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Experimental Studies |
1 From the Departments of Radiology (B.B.G., D.A.M., J.B.L., M.T., L.N., F.F.) and Pathology (G.F.M.), Thomas Jefferson University Hospital, 7th Floor Main Bldg, 132 S 10th St, Philadelphia, PA 19107; and Amersham Health, Oslo, Norway (A.T.). From the 2002 RSNA scientific assembly. Received November 8, 2002; revision requested January 15, 2003; final revision received June 13; accepted July 3. Supported by a grant from Amersham Health, Oslo, Norway. Address correspondence to B.B.G. (e-mail: barry.b.goldberg@jefferson.edu).
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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MATERIALS AND METHODS: Six swine with 17 melanomas were evaluated. Conventional gray-scale, color flow, and gray-scale phase-inversion harmonic US examinations were performed. A US contrast agent was administered in four sites around each melanoma (1-mL total dose). Lymphoscintigraphy was followed by injection of a blue dye and then dissection. SLNs identified at lymphatic US were characterized by two readers in consensus as normal or as having metastases; results were compared with histologic findings. Statistical analyses included the sign test and the 
statistic.
RESULTS: Lymphatic US depicted 28 SLNs, while lymphoscintigraphy depicted 27 "hot spots" suspected of representing SLNs (including two false-positive findings). Dissection after blue dye injection helped identify 31 SLNs. There were no false-positive US findings for SLN detection. Five of six nodes not seen with lymphoscintigraphy were detected with lymphatic US. The accuracy of SLN detection was 90% (28 of 31) for lymphatic US and 81% (25 of 31) for lymphoscintigraphy (P = .29). Lymphatic US correctly depicted metastases in 19 of 20 SLNs, and five of the eight normal SLNs were correctly characterized, with an accuracy of 86% ( = 0.62).
CONCLUSION: Detection of SLNs with lymphatic US compared favorably with that at lymphoscintigraphy. Lymphatic US can depict metastases within the SLN, which was not possible with lymphoscintigraphy.
© RSNA, 2004
Index terms: Animals • Lymphatic system, radionuclide studies, 997.12974 • Lymphatic system, US, 997.12981, 997.12983, 997.12988 • Melanoma, 997.329, 997.33
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In general, the detection of SLNs with blue dyes and radiopharmaceuticals is accurate. However, with the use of a blue dye, frequently there will be staining not only of the SLN but also of the adjacent lymph nodes, which often leads to a more extensive nodal dissection than is necessary. This problem is different from that of patients having multiple SLNs in different lymphatic drainage basins. Since most radioactive materials make use of small particles such as human serum albumin and colloid albumin, as well as filtered sulfur colloids, these small particles may drain well within the LCs. However, because of their small size, they may actually pass through the SLNs, resulting in identification of secondary lymph nodes (ie, nodes that are not SLNs) (4). Clearly, the techniques of blue dye and radioisotope injections for the detection of SLNs have pitfalls that can affect the surgical approach and success, as well as the clinical outcome. It should also be noted that lymphoscintigraphy is unable to provide information regarding the presence of metastatic infiltration in the SLNs.
Investigations have established the usefulness of a tissue-specific ultrasonographic (US) contrast agent (Sonazoid; Amersham Health, Oslo, Norway) that, when injected intravenously, is taken up by the macrophages of the reticuloendothelial system in the liver and spleen (5–7). This agent has been used successfully to detect tumors within the liver. After intravenous administration of this agent, the normal liver parenchyma becomes more echogenic (ie, contrast material–enhanced) as a result of the increased reflectivity of the contrast agent microbubbles of gas trapped within the macrophages, while tumors appear as hypoechoic voids as a result of displacement or destruction of normal liver tissue by the tumors (6–9). However, the enhancement of lymph node parenchyma after subcutaneous administration of this agent has not been reported, to our knowledge.
We hypothesized that US imaging of the regional lymphatic system after peritumoral injection of a US contrast agent could be used to identify LCs and SLNs and that LCs and SLNs identified with lymphatic US (lymphosonography) would correlate with those found with the established methods of lymphoscintigraphy and surgical dissection after an injection of blue dye. We also hypothesized that the destruction and/or displacement of the normal lymphatic tissue by metastatic tumor would result in a lack of contrast agent within the tumor-filled regions. Thus, the purpose of our study was to determine if LCs and SLNs with and without metastases can be detected with lymphatic US and if lymphatic US can be used to assess SLNs for the presence of metastatic infiltration.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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US Imaging
Conventional gray-scale, pulse-inversion harmonic gray-scale, and color flow US examinations of the primary tumors, SLNs, and LCs were performed by using an Elegra scanner (Siemens Medical Systems, Issaquah, Wash) and a 7.5-MHz linear-array transducer. Mechanical index values used for pulse-inversion harmonic gray-scale US after contrast agent administration ranged from 0.2 to 0.5 to reduce microbubble destruction. Other imaging parameters, including the system gain and depth of field, were optimized as necessary based on the imaging characteristics of the area under investigation. All US scans before and after contrast agent administration were obtained by the same experienced sonographer (D.A.M.) and recorded on a super VHS videotape, with individual still images digitally stored on the scanner’s hard drive for later analysis.
Baseline US (ie, before contrast agent administration) was performed to determine the size of the primary melanoma and to identify lymph nodes that could represent SLNs, as well as other masses. Determination of the size of melanomas and SLN identification based on the US data were accomplished by consensus between the study investigators (D.A.M., J.B.L., B.B.G.). A total of 1 mL of the US contrast agent was administered intradermally within 5 mm of the periphery of the primary tumor at 12-, 3-, 6-, and 9-o’clock positions (ie, four injections of 0.25 mL).
The area around the tumor was massaged for up to 5 minutes in an attempt to accelerate the movement of contrast agent microbubbles into the LCs that drained into the SLNs. The US contrast agent is composed of a lipid-stabilized suspension of perflurobutane microbubbles, with a mean diameter of 2.4–3.5 µm (7).
A variety of anatomic areas were assessed on the basis of the location of the primary melanoma, the course of the draining LCs, and the location of the SLNs. When the melanoma tumor being evaluated was located on the trunk above the umbilicus or on a forelimb, the lymphatic US evaluation was primarily (but not exclusively) focused on the area around the tumor and the ipsilateral axilla and/or supraclavicular regions. When the melanoma was below the umbilicus or on a hind limb, the lymphatic US evaluation was primarily (but not exclusively) focused on the ipsilateral superficial groin and deep iliac fossa.
In the first three swine studied (with 10 melanoma tumors), the entire 1 mL of the US contrast agent was injected in equal 0.25-mL doses at the four peritumoral locations (12-, 3-, 6-, and 9-o’clock positions) before lymphatic US was performed. In the later three swine (with seven melanomas), lymphatic US was performed after each 0.25-mL peritumoral injection. After contrast agent administration, lymphatic US was performed in an attempt to identify the LCs leading from the tumor, as well as to identify the location of the SLNs. The locations of LCs and SLNs at lymphatic US were determined by consensus (D.A.M., J.B.L., B.B.G.). Details about the location of the LCs and SLNs, including their distance beneath the skin and relationships to other anatomic landmarks, were noted to permit correlation with the results of blue dye and surgical dissection. A gel standoff pad (Aquaflex; Parker Laboratories, Fairfield, NJ) was used when necessary to improve visualization of very superficial structures.
Determination of the contrast agent transit time from the injection sites to the SLN was performed for one of the melanomas in each of the latter two swine. The duration of the lymphatic US examinations varied between animals because of the difference in the number and location of the primary tumors, but imaging was performed as long as 3 hours after contrast agent administration.
Color Doppler imaging with a high mechanical index (>0.9) was used to identify the presence of the contrast agent within the LCs and SLNs as an acoustic emission display (ie, contrast agent microbubble rupture depicted as transient color signals) (12,13). A consensus agreement (B.B.G., D.A.M., J.B.L.) was used to establish that the acoustic emission effect was related to the contrast agent within the affected structures. All tumors received two administrations of the contrast agent. The initial administration was used to identify LCs and SLNs by using pulse-inversion harmonic gray-scale US, and the second administration was given to refill those structures with contrast agent microbubbles after performing Color Doppler imaging.
The videotapes were reviewed in consensus by two blinded readers (B.B.G., L.N.) with experience in contrast-enhanced US to assess for the presence of metastatic infiltration in the contrast-enhanced SLNs. The readers were blinded to the results of histologic findings regarding the presence or absence of SLN metastases. The criterion used was that uniformly increased echogenic SLNs did not contain metastases, whereas SLNs that demonstrated areas that did not enhance had metastatic infiltration.
Lymphoscintigraphy
After lymphatic US evaluation, 1.85 MBq of filtered technetium 99m (99mTc) sulfur colloid was injected intradermally. The volume of each dose was 0.1 mL, and a total of four injections (a total of 7.40 MBq) were performed for each primary tumor assessed. Intradermal injections were administered around the primary tumor at 12-, 3-, 6-, and 9-o’clock positions (ie, into the same areas where the US contrast agent had been injected) in an attempt to detect SLNs. The injection site was massaged for approximately 5 minutes. Approximately 15 minutes after injection, images were obtained with a gamma camera (Starcam 300; GE Medical Systems, Milwaukee, Wis), initially with dynamic frame mode (one frame per 3 seconds) for 120 seconds and later with static mode (one frame per 60 seconds) for 30 minutes. The location of SLNs (ie, "hot spots") detected at lymphoscintigraphy was documented. All of the lymphoscintigraphic examinations were performed and interpreted by the same experienced nuclear medicine specialist (M.T.), without knowledge of the lymphatic US results.
Gross Pathologic and Histologic Findings
Ten to 15 minutes before the animal was sacrificed, a total volume of 0.5 mL blue dye (Patent Blue V Sodium Salt; Guerbet, Roissy, France) was injected in the same four injection sites as were the peritumoral injections of the US contrast agent and 99mTc, and the areas were massaged. The swine was then sacrificed by means of 0.25 mL/kg pentobarbital sodium and phenytoin sodium (Diamond Animal Health).
All surgical dissections of the LCs and SLNs were performed by the same individual (J.B.L.). During dissection, the blue dye was identified in the LCs, which could be followed to the SLNs, and their location was noted. Comparisons of the blue dye results with lymphatic US and lymphoscintigraphic findings were made at the time of dissection. Correlation of lymphoscintigraphic results with those of the blue dye was made by the nuclear medicine specialist (M.T.), while correlation of the blue dye results with lymphatic US findings was made in consensus by US specialists (B.B.G., D.A.M., J.B.L.). Digital photographs of the LCs and SLNs filled with blue dye were obtained.
Once the SLNs were exposed, pulse-inversion harmonic gray-scale US and color Doppler imaging were performed (D.A.M.) to identify the presence of the US contrast agent in the lymph nodes. A consensus agreement between investigators (D.A.M., J.B.L., B.B.G.) determined if contrast agent was present in the SLNs. The nodes were then surgically removed and tested for radioactivity (M.T.) prior to being placed in formaldehyde and sent for histologic analysis.
Histologic examination was performed to determine the presence of melanoma cells within the SLNs. The SLN specimens were sectioned, and analysis was performed by an experienced dermatopathologist (G.F.M.) using a video-based computerized image analysis system (Southern Micro Instruments, Atlanta, Ga) coupled to a microscope (BH-2; Olympus America, Orangeburg, NY). Because metastatic deposits in this model are known to involve cells with abundant melanin synthesis, tumor nodules in the lymph nodes could be mapped with computer-assisted pseudocolor imaging to better depict their spatial geometry related to cellular composition (14,15). With this technique, metastatic deposits appeared green, in contrast to the relatively nonmelanized lymph node parenchyma, which appeared pink. This approach permitted side-by-side comparisons of lymphatic US scans and histologic images of the SLNs.
Data Analysis
Comparisons of the lymphatic US scans and histologic findings were performed in consensus (D.A.M., B.B.G.) with review of US images and specimens. Additional consensus analyses performed by the same two investigators included determination of false-positive and false-negative lymphatic US and lymphoscintigraphic findings (as they compared with the standard of blue dye for detection of SLNs) and lymphatic US with histologic findings (for SLN metastases).
Sensitivity and specificity for the presence or absence of metastases within the SLNs were calculated as the number of true-positive and true-negative decisions divided by the total number of positive and negative cases, respectively. The overall accuracy was determined as the number of correct decisions divided by the total number of cases. The sensitivity of SLN detection rates with lymphatic US and lymphoscintigraphy was compared (with blue dye and surgical dissection as the standard) by using the exact sign test, with P values less than .05 indicating a significant difference. The exact test sign was used since there were less than 16 nonzero rankings. Moreover, the use of a nonparametric test avoids the issue of independent observations, which otherwise arise when multiple SLNs are analyzed from the same animal. The ability of lymphatic US to depict metastatic disease in SLNs was compared with that of histologic examination by using the statistic (values > 0.75 indicate excellent reproducibility and values between 0.40 and 0.75, good reproducibility).
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Pulse-inversion harmonic gray-scale US provided better depiction (ie, increased conspicuity) of contrast material within the LCs and SLNs than did conventional (nonharmonic) US. When conventional gray-scale US was used after contrast material administration, there was some increase in echogenicity of the SLNs, but the increased reflectivity seen with conventional US was minimal in the SLNs and could not be identified at all within the LCs. Enhancement of SLNs was observed with pulse-inversion harmonic gray-scale US as long as 3 hours after peritumoral injection of the US contrast agent, suggesting that the contrast agent microbubbles might be trapped (ie, phagocytized) by lymphatic macrophages and were not in transit through the SLN. Contrast material was never observed in LCs or in second echelon nodes beyond the SLNs. SLNs were detected with lymphatic US as far as 35 cm away from the melanoma tumor and the location of the injection site.
The lymphatic drainage pathways were variable, which made the prediction of the most likely courses of the LCs and the locations of the SLNs difficult. For example, in one case of a melanoma located on the lower right lateral chest wall, the pathway of a single LC was identified coursing through an intercostal space, around the lateral posterior aspect of the kidney, and ultimately draining into a right retrocaval SLN (Fig 4). Blue dye and surgical exploration helped identify an LC in the same location, which was most likely the same LC that was identified with lymphatic US. Histologic examination helped determine that the SLN was free of metastasis, which was consistent with the lymphatic US diagnosis. In another animal with a primary tumor in nearly an identical location (lateral chest wall), there were two separate LCs leading from the tumor, one of which coursed subcutaneously to an SLN located in the supraclavicular region and the other coursed inferiorly to an SLN in the pelvis. Again, these findings were confirmed with blue dye and dissection.
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SLNs that contained US-detectable metastases demonstrated areas of increased echogenicity (normal lymph node parenchyma) and areas that did not enhance as a result of tumor infiltration and displacement or destruction of the normal tissue (Figs 6, 7a). Twenty-two of the 28 SLNs detected with lymphatic US were classified (by the blinded readers in consensus) as having metastases. There was one false-negative lymphatic US finding for metastases, a small 9 x 9 x 4-mm SLN. There were three false-positive lymphatic US findings for metastases.
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Gross Pathologic and Histologic Examination
Thirty-one SLNs were identified by using blue dye with surgical dissection (considered the standard for SLN detection). After dissection of the swine, the blue dye within the LCs allowed visual identification of the locations, numbers, and courses of the LCs draining into the tumor and the location of the SLNs relative to the primary tumor (Fig 7c).
Tumor metastases were identified histologically in 21 of the 31 SLNs (Fig 7d). Histologic examination helped identify intranodal hemorrhage in one SLN and a florid sinus histocytosis in two SLNs. None of these three nodes contained metastases. Two of these three nodes were detected with lymphatic US, and they represented two of the three false-positive findings for metastases.
Data Analysis
There were three SLNs that were not detected with lymphatic US but that were identified with blue dye and dissection, one of which was also not detected with lymphoscintigraphy. Among the three SLNs not detected with lymphatic US, histologic examination determined that one had microscopic tumor deposits, one had florid sinus histocytosis, and one was normal. There were no false-positive lymphatic US findings in terms of SLN detection. The overall sensitivity of SLN detection was 90% for lymphatic US (28 of 31 correctly identified SLNs) and 81% for lymphoscintigraphy (25 of 31 correctly identified SLNs, excluding the two false-positive findings). When lymphatic US was compared with lymphoscintigraphy, the improvement was not statistically significant (P = .29).
The sensitivity and specificity of lymphatic US for correctly depicting metastatic disease in swine SLNs were 95% and 63%, respectively, with an overall accuracy of 86% (Table 2). These numbers were based on correctly identifying 19 of 20 SLNs with metastases and five of eight normal SLNs. The prevalence of metastases in the SLNs was 68% (21 of 31). There was good reproducibility between lymphatic US and histologic examination ( = 0.62, P < .001). It was possible with real-time lymphatic US to noninvasively follow the lymphatics from the primary tumor to the SLNs, to determine the location of the lymphatics and lymph nodes, and to detect metastases within the SLNs.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In general, detection of SLNs is an accurate procedure, but pitfalls exist. The surgeon may resect a prominent SLN but may overlook a smaller SLN that harbors microscopic metastasis. With lymphoscintigraphy, the area of radioactivity may be interpreted as being one SLN, especially if the adjacent SLN is much smaller. With lymphatic US, this problem should be reduced, because it is possible to demonstrate the spatial relationship of individual SLNs that are immediately adjacent to each other and the individual draining LCs prior to the surgical intervention. Some variation in the sensitivity of detecting SLNs by using both blue dye and radioactivity has been reported, from as low as 76% to as high as 97% (2,20). In these melanoma swine experiments, the sensitivity of lymphatic US in depicting SLNs was 90% compared with 81% for lymphoscintigraphy. Thus, our lymphatic US results were within the range reported in the literature. When lymphatic US was compared with lymphoscintigraphy, the improvement was not statistically significant (P = .29). Perhaps this was due to the relatively small number of melanomas examined and the use of a less powerful, exact, nonparametric test to bypass dependency issues (ie, having more than one tumor per animal) and to account for the small sample size.
There are other limitations to the established methods of SLN detection and localization. For instance, with the use of blue dyes it is not infrequent that there will be staining of not only the SLN but also of adjacent lymph nodes, which often leads to a more extensive nodal dissection than is needed. Most radioactive materials make use of small particles such as human serum albumin and colloid albumin, as well as filtered sulfur colloids. These small particles may drain well within the LCs; however, because of their size, they may actually pass through the SLNs, resulting in drainage into secondary lymph nodes (ie, nodes that are not SLNs). It has been shown that radioactive particles of larger size have the highest SLN detection rate (21).
The unpredictability of the LC pathways and the locations of SLNs relative to the location of the primary tumor suggest that each tumor must be thoroughly evaluated because the number and locations of a tumor’s SLNs can be highly variable. The relative ease with which the LCs could be visualized with lymphatic US without any substantial massaging of the injection site was established in these studies. The ability to noninvasively follow the US contrast agent in the LCs to the SLN(s) has advantages over the use of blue dye, since there is no need for dissection of the LCs. Injections at different sites around the primary tumor demonstrated (qualitatively) different rates of flow within the LCs, although the distances between the injection site and SLN were almost identical. It is possible that the increased pressure resulting from the injection of 0.25 mL of contrast material into the peritumoral area added sufficient localized pressure to force the contrast material into the LC and, therefore, increase its rate of movement. In other cases, massaging the injection site accelerated movement of the US contrast agent through the LCs. The rate of movement of the contrast material may also be related to the size of the LCs. Whatever the cause, the ease with which the contrast kinetics could be observed and documented is a novel feature of lymphatic US.
It should be noted that pulse-inversion harmonic gray-scale US is much more useful than conventional US to effectively perform lymphatic US examinations. Thus, it is the combination of pulse-inversion harmonic gray-scale US and the contrast material that results in effective lymphatic US examinations. When an attempt was made to localize the LCs and SLNs after contrast material administration, it was not uncommon to see other bright linear reflections. Some of these were likely related to small blood vessels and other structures, such as fibrous strands within muscles, as well as other linear tissue interfaces, such as pleural or peritoneal reflections. The reflectivity of these structures can give a false impression of them being contrast material–filled LCs. In these cases, color Doppler imaging was used to easily distinguish between contrast-enhanced LCs and nonenhanced linear echogenic structures. Within a relatively short time after color Doppler imaging was turned off, refilling of the LC could be seen with pulse-inversion harmonic gray-scale US. Color Doppler imaging of the acoustic emission phenomenon was also a highly effective way of confirming the presence of contrast material in the SLNs and to distinguish SNLs from other echogenic structures that did not contain contrast agent microbubbles.
Of particular interest was the exploration of the drainage patterns of the primary melanoma tumors by varying the normally accepted approach of performing simultaneous injections at four sites around the tumor. In the latter three swine, individual 0.25-mL injections were made and lymphatic US was performed after each injection. This allowed visualization of LCs that emanated from only that one injection site. This technique was used at the 12-, 3-, 6-, and 9-o’clock positions, and lymphatic drainage from each site was followed to the SLN(s).
After peritumoral injection of the US contrast agent, there were no cases of any secondary nodes (ie, non-SLNs) being detected, which suggests that the microbubbles were phagocytized by the reticuloendothelial cells within the lymphatic system as opposed to being in transit through the SLNs. The safety of intravenous administration of this US contrast agent has already been established in numerous animal studies and, more important, in human studies for the evaluation of both the liver and heart in the United States and Europe (9,22,23). There are no published reports, to our knowledge, on the safety of intradermal injection of this US contrast agent.
Mattrey et al (24) and Kono et al (25) have reported their experiences of using a US contrast agent for lymph node evaluations in animals. However, they did not use a naturally occurring malignancy model or comparisons with results of lymphoscintigraphy or blue dye with surgical dissection. Furthermore, their published reports did not describe the ability to visualize the LCs, which was a useful characteristic that was identified in our experiments.
Practical application: Other lymphogenic contrast agents have been used with computed tomography (26) and magnetic resonance imaging (27,28) to help identify regional nodal metastasis in animal models. Lymphatic US offers an advantage over these other methods in that the LCs can be followed to the SLNs in real-time. In addition, once an SLN is localized, US (by using the same scanner) can then be used to guide biopsy or surgical resection of the node for a definitive histologic diagnosis.
The future use of lymphatic US to localize SLNs in humans has several potential advantages over lymphoscintigraphy. There will be no problems related to working with radioactive agents (eg, handling and disposal) nor those associated with contamination of tissue and instrumentation with radioactive material at the time of surgery. While lymphoscintigraphy can sometimes depict LCs, it is not common nor expected clinically. As a result, it can be difficult to identify whether there is more than one SLN or whether there has been passage of the radioactive material through the SLN into secondary nodes. In addition, adjacent SLNs, especially if one SNL is beneath the other, may not be easily distinguished with lymphoscintigraphy but this should not be a problem with lymphatic US. Furthermore, lymphatic US has capabilities for this application that are lacking in the current methods of blue dye and radioisotope injections. Specifically, lymphatic US allows real-time imaging of contrast kinetics within the draining LCs from the tumor sites and provides anatomic images of SLN architecture, with the possibility of providing noninvasive determination of metastasis within the SLNs. While blue dye can demonstrate lymphatic pathways, it requires dissection (in some cases extensive) to identify them with clarity and to follow them to the SLNs.
In conclusion, these experiments have demonstrated the ability of lymphatic US to identify LCs and SLNs in swine with naturally occurring melanoma tumors. The results show no significant difference between lymphatic US and lymphoscintigraphy in the detection of SLNs. Lymphatic US appears to have some potential benefits over the existing methods used for SLN detection, including the ability to noninvasively follow in real-time the course of the LCs from the primary tumor to the SLN and to identify metastases within the SLNs. Additional research is needed to determine if this new method of SLN detection can be used in clinical applications.
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FOOTNOTES |
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Abbreviations: LC = lymphatic channel, SLN = sentinel lymph node
Author contributions: Guarantor of integrity of entire study, B.B.G.; study concepts, B.B.G., F.F., A.T.; study design, B.B.G., F.F., A.T., D.A.M., M.T.; literature research, B.B.G., G.F.M.; experimental studies, B.B.G., J.B.L., D.A.M., M.T., G.F.M., L.N., F.F.; data acquisition, B.B.G., D.A.M., J.B.L., M.T., G.F.M., L.N.; data analysis/interpretation, D.A.M., A.T., F.F., L.N., B.B.G.; statistical analysis, F.F.; manuscript preparation, B.B.G., D.A.M, G.F.M.; manuscript definition of intellectual content, B.B.G.; manuscript editing, D.A.M., B.B.G., F.F., G.F.M.; manuscript revision/review and final version approval, all authors
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