Epidemiology and outcomes of primary pediatric lung malignancies: Updates from the SEER database

Abstract

Background:

Primary pediatric lung malignancies are rare tumors. We provide an updated analysis of the epidemiology and prognosis of these tumors since the last SEER series published in 2009.

Methods:

The SEER 18 database from 1975 to 2016 was analyzed for patients ages 0–19 years with primary lung and/or bronchus neoplasms.

Results:

348 patients met inclusion criteria. The majority were white and ≥12 years of age. The most common histologies were neuroendocrine (41.4%) and blastoma (16.4%). 75.4% of patients had local-regional disease and 81.4% underwent surgery. Significant differences between histologies were seen for age, year at diagnosis, tumor laterality and location, stage, and treatment type. Median survival was 36.6 years (95% CI 33.3–37.4). Blastoma (HR 3.47) and squamous cell (HR 6.26) carried a significantly higher risk of death than neuroendocrine cancer diagnosis.

Conclusion:

Primary pediatric lung malignancies are rare, long-term survival is favorable but histology-dependent. Surgery continues to be an important treatment modality.

Introduction

Primary lung malignancies are a rare entity in the pediatric population. These unique tumors have an annual incidence of just 0.049 per 100,000 persons, thus making it difficult to study this disease.¹ These tumors encompass several histologic variants and their distribution is unique compared to those tumors seen in adults.^1,2

The current literature on pediatric lung neoplasms is limited to small-volume, single-institution, retrospective case series with limited long-term follow-up, prognostic data, and treatment data. The exceptions are two population-based studies. The first examined the Surveillance, Epidemiology, and End Results (SEER) database from 1973 to 2004 and analyzed 160 patients.¹ Most patients in this initial analysis were adolescent, white, and underwent surgical resection. Overall median survival was found to be 31.8 years. The most common histological subtypes were neuroendocrine, sarcoma, and mucoepidermoid, with neuroendocrine and mucoepidermoid tumors demonstrating the best survival. The second large scale study analyzed the National Cancer Database (NCDB) from 1998 to 2011 and included 211 patients. Both the SEER and NCDB studies had similar findings for patient demographics, histological subtypes, and overall median survival.²

While insightful into both the epidemiology and prognosis of this rare disease, both of these studies are limited by their relatively brief follow-up interval and small cohort sizes. By using the most recently available SEER database, this study provides an update on the epidemiology, histopathological features, and prognosis of primary pediatric lung neoplasms.

Methods

The SEER 18 database of the National Cancer Institute (NCI) was queried from the years 1975–2016 for primary pediatric lung neoplasms. Cases identified as having a lung and/or bronchus neoplasm by site and morphology recode (based on the International Classification of Diseases for Oncology 3rd Edition (ICD-O-3) by the World Health Organization (WHO) 2008) and who were between 0 and 19 years of age were included.

Histological tumor subtypes were identified and classified into the following groups: mucoepidermoid, neuroendocrine, adenocarcinoma, squamous cell carcinoma, small cell carcinoma, pulmonary blastomas, and other. The “other” histological group is comprised of the least common histological subtypes which includes neuroectodermal, lymphoepithelial carcinoma, large cell neuroendocrine, carcinoma not otherwise specified, neuroectodermal, histiocytoma, germ cell tumors, neuroblastomas, hemangioendothelioma, myofibroma, lymphoepithelial, and neuroepitheliomas.

Categorical study variables were summarized by their frequencies and percentages. Baseline characteristics between different histological groups were compared using chi-square test. Kaplan-Meier analysis was used to estimate survival probabilities. Cox proportional hazards model was used to identify risk factors associated with overall survival. The following variables were considered as potential predictors of survival: patient sex, race, age at diagnosis, disease histology and if the individual underwent surgical resection. All variables were checked for proportionality assumption. Only variables significant at the level of significance of 0.05 were retained in the final model. Analyses were performed using SAS version 9.4 (Cary, NC).

Results

Three hundred forty-eight (348) patients met inclusion criteria. One hundred eighty nine (189) cases occurred between 2005 and 2016, thereby doubling the number of new cases since the previous SEER analysis was published in 2009. Within the study cohort, 50.6% of cases were diagnosed during the year 2005 or later. Mean patient age was 13.2 years with a bimodal distribution in the age at time of diagnosis (Fig. 1). Patient sex was equally distributed by histological subtype; however, the majority of patients were white (81.4%) and age 12 years old and older (71.6%). The most common tumor histology subtype was neuroendocrine (41.4%) followed by blastoma (16.4%), and mucoepidermoid (10.6%). The majority of patients had unilateral (97.4%), local-regional disease (75.4%), and 81.4% of patients underwent surgery (Table 1). The histologic distribution of tumors has changed significantly since the previous SEER analysis (i.e., 1975–2004 vs 2005–2016), with a higher proportion of cases seen in the blastoma, mucoepidermoid, squamous, and adenocarcinoma histological subtypes and a lower proportion of sarcoma, small cell, and neuroendocrine subtypes. (supplementary material, sTable 1). Additionally, the proportion of cases presenting as regional disease has increased since the prior analysis from 67.3% to 80% (p = 0.022) (Table 2).

Fig. 1.

Distribution of age at time of diagnosis at two-year intervals.

Table 1.

Univariate of patient characteristics by histologic subtype.

Variables	Histology										p-value
	Total	Mucoepidermoid	Neuroendocrine	Squamous	Adenocarcinoma	Small Cell	Blastoma	Sarcoma	Other<	Unknown
	N = 348 (%)	N = 37 (%)	N = 144 (%)	N = 14 (%)	N = 29 (%)	N = 6 (%)	N = 57 (%)	N = 28 (%)	N = 26 (%)	N = 7 (%)
Sex											0.200
Male	171 (49.1)	20 (54.1)	64 (44.4)	5 (35.7)	11 (37.9)	3 (50.0)	29 (50.9)	16 (57.1)	19 (73.1)	4 (57.1)
Female	177 (50.9)	17 (45.9)	80 (55.6)	9 (64.3)	18 (62.1)	3 (50.0)	28 (49.1)	12 (42.9)	7 (26.9)	3 (42.9)
Race											0.056
White	281 (81.4)	27 (73.0)	120 (83.9)	9 (64.3)	26 (89.7)	6 (100.0)	49 (86.0)	24 (85.7)	17 (68.0)	3 (50.0)
Black	48 (13.9)	6 (16.2)	21 (14.7)	3 (21.4)	2 (6.9)	0 (0.0)	5 (8.8)	3 (10.7)	5 (20.0)	3 (50.0)
Other	16 (4.6)	4 (10.8)	2 (1.4)	2 (14.3)	1 (3.4)	0 (0.0)	3 (5.3)	1 (3.6)	3 (12.0)	0 (0.0)
Missing	3	0	1	0	0	0	0	0	1	1
Age at Diagnosis											<0.001
0–5 Years	68 (19.5)	3 (8.1)	1 (0.7)	0 (0.0)	2 (6.9)	0 (0.0)	50 (87.7)	8 (28.6)	3 (11.5)	1 (14.3)
6–11 Years	31 (8.9)	14 (37.8)	4 (2.8)	1 (7.1)	6 (20.7)	1 (16.7)	1 (1.8)	3 (10.7)	0 (0.0)	1 (14.3)
12–20 Years	249 (71.6)	20 (54.1)	139 (96.5)	13 (92.9)	21 (72.4)	5 (83.3)	6 (10.5)	17 (60.7)	23 (88.5)	5 (71.4)
Year at Diagnosis											0.012
1975–1989	56 (16.1)	2 (5.4)	34 (23.6)	3 (21.4)	4 (13.8)	2 (33.3)	1 (1.8)	3 (10.7)	5 (19.2)	2 (28.6)
1990–2005	116 (33.3)	13 (35.1)	48 (33.3)	3 (21.4)	8 (27.6)	2 (33.3)	17 (29.8)	15 (53.6)	7 (26.9)	3 (42.9)
2006–2016	176 (50.6)	22 (59.5)	62 (43.1)	8 (57.1)	17 (58.6)	2 (33.3)	39 (68.4)	10 (35.7)	14 (53.8)	2 (28.6)
Stage											<0.001
Regional	214 (75.4)	32 (97.0)	101 (91.0)	4 (36.4)	11 (45.8)	0 (0.0)	44 (80.0)	13 (56.5)	9 (40.9)	0 (0.0)
Distant	70 (24.6)	1 (3.0)	10 (9.0)	7 (63.6)	13 (54.2)	3 (100.0)	11 (20.0)	10 (43.5)	13 (59.1)	2 (100.0)
Missing	64	4	33	3	5	3	2	5	4	5
Laterality											0.002C +
Unilateral	331 (97.4)	37 (100.0)	143 (99.3)	11 (78.6)	26 (89.7)	5 (100.0)	57 (100.0)	26 (96.3)	24 (100.0)	2 (66.7)
Bilateral	9 (2.6)	0 (0.0)	1 (0.7)	3 (21.4)	3 (10.3)	0 (0.0)	0 (0.0)	1 (3.7)	0 (0.0)	1 (33.3)
Missing	8	0	0	0	0	1	0	1	2	4
Primary Tumor Location											0.317
Lower lobe	115 (38.6)	10 (27.0)	55 (40.1)	5 (41.7)	13 (59.1)	1 (33.3)	17 (35.4)	10 (45.5)	3 (18.8)	1 (100.0)
Middle lobe	35 (11.7)	7 (18.9)	18 (13.1)	1 (8.3)	2 (9.1)	0 (0.0)	6 (12.5)	0 (0.0)	1 (6.3)	0 (0.0)
Upper lobe	93 (31.2)	10 (27.0)	36 (26.3)	5 (41.7)	6 (27.3)	1 (33.3)	20 (41.7)	7 (31.8)	8 (50.0)	0 (0.0)
Main bronchus	40 (13.4)	9 (24.3)	22 (16.1)	0 (0.0)	1 (4.5)	1 (33.3)	3 (6.3)	2 (9.1)	2 (12.5)	0 (0.0)
Overlapping	15 (5.0)	1 (2.7)	6 (4.4)	1 (8.3)	0 (0.0)	0 (0.0)	2 (4.2)	3 (13.6)	2 (12.5)	0 (0.0)
Missing	50	0	7	2	7	3	9	6	10	6
Surgery											<0.001
Yes	281 (81.4)	37 (100.0)	130 (90.3)	7 (53.8)	19 (65.5)	2 (33.3)	55 (96.5)	17 (60.7)	12 (46.2)	2 (40.0)
No	64 (18.6)	0 (0.0)	14 (9.7)	6 (46.2)	10 (34.5)	4 (66.7)	2 (3.5)	11 (39.3)	14 (53.8)	3 (60.0)
Missing	3	0	0	1	0	0	0	0	0	2
Radiation											<0.001
Yes	55 (15.9)	1 (2.7)	8 (5.6)	7 (50.0)	8 (27.6)	3 (50.0)	8 (14.0)	9 (32.1)	11 (42.3)	0 (0.0)
No/Unknown	291 (84.1)	36 (97.3)	134 (94.4)	7 (50.0)	21 (72.4)	3 (50.0)	49 (86.0)	19 (67.9)	15 (57.7)	7 (100.0)
Missing	2	0	2	0	0	0	0	0	0	0
Chemotherapy											<0.001
Yes	119 (34.2)	1 (2.7)	10 (6.9)	9 (64.3)	16 (55.2)	4 (66.7)	41 (71.9)	16 (57.1)	20 (76.9)	2 (28.6)
No/Unknown	229 (65.8)	36 (97.3)	134 (93.1)	5 (35.7)	13 (44.8)	2 (33.3)	16 (28.1)	12 (42.9)	6 (23.1)	5 (71.4)

Table 2.

Disease stage distribution by year of diagnosis.

	Year of Diagnosis
Variables	Total	1975–2004	2005–2016	p-value
	N = 348 (%)	N = 159 (%)	N = 189 (%)
Stage				0.022
Regional	214 (75.4)	70 (67.3)	144 (80.0)
Distant	70 (24.6)	34 (32.7)	36 (20.0)
Missing	64	55	9

On univariate analysis, there was no difference in histological subtype with regard to sex or race. However, statistically significant differences were seen for age at time of diagnosis, year of diagnosis, tumor stage, primary tumor laterality, and treatment type: surgery, radiation, and chemotherapy (p < 0.05 for all) (Table 1). The majority of patients received surgery for all histologies, with the exceptions of small cell and “other” subtypes and are similar to the previous SEER analysis. Most notably, the percentage of patients with adenocarcinoma who underwent surgery demonstrated a statistically significant increase compared to the previous SEER series (41.7 vs 82.4%, p = 0.046) (supplementary material, sTable 2).

The use of chemotherapy and radiation remains dependent on histological subtype. The majority of patients with squamous cell, adenocarcinoma, small cell, blastoma, sarcoma, and “other” histological subtypes received chemotherapy as part of their treatment regimen. Radiation was used in only a minority of patients with the exception of squamous cell and small cell tumors, in which 50% of patients received radiation therapy. The rates of chemotherapy and radiation therapy have not changed significantly for most subtypes since the previous SEER database analysis, with the exceptions of neuroendocrine and blastoma subtypes. Neuroendocrine tumors demonstrated a statistically significant increase in the use of radiation (1.4 vs 10.0%, p = 0.032), while blastoma tumors demonstrated a statistically significant decrease in the use of chemotherapy (93.8 vs 63.4%, p = 0.046) (supplementary material, sTable 2).

Overall 10-year survival probability was 79% (95% confidence interval (CI) 74–85%) while 30-year survival probability was 60% (95% CI 50–68%) (Table 3). The highest 20-year survival of 77% (95% CI 56–89%) was observed among sarcoma patients with blastoma having the lowest (41%, 95% CI 10–71%). When compared to the previous SEER database analysis, 10-year survival significantly decreased overall (88–64%, p = 0.0009) and most notably for mucoepidermoid (100–59%, p = 0.013) and neuroendocrine tumors (97–72%, p = 0.0004) (supplementary material, sTable 3). Median overall survival was 36.6 years (95% CI 33.3–37.4 years), with the highest median survival seen in the neuroendocrine (36.6 years) and adenocarcinoma (36.8 years) subtypes (Table 4, Figs. 2 and 3).

Table 3.

Survival estimates in ten-year intervals for the overall cohort and each histological subtype.

Histological Subtype	Time Interval (years)	Survival Probability	95% CI
Overall	10	79%	74–85%
	20	63%	55–71%
	30	60%	50–68%
	40	31%	18–46%
Mucoepidermoid	10	84%	63–94%
	20	62%	32–81%
	30	62%	32–81%
Neuroendocrine	10	89%	82–94%
	20	71%	59–80%
	30	67%	55–77%
Squamous	10	NR
	20	NR
	30	NR
Adenocarcinoma	10	88%	66–96%
	20	58%	9–89%
	30	58%	9–89%
Blastoma	10	62%	45–75%
	20	41%	10–71%
	30	NR
Sarcoma	10	77%	56–89%
	20	77%	56–89%
	30	77%	56–89%

^*CI, confidence interval; NR = no patients under observation at this time.

Table 4.

Median survival (if reached) by histological subtype.

Histology Group	Median Survival (years)	95% CI
Mucoepidermoid	NR
Neuroendocrine	36.6	33.3–41.1
Squamous	NR
Adenocarcinoma	36.8	10.3–36.8
Blastoma	18.0	N/A
Sarcoma	NR

^†CI, confidence interval; NR, no patient under observation at this time.

Fig. 2.

Kaplan-Meier survival curve for the entire cohort. Legend: Median overall survival of 36.6 years (95% CI 33.3–37.4).

Fig. 3.

Kaplan-Meier survival curves for each histological subtype.

Tumor histology, stage, and undergoing surgery were identified as significant predictors of survival (Table 5). Patients with blastoma histology demonstrated an almost 3.5-fold increase in the risk of death (HR = 3.47, 95% CI 1.80–6.69, p = 0.0002) and those with squamous cell histology demonstrated an over 6-fold increase in the risk of death (HR = 6.26, 95% CI 1.66–23.58, p = 0.007) as compared to patients with neuroendocrine neoplasms. Patients who did not undergo surgery also had an increased risk of death (HR = 6.29, 95% CI 2.92–13.54, p < 0.001). There was no statistically significant difference in survival between patients with local/regional and distant disease.

Table 5.

Cox model for overall survival.

Variable	Categories	Hazard ratio (95% CI)	p-value	DF
Histology	Neuroendocrine	Reference	0.002	5
	Mucoepidermoid	1.15 (0.49–2.68)	0.747	1
	Squamous	6.26 (1.66–23.58)	0.007	1
	Adenocarcinoma	1.35 (0.51–3.57)	0.549	1
	Blastoma	3.47 (1.80–6.69)	<0.001	1
	Sarcoma	1.22 (0.49–3.07)	0.673	1
Stage	Local/Regional	Reference	0.040	2
	Distant	0.47 (0.18–1.22)	0.122	1
	Unknown	0.42 (0.02–0.91)	0.028	1
Surgery	Yes	Reference	–	–
	No	6.29 (2.92–13.54)	<0.001	1

^‡CI, confidence interval; DF, degrees of freedom.

Because surgery was a significant predictor of survival, univariate comparison of patients who were treated with and without surgery was performed. Patients who did not receive surgery were predominantly 12–20 years old, male, white, and presented with distant disease (supplementary material, sTable 4). The major histologies were neuroendocrine, sarcoma, and “other” and the majority of patients received chemotherapy as a treatment. Compared to the previous SEER database analysis cohort, there was no significant difference in patient demographics, tumor characteristics, or treatment in those that did not receive surgery compared to those that did undergo surgical resection (supplementary material, sTable 4). Compared to patients who did not receive surgery, those treated with surgery were more often female (54.4 vs 35.9%, p = 0.008), presented with regional disease (86.7 vs 23.5%, p < 0.001) and were less likely to receive chemotherapy (26.0 vs 70.3%, p < 0.001) and radiation (10.0 vs 42.9%, p < 0.001) (supplementary material, sTable 5).

Discussion

This updated SEER analysis of primary pediatric lung malignancies demonstrates an increase in reported cases and a substantial increase in the number of cases since the previous SEER publication. While overall survival remains favorable, overall survival was decreased when compared to the previous analysis. The most common histological subtype continues to be neuroendocrine. Statistically significant differences between various histologies were seen for age of diagnosis, year of diagnosis, primary tumor laterality, stage at presentation, and treatment type. Overall median survival was high at 36.6 years; however, patients with blastoma and squamous cell histologies carried a significantly higher risk of death compared with other histological subtypes. Treatment modalities are mostly unchanged with several exceptions based specifically on tumor histology. This updated data provides a more accurate representation of the prognosis of these rare tumors and can aid physicians, patients, and families in treatment decisions and aid in setting prognostic expectations.

Annual incidence from the previous SEER analysis was 5.1 cases per year. This analysis found an annual incidence of 15.8 cases per year since 2005 which is similar to the NCDB analysis from 1998 to 2011 that found an annual incidence of 16 cases per year.^1,2 The increase in the use of cross-sectional imaging in pediatric patient, and the ability for imaging to detect smaller lesions with greater sensitivity may be a possible explanation for the rising annual incidence.^3-8 Most new pediatric lung malignancies are found in adolescents, are symptomatic lesions, smaller than 5 cm, and diagnosed upon serial imaging.^1-6 Therefore, it stands to reason that the diagnosis of asymptomatic, incidental tumors and smaller symptomatic tumors may contribute to the rising annual incidence. Additionally, over the past decade, a better understanding of the radiographic characteristics of these lesions has allowed for better discrimination between true malignancies, congenital malformations, infectious, and inflammatory lesions and thus can shorten the duration from identification to diagnosis.^4,9,10 However, without data on current trends in diagnostic modalities in pediatric lung malignancies, an exact reason is not apparent.

The rarity of lung malignancies in pediatric patients has made the topic difficult to study since the majority of these tumors are benign or represent metastatic spread from an extrapulmonary source.^11-13,15 The first large systemic review was published in 1983 and documented 230 cases of primary pulmonary neoplasms in children, of which 65.6% were malignant.¹³ A decade later, a systemic review by Hancock et al. included 383 patients and reported 291 malignant cases (76%).⁵ However, the modern literature consistently demonstrates the predominance of benign primary pediatric lung tumors.^{3,6,9,11,12,15} The differences between current and past studies likely represent an evolution of our current understanding rather than a true change in histopathologic profile.

The histopathologic distribution of these malignancies varies somewhat amongst series, but notable consistencies are also found. This series again demonstrates that neuroendocrine tumors and blastomas are the most common histopathological subtypes, although with significant changes in distribution compared to last SEER database analysis.^1,3-5,11,15 Among infants and children, blastomas are the predominant histology with 87.7% occurring in patients ages 0–5 years of age and comprising 73.5% of tumors within this age group, which coincides with the lesion’s association with congenital lung malformations. Neuroendocrine tumors are predominantly seen among adolescents, comprising 55.8% of tumors in patients ages 12–20 years with 96.5% of neuroendocrine subtypes occurring in this age group.^14,16,17 While appendiceal tumors comprise the vast majority (80%) of neuroendocrine tumors diagnosed in pediatric patients, bronchial tumors are ranked second (11%) and are generally more aggressive than their indolent appendiceal counterparts.^18,19 Pediatric pulmonary neuroendocrine tumors have a greater predilection for atypical carcinoid histology, which are often asymptomatic and have a greater predilection for metastasis and poor survival.^14,18,20-23 Nonetheless, overall survival for primary lung neuroendocrine tumors in children is excellent with previous long-term disease-free survival rates reported at >95%.²⁴ Resection with negative margins is standard for neuroendocrine tumors and is often accomplished with parenchymal-sparing procedures.^2,20,24 As surgical intervention has been shown to be a significant predictor of survival, this is likely a contributing factor to the favorable survival for neuroendocrine histology.^1,2,20,24,25 However, since 2004, 10-year survival estimates for neuroendocrine tumors has significantly decreased, reflecting that the current high overall survival may be driven by a few long-term survivors and overall prognosis may actually be declining and/or overall lower for this subtype.

This study again demonstrates that overall median survival continues to be favorable at 36.6 years, compared to 31.8 years from the previous SEER analysis.¹ Previously, neuroendocrine, mucoepidermoid, and sarcoma histologies have demonstrated the highest long-term survival rates, while adenocarcinoma and squamous cell carcinoma were shown to have the lowest survival rates^1,2 In this series, neuroendocrine, mucoepidermoid, sarcoma, and adenocarcinoma histology all demonstrated favorable survival rates that exceeded 50% at 20 years after diagnosis. Mucoepidermoid tumors have consistently been linked with favorable outcomes in pediatric patients as these tumors are almost universally low-grade and present with localized disease.^2,3,14,26,27 Both the larger cohort and longer-term follow up in this series have revealed blastoma histology to be a significant predictor of poor prognosis with a median survival of only 18 years, whereas prior studies were unable to reach a median survival.^1,2

Both primary pediatric pulmonary adenocarcinoma and squamous cell carcinoma have previously been shown to have a poor prognosis with both often diagnosed during adolescence and with distant disease.^1,2,4,28,29 Again, squamous cell histology was again seen to have a very poor prognosis with no surviving patients at 10 years and a 6.26 times greater risk of death compared to neuroendocrine histological subtype.^1,2 However, while adenocarcinoma histology had a previously reported median survival of only 14 months with a 5-year overall survival of 26%, this series demonstrates a large improvement with a median survival of 36.8 years and 10-year overall survival of 88%.^1,2,28 This series includes 19 additional cases of adenocarcinoma since the previous SEER in 2004 and the improvement in survival may be due to the increased number of patients treated with surgery (82.4% vs 41.7%, p = 0.046), perhaps indicating both identification and treatment of disease at an earlier stage.

This study has several limitations, some of which are inherent to the SEER database as it does not accurately record data on chemotherapy and radiotherapy regimens or whether systemic therapy was given in the neoadjuvant or adjuvant setting. While we report on the available information on these two treatment modalities, interpretation must be done cautiously given the data limitations. Similarly, while surgical intervention was found to be an important positive prognostic indicator, specific data regarding the type of surgical resection performed, the resectability of primary tumors, and adequacy of the resection performed (i.e. margin status), are not available through the dataset. As with other retrospective databases, there is both incomplete and unknown variables within the dataset. Survival analysis beyond 20 years should also be interpreted with caution as, after 20 years, the number of patients who are alive with appropriate follow-up begins to decline, and survival estimates beyond this time are less accurate.

Conclusion

Pediatric lung malignancies continue to be a rare disease despite an increase in the number of reported cases over the past two decades. Overall, these lesions continue to have a favorable prognosis, but is dependent upon histological subtype and treatment(s). This knowledge can be used to better inform patients and families on the outcomes and prognosis of these unique tumors and guide discussions regarding treatment decisions. As diagnostic modalities become better equipped to detect these rare tumors, continued data reporting on these lesions will aid in developing better evidence-based treatment guidelines.