit
Blinding
Control
Stratification
Dynamic allocation
Institution consideration
Blocking
Concealment

Intervention
No. of arms
Purpose of intervention
Type of intervention
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Interventions/Control_2
Interventions/Control_3
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Interventions/Control_5
Interventions/Control_6
Interventions/Control_7
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Interventions/Control_9
Interventions/Control_10

Eligibility
Age-lower limit	Not applicable
Age-upper limit	Not applicable
Gender	Male and Female
Key inclusion criteria	We will include full article, brief report, and conference abstract published in any language that provide data for sensitivity and specificity by immunohistochemical markers to diagnose adenocarcinoma and squamous cell carcinoma of the lung. Case-control study design consisted of patients with adenocarcinoma and squamous cell carcinoma will be accepted though case-control design may be counted as risk of bias according to Quality Assessment of Diagnostic Accuracy Studies-2(QUADAS-2). Target population will be patients with NSCLC. Commonly used pathological criteria will be accepted along with WHO 2015 criteria. Patients with both surgical and biopsy specimens will be allowed. Specimen outside the lung such as lymph nodes and pleural effusion will be accepted. Immunocytochemical stein using pleural effusion cell block will be also accepted along with immunohistochemical stein. Target immunohistochemical markers include P40, CK5/6, P63, and desmocollin-3 (DSC3) for squamous cell carcinoma and TTF-1, Napsin A, and cytokeratin 7 (CK7) for adenocarcinoma. Immunohistochemical technique using any commercially available antibodies and non-commercial antibodies will be accepted. Reference test should be pathological diagnosis by pathologists.
Key exclusion criteria	An article that provide data of either sensitivity or specificity will be excluded since bivariate analysis is not applicable to such data. Specificity evaluated among lung cancer cases will not be used for our analysis because analysis including both NSCLC and small-cell lung cancer will underestimate the specificity of markers. Studies focusing on non-pulmonary cancers and metastatic lung cancer of non-pulmonary origin will be excluded. Similarly, studies that compared NSCLC subtypes and mesothelioma will not be accepted.
Target sample size

Research contact person
Name of lead principal investigator	1st name Nobuyuki Middle name Last name Horita
Organization	Yokohama City University Hospital
Division name	Chemotherapy Center
Zip code	236-0004
Address	3-9, Fikuura, Kanazawa, Yokohama, Japan
TEL	045-787-2800
Email	horitano@yokohama-cu.ac.jp

Public contact
Name of contact person	1st name Nobuyuki Middle name Last name Horita
Organization	Yokohama City University Hospital
Division name	Chemotherapy Center
Zip code	236-0004
Address	3-9, Fikuura, Kanazawa, Yokohama, Japan
TEL	0457872800
Homepage URL
Email	horitano@yokohama-cu.ac.jp

Sponsor
Institute	Yokohama City University Hospital
Institute
Department

Funding Source
Organization	Yokohama City University Hospital
Organization
Division
Category of Funding Organization	Other
Nationality of Funding Organization

Other related organizations
Co-sponsor
Name of secondary funder(s)

IRB Contact (For public release)
Organization	IRB not approved
Address	3-9, Fikuura, Kanazawa, Yokohama
Tel	0457872800
Email	horitano@yokohama-cu.ac.jp

Secondary IDs
Secondary IDs	NO
Study ID_1
Org. issuing International ID_1
Study ID_2
Org. issuing International ID_2
IND to MHLW

Institutions
Institutions

Other administrative information
Date of disclosure of the study information	2020 Year 09 Month 03 Day

Related information
URL releasing protocol
Publication of results	Unpublished

Result
URL related to results and publications
Number of participants that the trial has enrolled
Results
Results date posted
Results Delayed
Results Delay Reason
Date of the first journal publication of results
Baseline Characteristics
Participant flow
Adverse events
Outcome measures
Plan to share IPD
IPD sharing Plan description

Progress
Recruitment status	Main results already published
Date of protocol fixation	2020 Year 09 Month 03 Day
Date of IRB	2000 Year 09 Month 03 Day
Anticipated trial start date	2020 Year 09 Month 03 Day
Last follow-up date	2021 Year 09 Month 03 Day
Date of closure to data entry
Date trial data considered complete
Date analysis concluded

Other

Other related information

Study overview The protocol of this systematic review and meta-analysis of diagnostic test accuracy was composited following standard guidelines for systematic review of diagnostic test accuracy and PRISMA-DTA. Approval of Institutional Review Board was not required because of the nature of this study. Study search Four major electric databases, namely PubMed, Web of Science, Cochrane, and Embase will be searched on September 3, 2020. The following formula will be applied for PubMed: ((P40 OR deltaNp63 OR delta-NP63) OR (P63 OR DBR16.1) OR (ck5/6 OR Cytokeratin 5/6) OR (desmocollin 3 OR desmocollin-3 OR DSC3 OR DSC-3) OR (TTF1 OR TTF-1 OR Thyroid transcription factor-1 OR Thyroid transcription factor 1) OR (NapsinA OR Napsin A OR TA02 OR aspartic protease) OR (CK7 OR cytokeratin7 OR cytokeratin 7)) AND ((sensitivity AND specificity) OR (diagnostic test accuracy) OR (likelihood ratio) OR (sensitivity AND adenocarcinoma AND squamous)) AND (NSCLC OR lung OR pulmonary OR bronchial OR pleural OR respiratory OR bronchoscopy) AND (NSCLC OR adenocarcinoma OR squamous OR squamous-cell OR non-small OR non small). Risk of bias QUADAS2 was applied to assess the risk of bias in each study. Statistics Bivariate model will be used to obtain pooled sensitivity and specificity and to draw a summary receiver operating characteristic curves (SROC). We will obtain DOR by DerSimonian-Laird random-model. Publication bias for DOR will be checked by visual inspection and by Begg-Kendall test after a funnel plot will be drawn uding RevMan ver. 5 (Cochrane, London, UK). DOR will be calculated by "madauni" command ("netmeta" package of R project, Gerta Rucker, Denmark). Sensitivity and specificity will be pooled by "reitsma" command ("netmeta" package of R project, Gerta Rucker, Denmark). The statistical threshold for significance will set at 0.05.

Management information
Registered date	2020 Year 09 Month 03 Day
Last modified on	2022 Year 11 Month 18 Day

Link to view the page
URL(English)	https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000047560