{'fraction_non_alphanumeric': 0.047499285510145754, 'fraction_numerical': 0.02817947985138611, 'mean_word_length': 5.141102141102141, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
A Systematic Review and Meta-Analysis of C-Arm Cone-Beam CT-Guided Percutaneous Transthoracic Needle Biopsy of Lung Nodules

Summary Background A systematic review and meta-analysis of all available publications was performed to evaluate the diagnostic accuracy of percutaneous transthoracic needle biopsy (PTNB) using a C-Arm Cone-Beam CT (CBCT) system in patients with lung nodules. Material/Methods Thedatabases of PUBMED, OVID, EBSCO, EMBASE, and China National Knowledge Infrastructure (CNKI) were systematically searched for relevant original articles on the diagnostic accuracy of CBCT-guided PTNB for the diagnosis of nodules in the lungs. Diagnostic indices including sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR) and diagnostic score (DS) were calculated. Moreover,summary receiver operating characteristic curves (SROC) were constructed with Stata (version 13.0), Rev Man (version 5.3), and Meta-disc (version 1.4) software. Other clinical indices such as incidence of complications were also recorded. Results Eight studies met the inclusion and exclusion criteria for the meta-analysis. The pooled sensitivity, specificity, PLR, NLR, DOR, DS, and SROC with 95% confidence intervals were 0.96 (0.93–0.98), 1.00 (0.91–1.00), 711.15 (9.48–53325.89), 0.04 (0.02–0.07), 16585.29 (284.88–9.7e+05), 9.72 (5.65–13.78), and 0.99 (0.97–0.99), respectively. The incidence of pneumothorax and hemorrhage was 10–29.27% and 1.22–47.25%, respectively. Conclusions CBCT-guided PTNB has an acceptable rate of complications and is associated with a reasonable radiation exposure. Moreover, it is a highly accurate and safe technique for the diagnosis of lung nodules and can be recommended to be used in routine clinical practice.


Background
An accurate diagnosis of a pulmonary nodule is of high importance, as the patient may benefit from either conservative, surgical or chemotherapeutic treatment options [1][2][3]. Percutaneous transthoracic needle biopsy (PTNB) with image guidance has been regarded as a highly safe and accurate diagnostic technique for assessing both benign and malignant lung nodules [4][5][6]. Generally, PTNB can be performed under various image guidance modalities such as ultrasonography (USG), conventional fluoroscopy, computed tomography (CT) and CT fluoroscopy. PTNB under USG is the quickest, safest and least expensive of all the modalities but is not appropriate for a safe sampling of deep nodular lesions [7]. CT-guided PTNB, considered both accurate and safe [8], is being increasingly used in many medical centers, replacing conventional fluoroscopy as the primary method of guidance. However, conventional CT guidance has its limitations due to the lack of real-time monitoring and gantry tilting for a more accessible needle pathway to the target lesion [9].
CT fluoroscopy, which allows both a real-time monitoring of target lesions and gantry tilting [10], overcomes the disadvantages posed by conventional CT guidance and is considered as the gold standard technique to guide percutaneous biopsies of pulmonary nodules [11]. Nevertheless, limitations in these procedure do exist and include a small gantry bore, limited imaging plane orientation and radiation exposure to operators [12]. In the recent years, we have seen the introduction of C-arm cone-beam CT (CBCT) with a flat-panel detector system into clinical practice, in which a cone-beam x-ray tube and a flat-panel detector are fitted to a C-arm gantry. This allows us to work with a real-time fluoroscopy, angiography, CT images and subsequent 3D reconstructions [13].
We realize that numerous studies have been published on the diagnostic accuracy of PTNB with the use of the CBCT system in patients with lung nodules [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31]. However, there are no studies in which researchers have investigated the diagnostic accuracy of CBCT-guided PTNB by way of a systematic review or a meta-analysis. Therefore, the purpose of this article was to investigate the value of CBCT-guided PTNB in the diagnosis of pulmonary nodules through a systematic review and meta-analysis.
Other databases, such as Springer link were also searched for relevant articles. Two observers independently checked the reference list of all documents initially found in the PUBMED, EMBASE and other databases to look for additional articles. Publication date or language was not restricted. The articles were limited to studies in humans. The following publication types were excluded -review articles, commentaries, letters and case reports. The remaining relevant articles were then taken into consideration based upon their title and/or abstract.

Inclusion and exclusion criteria
Two investigators checked every potential study independently. Disagreements were resolved in consensus with another researcher. The documents with the following characteristics were included in this systematic review and meta-analysis -(a) Focus on the value of CBCT-guided PTNB in the diagnosis of pulmonary nodules; (b) Imaging and/or close clinical follow-up (at least 6 months) and/or careful surgical inspection and/or histopathological analysis were/was used as the reference standard; (c) Both prospective and retrospective studies; (d) Sufficient data [TP (true-positive), TN (true-negative), FP (false-positive), and FN (false-negative)] could be found or calculated from the original study; and (e) Studies having at least 20 subjects.
Studies that did not fulfill the inclusion criteria were not taken into consideration. Moreover, studies with a large number of subjects were considered for evaluation so as to avoid duplication of information. Emails were sent to those authors for missing data if their studies did not report sufficient data.

Data extraction and quality evaluation
All publications meeting the inclusion criteria were evaluated. Three investigators independently conducted the relevant data extraction and quality assessment. Debates were resolved through discussion.
Methodological quality was assessed independently according to the QUADAS-2 (Quality Assessment of Studies of Diagnostic Accuracy included on Systematic Reviews) guidelines as provided by Whiting et al. [32]. Disagreements were resolved in consensus with another researcher.
For each article, the following data were extracted: (a) study descriptions (first author, publishing year, study design etc.); (b) baseline characteristics of the participants (age, number of nodules, lesion size, etc.); (c) characteristics of the procedures (technical success rate, procedure time, radiation doses, biopsy needle and complications); and (d) data on TP, FP, TN and FN.

Statistical analysis
Standard methods recommended for meta-analyses of diagnostic tests were used [33]. Pooled estimates of sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR) and diagnostic score (DS) were calculated at a patient level. A constructed summary receiver operating characteristic (SROC) curve was calculated to present the accuracy of CBCT-guided PTNB for lung nodules. A bivariate mixedeffects binary regression modeling framework was used to calculate the pooled estimates of sensitivity, specificity, PLR, NLR, DOR, DS, and area under the curve (AUC). Heterogeneity was evaluated by calculating the I 2 statistic [33,34], ranging from 0% (no heterogeneity) to 100% (great heterogeneity) with less than 50% I 2 statistic across the included studies considered to possess either absent or moderate heterogeneity. The Spearman rank correlation test was applied to assess the threshold effect among the studies. Sensitivity analysis and subgroup analysis were also conducted whenever possible. Analyses of all the statistics in this systematic review and meta-analysis were performed with Stata (version 13.0), Rev Man (version 5.3), and Meta-disc (version 1.4) software. P values of less than 0.05 were considered to be of statistical significance.

Literature retrieval and the results
Two hundred and thirty original articles were identified for selection after a thorough computer literature search and a careful verification of references. After screening the titles and abstracts, 212 items were excluded because one or more inclusion criteria were not fulfilled. The remaining 18 studies were evaluated by reading the full text. Of these, 7 were excluded because the subjects enrolled in these studies originated from the same institution or medical center [22][23][24][25][26][27][28]; 3 were excluded because of insufficient data to construct 2×2 tables of TP, FP, FN, and TN [29][30][31]. As a result, only 8 articles [14][15][16][17][18][19][20][21] were included in this metaanalysis, having met the inclusion criteria. Figure 1 shows a detailed flowchart of study selection and the results of this systematic review and meta-analysis.

Diagnostic accuracy of PTNB using CBCT
The pooled statistical results of this meta-analysis indicated that: sensitivity, specificity, PLR, NLR, DOR, DS and AUC with 95% confidence intervals were 0.96 (0.93-0.98), 1.00 (0.91-1.00), 711.15 (9.48-53325.89), 0.04 (0.02-0.07), 16585.29 (284.88-9.7e+05), 9.72 (5.65-13.78), and 0.99 (0.97-0.99), respectively. A forest plot ( Figure 3) lists the sensitivity, specificity, and 95% confidence intervals for each study in detail. The forest plot in Figure 4 summarizes the PLR, NLR, and 95% confidence intervals for each study in detail. The forest plots of the DOR and DS are shown in Figures 5 and 6, respectively. The AUC was 0.99, indicating a very good overall diagnostic accuracy of CBCT-guided PTNB for lung nodules across the 8 studies (shown in Figure 7). A subgroup analysis (data not shown) was also performed on the basis of the country in which the investigations were conducted (South Korean vs. Non-South Korean).  10), and 47.93 (95% confidence intervals: 5.78-90.09), respectively, which indicated that there were different degrees of heterogeneity across the eight investigations. The Spearman correlation coefficient was equal to 0.119 (p=0.77), indicating that there was no threshold effect in this systematic review and meta-analysis. Furthermore, the sensitivity analysis results showed that the data in this systematic review and meta-analysis were in a relatively robust situation (data not shown).

Radiation exposure dose and complications
The mean total procedure time was documented to be between 12 to 32 minutes, with a mean radiation exposure dose ranging from 2.9 to 14.3 mSv. The incidence of procedure-related pneumothorax was between 10% to 29.27%, and the rate of chest tube drainage was reported to range from 1.22% to 47.25%. The rate of hemorrhage ranged between 1.22% to 47.25%, with one patient requiring bronchial artery embolization, as reported in the study by Lee et al. [18]. In addition, there was one case of subcutaneous emphysema in the study by Choi et al. [17]. Apart from the adverse effects mentioned above, no other complications Original Article were recorded in these eight studies analyzed in this systematic review and meta-analysis.

Discussion
In clinical practice, patients with suspected lung nodules often require a chest examination by way of radiography or computed tomography (CT) with or without administration of a contrast agent. Even then, the benign or malignant nature of the lung nodules is often difficult to be comprehensively evaluated on the basis of simple morphological changes in the imaging studies such as chest radiography or CT. In such situations, an image-guided percutaneous lung biopsy is often recommended. Among the interventional procedures, PTNB with CBCT has played an essential role in the diagnosis of patients with lung nodules since its introduction [13,35]. With respect to CBCT-guided PTNB, a foundation has already been laid [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31], with a variety of clinical applications and ongoing investigations being performed using a CBCT system [36,37]. showed that EUS-guided PTNB is a safe procedure for the invasive staging of lung cancer with an added advantage of increased sensitivity of confirming metastasis to mediastinal lymph nodes seen on CT scans and a potential to prevent unnecessary surgery in a large proportion of cases, which was not possible with CT [39]. Gu [41]. However, all the four studies mentioned above either focused on the overall accuracy of PTNB or did not calculate the diagnostic accuracy values of CBCT-guided PTNB.
This study was in line with the reporting standards recommended by the meta-analysis of diagnostic and screening tests group [42]. To the best of our knowledge, this is the first study that has evaluated the diagnostic accuracy of CBCT-guided PTNB for lung nodules by way of a systematic review and meta-analysis. The study herein includes 8 eligible studies and found that CBCT-guided PTNB can be used as one of the primary examinations for lung nodules with a relatively high diagnostic accuracy. The systematic review and meta-analysis results reported herein also showed that CBCT-guide PTNB has an excellent accuracy in the diagnosis of lung nodules, with an AUC of 0.99. Taking the pooled results of sensitivity, specificity, PLR, NLR, DOR, DS, and AUC into account, CBCT-guided PTNB has a potential to raise the accuracy of diagnosing lung nodules.
Fortunately, there were no severe complications such as air embolism, procedure-related death or needle tract metastasis in the eligible eight studies. The incidence of adverse effects in these studies was considered to be within an acceptable

A B
Original Article range. In terms of CBCT-guided PTNB-related complications, pneumothorax was reported to occur in approximately 17.0% (196) and haemoptysis in 6.9% (80) of all lung biopsy cases in the largest study conducted by Lee et al. [18]. Of the 196 cases of pneumothorax, only 6.6% (1.1% of all 1153 PTNBs) required drainage with catheter insertion [18]. As for hemorrhage, bronchial artery embolization was required in only one patient (1.3%) because of a massive hemorrhage in the same study [18]. The incidence of procedure-related complications was distinctly low in our meta-analysis study. It is reasonable to think that this very low incidence of procedure-related complications was possible as the CBCT system enabled the investigators to select a safer and more accurate targeting route in navigating the needle to the target during PTNB. Furthermore, the coaxial needle technique also played an essential role in the reduction of complications by avoiding repeated pleural punctures or passages [24].
Interestingly, the use of virtual guidance was also a significant protective factor for the occurrence of both pneumothorax and hemorrhage [18]. In addition, the needle-pleural angle is a novel predictor of pneumothorax reported by Li et al. [8]. De et al. mentioned that non-calcified density was a positive predictive factor for the diagnosis, whereas the use of MPR (multiplanar reformatting) imaging, an useful method to plan the needle path while performing needle aspiration, can improve the diagnostic accuracy of CT-guided PTNB [43].   [14] used a lower-quality angiography mode (92 kV, 28 mA). It has been shown that CBCTguided PTNB results in a significant reduction of radiation exposure compared to other modalities such as conventional CT and fluoroscopic guidance and it can be a safe and useful procedure for diagnosing pulmonary lesions [44][45][46][47].
The decrease in radiation exposure in CBCT-guided PTNB, to both the patient and the operator, has been attributed to the application of a small field of view or collimation [18].
Our research was based upon a comprehensive literature retrieval and meticulous data extraction. However, a few limitations should be taken into account in our analysis. Firstly, most studies included in our meta-analysis had a retrospective design, thus, there may have been a selection bias. Secondly, there was the presence of indeterminate nodules or non-diagnosed patients in the enrolled studies, which may have led to a higher estimate of the diagnostic accuracy of CBCT-guide PTNB for lung nodules. Thirdly, these studies do not compare between the diagnostic accuracy of CBCT-guide PTNB and CT-guided or CT fluoroscopyguided biopsy. Therefore, we cannot currently recommend which method of is better. Nevertheless, there is a significant reduction in radiation exposure time in CBCT-guided PTNB compared to methods such as conventional CT and fluoroscopic guidance [44][45][46][47] which obviously is beneficial to the patient. Finally, our study was based on studies that were published in English only, which hypothetically might have caused the so-called "Tower of Babel" bias [48]. Lastly, further prospective studies need to be performed to compare different methods for diagnosing lung nodules.

Conclusions
In conclusion, despite the above-mentioned problems, we believe that PTNB under CBCT guidance can be recommended in clinical practice, considering its high diagnostic accuracy and the number of complications and radiation exposure in an acceptable range. For future research, it is  important to improve study design and reporting of accuracy results. When more data become available, an update of this systematic analysis and meta-analysis should be conducted.