Research ArticleClinical Investigation

High Tumor Uptake on 18F-FDOPA PET/CT Indicates Poor Prognosis in Patients with Metastatic Midgut Neuroendocrine Tumors: A Study from the Groupe d’étude des Tumeurs Endocrines and ENDOCAN-RENATEN Network

Ophélie De Rycke, Marine Perrier, Éric Ouvrard, Clément Mennetrey, Choaib Lachachi, Aurélie Bando-Delaunay, David Morland, Bernard Goichot, David Taieb, Thomas Walter, Guillaume Cadiot, Jérôme Cros, Olivia Hentic, Philippe Ruszniewski, Rachida Lebtahi, Alessio Imperiale and Louis de Mestier
Journal of Nuclear Medicine November 2023, 64 (11) 1699-1705; DOI: https://doi.org/10.2967/jnumed.123.265584

Abstract

PET/CT with 6-18F-fluoro-l-dopa (18F-FDOPA) has high diagnostic performance for midgut neuroendocrine tumors (NETs). We explored the prognostic role of 18F-FDOPA PET/CT uptake in metastatic midgut NETs. Methods: We included, in a test cohort (n = 166) and a full external validation cohort (n = 86), all consecutive patients with metastatic midgut NETs who underwent 18F-FDOPA PET/CT in 5 expert centers from 2010 to 2021. We measured the maximal uptake (SUVmax and SUVpeak) of the tumor and nontumor liver on each 18F-FDOPA PET/CT scan. We measured overall survival (OS) from the time of PET/CT and assessed prognostic factors using Kaplan–Meier and multivariable Cox proportional-hazards analyses in the test cohort, with replication in the validation cohort. Results: Patients had similar characteristics in both cohorts. In the test cohort, median follow-up was 60.3 mo. Patients with an SUVpeak tumor-to-liver (T/L) ratio of more than 4.2 had significantly shorter survival than those with a ratio of 4.2 or less (P = 0.01), with a 5-y OS rate of 74.1% ± 4.5% versus 95% ± 3.4%, respectively. On multivariable analysis, an SUVpeak T/L ratio of more than 4.2 remained associated with shorter OS (hazard ratio, 2.30; 95% CI, 1.02–5.22; P = 0.046) after adjustment for age, grade, number of previous lines, number of metastatic sites, and presence of carcinoid syndrome. In the validation cohort, the 5-y OS rate was 100% versus 57.8% ± 12.5% in patients with an SUVpeak T/L ratio ≤ 4.2 or > 4.2, respectively (P = 0.075). An increasing SUVpeak T/L ratio over time tended to have a pejorative prognostic impact. Conclusion: Tumor uptake on 18F-FDOPA PET/CT is an independent prognostic factor in patients with metastatic midgut NETs.

Neuroendocrine tumors (NETs) are a heterogeneous group of rare neoplasms with an increasing incidence (1). Midgut NETs are among the most frequent localizations of NETs and encompass NETs arising from the jejunum, ileum, appendix, and cecum (1). They derive from enterochromaffin cells able to produce serotonin and other hormones and peptides, whose hypersecretion can cause carcinoid syndrome (2). Apart from appendiceal NETs, 50%–65% of patients with midgut NETs have distant metastases, mainly in the liver (3). Nevertheless, because of their relatively slow evolution, overall survival (OS) is generally prolonged even in cases of metastases (1). The main prognostic factors for patients with metastatic midgut NETs include metastatic extension, notably extrahepatic; tumor volume, including liver involvement; tumor grade determined by the Ki-67 index; and hormone complications such as carcinoid heart disease (4,5).

Nuclear medicine plays an important role in the diagnosis, characterization, follow-up, and treatment of metastatic midgut NETs. 68Ga-labeled somatostatin analogs used for somatostatin receptor PET/CT have achieved consensus among expert panels as a forefront radiopharmaceutical for midgut NETs (6,7). Besides, midgut NETs have the ability to metabolize the dopamine precursor 3,4-dihydroxyphenylalanine (DOPA), whose amino acid analog 6-18F-fluoro-l-dopa (18F-FDOPA) is a radiotracer available for PET imaging. 18F-FDOPA PET/CT has excellent diagnostic performance for midgut NETs—superior to that of morphologic imaging and somatostatin-receptor scintigraphy—and yields a significant clinical impact (8–10). In addition, several recent head-to-head comparisons reported that 18F-FDOPA PET/CT has a higher sensitivity than 68Ga-DOTATOC PET/CT at the lesion scale (11–15).

Whereas the diagnostic role of 18F-FDOPA PET/CT is now well described, its prognostic impact has never, to our knowledge, been explored. The objective of this study was to assess the prognostic value of tumor uptake on 18F-FDOPA PET/CT in patients with metastatic midgut NETs.

MATERIALS AND METHODS

Patients

We performed a retrospective multicentric study under the auspices of the Groupe d’étude des Tumeurs Endocrines. 18F-FDOPA PET/CT has been approved and available in France since 2007, whereas 68Ga-DOTATOC PET/CT was approved in 2017. Because of the superior performance of 18F-FDOPA PET/CT compared with somatostatin-receptor scintigraphy (111In-chloride [Octreoscan; Curium]) in patients with metastatic small-intestine NETs (9,10), it has been used routinely for diagnosis, staging, and restaging.

We reviewed the medical records of all consecutive patients with midgut NETs and liver metastases who underwent at least one 18F-FDOPA PET/CT scan between January 1, 2010, and January 1, 2021, in 1 of 5 centers of the French NET expert network (ENDOCAN-RENATEN). We excluded patients with poorly differentiated neuroendocrine carcinoma and those without a 18F-FDOPA PET/CT scan available for review, without metastases visible on a 18F-FDOPA PET/CT scan, or without clinical data available. This study was performed according to the Helsinki convention. Data collection was anonymous after patient consent and institutional review board approval (CEERB Paris-Nord University approval 00006477-15-073).

Data Collection and 18F-FDOPA PET/CT Analysis

We retrospectively collected the main characteristics of patients at baseline (date of the first 18F-FDOPA PET/CT scan) using a standardized chart. Anonymized data collection included epidemiologic variables, detailed tumor staging, pathologic characterization, prior treatments, and survival.

All 18F-FDOPA PET/CT examinations were performed on hybrid PET/CT devices equipped with 3-dimensional time-of-flight technology and without iodinated contrast-medium administration. Patients in a given center were scanned on the same instrument. Patients were injected with an 18F-FDOPA dose of 3–4 MBq/kg. 18F-FDOPA (Dopacis; Cisbio International) was used in the setting of marketing authorization. The PET/CT protocol included an acquisition from the upper thigh to the top of the skull (3–5 min/step or continuous bed motion when available), starting approximately 60 min after injection of 18F-FDOPA. Carbidopa premedication (200 mg orally) 60–90 min before 18F-FDOPA injection was used in 24 patients in the validation cohort. PET image datasets were reconstructed iteratively (ordered-subsets expectation maximization algorithm) using non–contrast-enhanced data for attenuation correction. All 18F-FDOPA PET/CT scans were reviewed at each site by 1 expert nuclear physician, masked to clinical and survival data, after an initial central study board meeting was held to define the methodology of measurements in order to homogenize data collection.

The SUV was determined as a measure of 18F-FDOPA uptake using the region-of-interest technique. The maximum voxel (SUVmax) and a 1-mL sphere at the region of highest uptake (SUVpeak) were measured, as well as normal liver parenchyma, in each patient. To reduce potential partial-volume effects, the reference region of interest in the liver was kept consistently at 2 cm in diameter. We calculated the tumor-to-liver (T/L) ratios for SUVmax and SUVpeak.

Statistical Analyses

We divided the study population between a test cohort, including all patients from Beaujon Hospital, and a full external validation cohort, including all patients from the other centers. Quantitative variables were described using median and interquartile range (IQR) and compared using the Mann–Whitney test. Qualitative variables were described using frequency and percentage and compared using the χ2 test. Correlations between quantitative data were assessed using the Spearman test.

The primary endpoint was OS, measured between the date of the first 18F-FDOPA PET/CT scan and the date of death from any cause. Patients were censored if they were alive at the last follow-up. OS was estimated using the Kaplan–Meier method, expressed as median and 95% CI, and compared using the log-rank test. We determined the threshold of the SUVpeak or SUVmax T/L ratio corresponding to the highest prognostic value in the test cohort using receiver operating characteristic curves and the Youden index method. Then, independent prognostic factors were explored in the test cohort using univariate and backward-stepwise multivariate Cox proportional-hazards analyses. The prognostic impact of the best SUV ratio threshold was confirmed in the full external validation cohort using log-rank and univariate Cox proportional-hazards analyses.

Finally, in patients (whole cohort) who underwent an additional 18F-FDOPA PET/CT scan during their follow-up, we explored the prognostic impact of the best SUV ratio threshold on the last 18F-FDOPA PET/CT scan, and that of the increase in the best SUV ratio between the first and the last 18F-FDOPA PET/CT scans. A P value of less than 0.05 was considered significant.

The results of this study were reported in accordance with the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology)/REMARK (Reporting Recommendations for Tumor Marker Prognostic Studies) guidelines (Supplemental Table 1; supplemental materials are available at http://jnm.snmjournals.org). In the absence of previous publications reporting on the prognostic role of 18F-FDOPA PET/CT in patients with NETs, no prognostic hypothesis could be formulated, hence hampering calculation of a specific sample size. All the analyses were performed using Prism (version 6; GraphPad) and SPSS (version 20; IBM) software.

RESULTS

Characteristics of Patients

We identified 280 consecutive patients in total. After we excluded 28 patients, 252 were finally included in the study: 166 managed in Beaujon University Hospital, composing the test cohort, and 86 from the 4 other expert centers, composing the full external validation cohort (Fig. 1).

FIGURE 1.
FIGURE 1.

Flowchart of study. siNET = small-intestine NET.

The main characteristics of the test cohort are displayed in Table 1. Midgut NETs originated from the ileum in 91% of cases and were mostly classified as grade 1. At baseline, one third of patients had carcinoid syndrome. Hepatic and extrahepatic metastases were present in 88% and 73.5% of patients, respectively. Most patients (69.9%) had previously undergone surgical resection of the primary NET or metastatic lesions, and 54.8% of patients had received nonsurgical antitumor treatments, mostly somatostatin analogs.

View this table:
TABLE 1.

Baseline Characteristic of Patients at Time of 18F-FDOPA PET/CT, in Test and Validation Cohorts

Of note, the 166 patients included in the test cohort accounted for 59.1% of all patients managed in the same institution during the same period for a metastatic small-intestine NET. In comparison, the 112 patients with a metastatic small-intestine NET who did not undergo 18F-FDOPA PET/CT had similar survival, indicating that our test cohort was representative of the whole consecutive population of patients (Supplemental Fig. 1).

Prognostic Impact of SUVpeak T/L Ratio in Test Cohort

The median SUVpeak T/L ratio was 7.3 (IQR, 4.0–11.5), and the median SUVmax T/L ratio was 8.5 (IQR, 5.3–12.8). The correlation between the SUVpeak and SUVmax T/L ratios was excellent (r = 0.93, P < 0.001). The lesion with the highest uptake, that is, used to measure SUVpeak and SUVmax, was more frequently a liver metastasis (54.8%) or another distant metastasis (lymph node, peritoneal, bone, or lung in 12.7%, 10.2%, 5.4%, and 0.6%, respectively) than a primary midgut NET (1.8%) or a regional lymph node (14.5%).

The median follow-up after the 18F-FDOPA PET/CT scan was 60.3 mo (95% CI, 55.9–65.1), during which 47 patients died. We determined that an SUVpeak T/L ratio of more than 4.2 best predicted survival. Examples are displayed in Figure 2. Patients with an SUVpeak T/L ratio of more than 4.2 had significantly shorter survival than those with a ratio of 4.2 or less (P = 0.01), with a 5-y OS rate of 74.1% ± 4.5% versus 95% ± 3.4%, respectively (Fig. 3A). On univariate Cox proportional-hazards analysis, an SUVpeak T/L ratio of more than 4.2 was associated with a 2.62-fold increased risk of death (95% CI, 1.22–5.62; P = 0.014).

FIGURE 2.
FIGURE 2.

Examples of whole-body 18F-FDOPA PET images in patients with metastatic midgut NET and high tumor SUVpeak (T/L ratio, 17) (A) or low tumor SUVpeak (T/L ratio, 2.3) (B).

FIGURE 3.
FIGURE 3.

Impact of SUVpeak T/L ratio on OS in patients with midgut NETs who underwent 18F-FDOPA-PET/CT. (A) Test cohort (n = 166, P = 0.01). (B) External validation cohort (n = 86), P = 0.075).

On multivariate Cox proportional-hazards analysis (Table 2), an SUVpeak T/L ratio of more than 4.2 was independently associated with a significantly increased risk of death (hazard ratio, 2.30; 95% CI, 1.02–5.22; P = 0.046), after adjustment for age, grade, number of previous lines, number of metastatic sites, and presence of carcinoid syndrome.

View this table:
TABLE 2.

Univariate and Multivariate Cox Proportional-Hazard Models of Factors Associated with OS

Prognostic Impact of SUVpeak T/L Ratio in External Validation Cohort

The full external validation cohort included 86 patients from 4 expert centers. Baseline characteristics were similar to those of the test cohort, except that higher proportions of these patients had undergone prior metastasis surgery (34% vs. 18.7%, P = 0.008) and no prior nonsurgical antitumor treatment (59.3% vs. 45%, P = 0.034) (Table 1).

The median SUVmax T/L ratio was 9.2 (IQR, 5.4–12.1), and the median SUVpeak T/L ratio was 8.0 (IQR, 4.5–11)—without significant differences from the test cohort (P = 0.94 and P = 0.57, respectively).

The SUVpeak T/L ratio maintained its prognostic impact in the full external validation cohort. The 5-y OS rate was 100% for an SUVpeak T/L ratio of 4.2 or less versus 57.8% ± 12.5% (P = 0.075) for more than 4.2 (Fig. 3B). The prognostic impact of the SUVpeak T/L ratio was not different when studied in the subgroup of patients who received carbidopa premedication (Supplemental Fig. 2).

Prognostic Impact of Tumor Uptake on Subsequent 18F-FDOPA PET/CT

Overall, 104 patients underwent an additional 18F-FDOPA PET/CT scan during their follow-up. The median interval between scans was 28.5 mo (11.4–61.3). Patients with an SUVpeak T/L ratio of more than 4.2 on the additional 18F-FDOPA PET/CT scan had shorter survival than those with a ratio of 4.2 or less, with 5-y OS rates of 45.5% ± 15.8% versus 74.5% ± 17.1%, respectively (Fig. 4A). However, this difference was not statistically significant (P = 0.183).

FIGURE 4.
FIGURE 4.

Prognostic impact of subsequent 18F-FDOPA-PET/CT. (A) Prognostic impact of SUVpeak T/L ratio measured on subsequent 18F-FDOPA PET/CT scan (P = 0.183). (B) Prognostic impact of variation of SUVpeak T/L ratio between initial and subsequent 18F-FDOPA-PET/CT scans (P = 0.175).

Similarly, patients for which the SUVpeak T/L ratio increased between scans had shorter survival than patients for which it decreased, with 5-y OS rates of 41.8% ± 19% versus 70.5% ± 13.3%, respectively (Fig. 4B). However, this difference was not statistically significant (P = 0.175).

Correlation Between SUVpeak T/L Ratio and Disease Characteristics

We assessed whether SUVpeak T/L ratio correlates with clinical features among all patients. This ratio correlated with the urine 5-hydroxylindolacetic acid concentration (available for 145 patients, r = 0.436, P < 0.001) and, to a lesser extent, with plasma chromogranin A (available for 149 patients, r = 0.22, P = 0.007). Accordingly, the ratio was higher in patients with carcinoid syndrome (9.8; IQR, 6.3–12.7, vs. 6.6; IQR, 3.5–10.3; P < 0.001). The ratio did not correlate with Ki-67 index (r = −0.05, P = 0.42) or age (r = 0.06, P = 0.33). Conversely, it tended to be higher in patients with extrahepatic metastases (7.8; IQR, 4.4–11.6, vs. 7.0; IQR, 3.3–10.3; P = 0.06).

DISCUSSION

We demonstrated that 18F-FDOPA PET/CT has a significant prognostic impact in patients with metastatic midgut NETs. To the best of our knowledge, this was the first study showing the prognostic value of 18F-FDOPA PET/CT, in addition to its already known diagnostic impact, in a large multicentric cohort of patients with metastatic midgut NETs. Therefore, SUVpeak T/L ratio measured on 18F-FDOPA PET/CT could contribute, along with other known prognostic factors (e.g., tumor grade, number of metastatic sites, and tumor burden), to a better assessment of the prognosis of patients with metastatic midgut NETs and better choice of the most appropriate management.

In the test cohort comprising 166 patients with metastatic midgut NETs, an SUVpeak T/L ratio of more than 4.2, which relies on the lesion with highest uptake, was determined as the threshold with the highest prognostic impact on univariable analysis (P = 0.01). This prognostic impact remained statistically significant (hazard ratio, 2.3; 95% CI, 1.02–5.22; P = 0.046) after adjustment for classic prognostic factors related to the patient (age), disease extension (metastatic sites), biologic aggressiveness (grade), evolution (previous lines), or presence of carcinoid syndrome, the last of which was biologically associated with 18F-FDOPA uptake. Then, this result was replicated in the full external validation cohort containing 86 patients. Although the significance threshold was not reached in that cohort (P = 0.075), the reason was likely a lack of power since the prognosis of patients with an SUVpeak T/L ratio of 4.2 or less could not be improved further (100% survival)—which is by itself a strong argument supporting the prognostic impact of 18F-FDOPA uptake.

A prognostic factor is all the more relevant if it remains prognostic when measured at different time points of disease evolution, as illustrated by the prognostic impact of the Ki-67 index increase on new biopsies in patients with NETs (16). Hence, we performed sensitivity analyses among patients who underwent an additional 18F-FDOPA PET/CT scan during their follow-up and found that an SUVpeak T/L ratio of more than 4.2 on the second scan, as well as an increase in the ratio between the 2 scans, were associated with shorter survival. Although the differences did not reach significance, this finding strengthens the prognostic relevance of 18F-FDOPA PET/CT. Of note, whereas our study was not designed to identify the optimal SUVpeak T/L ratio threshold on subsequent scans, future studies should explore the dynamic prognostic role of 18F-FDOPA PET/CT over time.

The mechanisms underlying the prognostic impact of 18F-FDOPA PET/CT are unclear. 18F-FDOPA enters NET cells through the L-type neutral amino acid transporters LAT1 and LAT2, which are activated on their heterodimerization with the surface glycoprotein CD98/4F2hc (17,18). Then, intracellular metabolism is ensured through intracellular vesicular monoamine transporters and decarboxylation by the aromatic l-amino acid decarboxylase. This is the rate-limiting enzyme of serotonin and catecholamine biosynthesis and is highly active in midgut NETs, explaining high 18F-FDOPA retention in these neoplasms (19,20). Therefore, higher 18F-FDOPA uptake may reflect higher metabolism and biologic aggressiveness of NET cells, reflected by increased nutrient supply. Accordingly, increased expression of LAT1 and CD98/4F2hc were found to be associated with higher biologic aggressiveness and poorer prognosis in different malignancies (18), including digestive and lung NETs (21–24). Besides, LAT1 mediates the influx of essential amino acids, including tryptophan, a necessary substrate for the biosynthesis of serotonin, whose hypersecretion can lead to carcinoid syndrome (25). Hence, it is not surprising that high 18F-FDOPA uptake correlated with the presence of carcinoid syndrome and the level of 5-hydroxyindolacetic acid, as reported before (15,26). Finally, LAT1 and CD98/4F2hc expression is associated with activation of the mammalian-target-of-rapamycin pathway (23,27). Future studies should explore whether 18F-FDOPA uptake could serve as a predictive marker for mammalian-target-of-rapamycin inhibitors, which have demonstrated efficacy in NETs (28,29).

Future investigation should focus on specifying the ranking of 18F-FDOPA PET/CT in comparison with other nuclear imaging techniques available for NETs, especially PET/CT using 68Ga-DOTA-peptides. Both techniques have high diagnostic performance, whereas 68Ga-DOTA-peptide PET/CT has an exclusive theranostic impact because it predicts the efficacy of peptide-radionuclide radiation therapy targeting somatostatin receptors. In addition, the prognostic role of 68Ga-DOTA-peptide PET/CT has been reported, with higher tumor uptake indicating better prognosis (30,31). Conversely, higher uptake on 18F-fluorodesoxyglucose PET/CT is associated with poorer prognosis in patients with digestive NETs (32). Hence, noninvasive prognostic assessment using nuclear medicine would likely benefit from a multiparametric approach using several radioisotopes, among which the precise role of 18F-FDOPA should be better specified.

The main limitation of our study was its retrospective design, although there was a low proportion of missing data and there were protocolized clinical collection and 18F-FDOPA PET/CT measurements. We present here the largest comprehensive cohort of patients with metastatic midgut NETs and 18F-FDOPA PET/CT imaging available, to the best of our knowledge. Although some patients had to be excluded, mainly because they lacked available 18F-FDOPA PET/CT scans or a liver metastatic target, exclusions were limited and were unlikely to induce a selection bias. Several factors can influence SUVs, including the machine type, injected activity, and acquisition time (26). Notably, the fact that no early PET acquisition was done may influence the sensitivity with which liver metastatic lesions are detected. These potential biases were minimized by normalizing tumor uptake for the nontumor liver on the same PET scan, as the 18F-FDOPA biodistribution data show a relatively constant hepatic uptake intensity (6). Finally, we split patients into a test cohort composed of all patients from Beaujon Hospital (n = 166, 66%) and a validation cohort composed of all patients from the 4 other centers (n = 86, 34%), because it was the only way to perform a full external validation cohort, which is the methodologic reference, and because, otherwise, the separation of all patients into two thirds (test) and one third (validation) would have caused patients from one center to represent 66% of each cohort, hence resulting in a major center-effect bias.

CONCLUSION

We demonstrated in a large comprehensive cohort that SUVpeak T/L ratio measured on 18F-FDOPA PET/CT had a significant prognostic impact in patients with metastatic midgut NETs. This result was confirmed in a multivariable analysis and was replicated in a full external validation cohort. Future translational studies should explore the molecular bases of this prognostic impact and aim at identifying potential related therapeutic targets.

DISCLOSURE

This study was financed by an academic research grant from the Groupe d’étude des Tumeurs Endocrines (Fonds de Recherche 2020). Marine Perrier receives support from Adacap and Ipsen for attending meetings. Aurélie Bando-Delaunay is a consultant for Adacap, Boston Scintific, and SIRTex. Bernard Goichot is a consultant for Adacap and Ipsen and receives support from Ipsen for attending meetings. David Taieb is a lecturer and consultant for Adacap and receives support from Adacap for attending meetings. Thomas Walter receives research support from Ipsen and Roche SAS; is a consultant or on the advisory board for Adacap, Ipsen, Terumo, and Servier; and receives support from Ipsen and Servier for attending meetings and from Adacap, Bayer, Bristol-Myers Squib, Incyte, and Ipsen for attending educational events. Guillaume Cadiot is a consultant for Adacap and Ipsen and receives honoraria from Esteve. Jérôme Cros receives honoraria from Adacap for presentations. Olivia Hentic is a consultant for Adacap and Ipsen and receives support from Esteve and Ipsen for attending meetings. Philippe Ruszniewski is an advisor to Adacap, Ipsen, and ITM Solucin. Rachida Lebtahi is a consultant to Adacap, Ipsen, and SIRTex. Louis de Mestier is a consultant to Adacap, Esteve, Ipsen, Mayoli, and SIRTex; receives research support from Esteve; and receives support from Ipsen for attending meetings. No other potential conflict of interest relevant to this article was reported.

KEY POINTS

QUESTION: What is the prognostic role of tumor uptake on 18F-FDOPA PET/CT in patients with metastatic midgut NETs?

PERTINENT FINDINGS: We studied 252 consecutive patients with metastatic midgut NETs who underwent 18F-FDOPA PET/CT, and we measured SUVmax and SUVpeak. A T/L SUVpeak ratio of less than 4.2 was associated with good prognosis in a test cohort, on multivariable analysis and in a full external validation cohort.

IMPLICATIONS FOR PATIENT CARE: In addition to its high diagnostic performances, the independent prognostic impact of 18F-FDOPA PET/CT encourages its use for the evaluation of patients with metastatic midgut NETs, to improve case-by-case management.

ACKNOWLEDGMENTS

We thank the patients and their organization (Association des Patients Porteurs de Tumeurs Endocrines Diverses) for their participation. We also thank the ENDOCAN-RENATEN clinical network, a French Organization for Neuroendocrine Neoplasm Management constructed and supported by the Groupe d’étude des Tumeurs Endocrines.

Footnotes

  • Published online Aug. 31, 2023.

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  • Received for publication February 10, 2023.
  • Revision received July 17, 2023.
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