ectopic cushing's syndrome: experience from a tertiary care centre

Indian J Med Res 129, January 2009, pp 33- 41

33

Cushing’s syndrome refers to the symptoms and signs that result from excessive tissue exposure to glucocorticoids. Endogenous Cushing’s syndrome is

Ectopic Cushing’s syndrome: Experience from a tertiary care centre

A. Bhansali, Rama Walia, S.S. Rana*, P. Dutta, B.D. Radotra**, N. Khandelwal† & S.K. Bhadada

Departments of Endocrinology, *Cardiothoracic Surgery, **Pathology & †Radiodiagnosis, Postgraduate Institute of Medical Education & Research, Chandigarh, India

Received June 8, 2007

Background & objectives: Ectopic secretion of adrenocorticotropic hormone (ACTH) is rare, contributing to 10 per cent cases of endogenous Cushing’s syndrome. We describe our experience of about two decades of patients with ectopic Cushing’s syndrome (ECS) seen at a tertiary care centre from north India.

Methods: Records of patients with ECS from 1985 to 2006 were retrospectively reviewed that included the presenting manifestations, clinical symptoms and signs, biochemical investigations including plasma cortisol, ACTH and high dose dexamethasone suppression test (HDDST), imaging modalities to localize the non pituitary source of ACTH production, management and follow up of these patients.

Results: The study group included 12 patients (7 men) with mean (±SD) age at presentation 27.6 ± 9.5 yr (range 13 to 48 yr) and the mean lag period between onset of symptoms and the diagnosis was 18.3 ± 12.9 months with a range of 3 to 48 months. The weight loss (41.7%) followed by hyperpigmentation (25%) and infections (16.7%) were the common presenting manifestations. Cuticular atrophy (100%), hypertension (100%), bruise (92%) and proximal myopathy (83%) were the commonest signs. Plasma cortisol at 0800 h was 1267.3 ± 483.3 nmol/l and at 2200 h was 1214.9 ± 442.6 nmol/l indicating loss of circadian rhythm. The mean plasma ACTH was 221.1 ± 55.9 (range 21.7 to 950 pg/ml). All but 2 patients had non-suppressibility of 0800 h plasma cortisol with HDDST. Five patients had thymic carcinoid, 3 had bronchial and one each had islet, hepatic and gut carcinoid and one had medullary thyroid carcinoma as a cause of ectopic ACTH secretion. The mean duration of follow up of these patients was 42.6 months and only two could sustain cure while remaining had either residual or recurrence.

Interpretation & conclusion: Ectopic Cushing’s syndrome is a rare disease with varied manifestations and associated with increased morbidity and mortality. It presents with clinical features quite similar to classical Cushing’s. Surgery with removal of primary tumour was found to be treatment of choice.

Key words Carcinoid - corticotrophin - Cushing’s disease - ectopic Cushing’s syndrome - neuroendocrine tumour

inordinately (75-80%) caused by adrenocorticotropic hormone (ACTH) secreting pituitary adenomas and the remaining 20-25 per cent is contributed by adrenal

neoplasias (10-15%) and ectopic ACTH secretion (10%)1,2. Non pituitary (ectopic) sources of ACTH include small cell carcinoma of the lung in half the patients and rest are from the various neuroendocrine tumours namely bronchial and thymic carcinoids, and rarely from gut carcinoid3,4. Ectopic Cushing is very rare with a prevalence of one case per million per year and most of these have been described as lone case reports and a few series3-17.

Characteristically ectopic ACTH production is said to cause a clinical syndrome which, unlike pituitary dependent Cushing disease is of rapid onset associated with rapid weight loss, muscle weakness, hypokalemic metabolic alkalosis, glucose intolerance, high levels of plasma cortisol and ACTH. In such patients there is usually an obvious underlying tumour and most commonly it is a small cell carcinoma of the lung. However, relatively benign tumours, in particular slowly growing carcinoid tumours2,3 can give rise to a clinical syndrome which is indistinguishable from pituitary Cushing disease. Clinical manifestations of glucocorticoid and/or androgen excess may be the only clues for carcinoids, though they sometimes may present with marked hyperpigmentation, diarrhoea, flushing, and/or palpitations18. Biochemically, these neoplasms have been described to secrete various biologically active substances including gastrin, insulin, calcitonin and vasoactive intestinal peptide, as well as corticotropin. Nevertheless, localization of ectopic source of ACTH is not always easy and sometimes it could be delayed from months to years. Because of this, these patients have increased morbidity and consequently culminating into enhanced mortality. We describe our experience of patients with ectopic Cushing’s syndrome from a tertiary care centre in north India, seen during last 22 years.

Material & Methods

Between 1985 and 2006, 156 patients attending Endocrine Clinic at Nehru Hospital, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, were diagnosed to have endogenous Cushing’s syndrome (CS). Of these 12 had ectopic ACTH syndrome constituting 7.7 per cent of cases. The case records of these patients were reviewed retrospectively. The diagnosis of Cushing’s syndrome was based on clinical features of protein catabolism and/or features of androgen excess. Protein catabolism was evident in the form of striae, easy bruisability, muscle weakness, and cuticular

and pulp atrophy. Androgen excess manifested as hirsutism, virilization and defeminization as oligo/amenorrhoea in women. The diagnosis of endogenous Cushing’s syndrome was based on step-wise approach: first, the definitive determination of the presence of hypercortisolemic state; second whether CS is ACTH dependent or not, and third if CS is ACTH dependent, then localization of the source of ACTH production. Biochemically, diagnosis was based on elevated basal cortisol levels with loss of circadian rhythm, inappropriately elevated ACTH levels in relation with 2200 h cortisol and nonsuppressible serum cortisol to low dose dexamethasone. ACTH dependency of CS was indicated by high ACTH levels (> 23 pg/ml) in the presence of elevated cortisol levels ( >210 nmol/l)26.

The ectopic source of ACTH was localized by imaging including computerized tomography, (Light speed GE Medical System, USA) and magnetic resonance imaging (Somatom, Siemens, Germany 1.5 Tesela) wherever indicated in all of these patients.

Biochemical methods: Plasma cortisol was measured by in-house radioimmunoassay (RIA) by using tritium labelled cortisol after dextran charcoal separation with intra-assay and inter-assay coefficients of variation being <8 per cent19. Plasma ACTH was measured by immunoradiometric assay (Immulite, 2500 ACTH, Germany). Low dose dexamethasone suppression test (LDDST) followed by high dose dexamethasone suppression test (HDDST) were performed as per Liddle’s protocol20. Loss of circadian rhythm was defined as cortisol levels at 2200 h being more than 50 per cent of the 0800 h values. Suppression of 0800 h plasma cortisol to <140 nmol/l after LDDST and failure to suppress 0800 h cortisol by 50 per cent of basal 0800 h value following HDDST was considered as nonsuppressible. Oral glucose tolerance test with 75 g glucose and measurement of serum electrolytes were performed in all the patients.

Results

Twelve patients were diagnosed to have ectopic Cushing’s syndrome (ECS) including 7 men and 5 women. Their age ranged between 13 to 48 yr with mean + SD of 27.6 + 9.5 yr. The mean (+SD) lag period between onset of symptoms and diagnosis was 18.3 + 12.9 months with a range of 3 to 48 months.

The presenting manifestations, and symptoms and signs are summarized in Tables I. They had

34 INDIAN J MED RES, JANUARY 2009

mean (+SD) body mass index (BMI) of 22.9±3.7 kg/m2. Eight (66.7%) patients presented with weight gain and four (33.3%) with weight loss. The clinical presentation was quite typical in 7 patients and unusual in 5 patients. Among unusual manifestations, two patients presented with manic depressive psychosis, one patient each sought medical advice for dry cough, recurrent loose motions, and recurrent pyoderma. The clinical signs included, hypertension and cuticular atrophy in all (100%), bruises in 11 (92%), proximal muscle weakness in 10 (83.3%), hyperpigmentation in 9 (75%), centripetal obesity in 7 (58.3%), and striae in 8 (66.7%). Two boys did not have signs of puberty, while 4 of 5 (80%) of women were oligo/amenorrhoeic. One had vertebral collapse at presentation.

On biochemical evaluation, 7 (58.3%) patients were found to be diabetic while hypokalemia (< 3.5 mEq/l) with metabolic alkalosis was present in 5 (41.7%). All patients failed to demonstrate the normal circadian rhythm of plasma cortisol (Table II), and had inappropriately elevated levels of ACTH at 2200h (where measured) in relation with cortisol. The mean plasma cortisol at 0800 h was 1267.3 ± 483.3 nmol/l with a range of 600-2400 nmol/l, and at 2200 h was 1214. 9 ± 442.6 nmol/l with a range of 480-2000 nmol/l. The mean plasma ACTH was 221.1 ± 55.9 pg/ml. The mean plasma cortisol after LDDST was 1140.75 ± 434.1 nmol/l showing nonsuppressibility in all the 12 patients. The mean plasma cortisol after HDDST was 943.6 ± 385.3 nmol/l and depicting nonsuppressibility in 10 (83.3%) out of 12 patients. Urinary hydroxyl-indoleacetic acid (HIAA) was elevated in 2 (16.7%) patients only.

Tumour localization: Localization of the source of ACTH in these patients, as some of them had unusual sites of carcinoid, was difficult and led to considerable delay. Ultrasonography of the abdomen

revealed tumour of the pancreas in one patient as he presented with palpable mass in the epigastrium, and nodular lesions in the liver in another patient. CT scan of the chest localized anterior mediastinal mass in five patients. The bronchial masses were located in right upper lobe and middle lobe in one patient each (Fig. 1a) and a nodule in the left bronchus was found in one patient. Other methods of localization included colonoscopy in one patient who underwent the same for recurrent diarrhoea and was found to have colonic polyps (Table II). The patient who had thyroid nodule on palpation, FNAC confirmed the diagnosis of medullary thyroid carcinoma (MTC). Bilateral adrenal hyperplasia (Fig. 1b) was present in 9 patients and remaining three had normal adrenals. MRI/CT of the pituitary was performed in 10 and only one showed diffuse enlargement, which regressed after curative surgery for bronchial carcinoid (Fig. 1c, 1d). All patients except one who presented with thyroid nodule, showed carcinoid picture on histopathology with nesting trabecular pattern of round cells with rosette formation with fibrovascular core. Cytoplasm was amphophilic with prominent nuclear chromatin (Fig. 2) suggestive of carcinoid. ACTH immunostaining on respective tumour tissues was positive in all four patients, in whom it was available (Fig. 2).

Management and outcome: Of the five patients with thymic carcinoids, three patients underwent surgery with excision of the tumour. In these three patients the surgery was successful, and they were cured of the disease clinically as well as biochemically post-operatively. But they all had recurrence during follow up at variable period of 30-84 months and all three died, two because of metastatic disease, the third one died unattended at home. One patient had anterior mediastinal widening with Hounsefeld value of -40 on CT chest suggestive of lipomatosis (Fig. 3a). He had normal pituitary on MR imaging and underwent

Table I. Presenting manifestation and signs and symptoms in patients with ectopic Cushing’s syndrome (n= 12)

Presenting manifestations No. (%) Signs & symptoms No. (%)

Weight loss 4 (33.3) Cuticular atrophy 12 (100)

Hyperpigmentation 2 (25) Hypertension 12 (100)Recurrent loose motions 2 (16.7) Bruise 11 (91.7)Infections Recurrent pyoderma (1), Pneumonia (1) 2 (16.7) Proximal myopathy 10 (83.3)Dry cough 1 (8.3) Hyperpigmentation 9 (75)Manic depressive psychosis 1 (8.3) Centripetal obesity 8 (66.7)

Striae 8 (66.7)Diabetes 7 (58.3)Menstrual irregularities 4/5 (80)Hirsutism 1/5 (20)

BHANSALI et al: ECTOPIC CUSHING’S SYNDROME 35

Tab

le I

I. P

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No.

Age

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Cor

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H

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AC

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Man

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AM

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134

M18

1480

1500

1400

1200

359

Thy

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car

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T c

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Sur

gery

R

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TD

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30

231

M12

1400

1680

1360

1280

950

Thy

mic

car

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T c

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Sur

gery

+ R

T

Rec

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nce-

RT

an

d C

TD

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42

332

F24

1200

1100

640

640

96T

hym

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CT

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84

432

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480

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100

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370

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622

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640

440

660

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879

709

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bilateral adrenalectomy. During follow up, 6 months later, he presented with rapidly increasing diffuse hyperpigmentation and repeat CT chest showed anterior mediastinal mass invading surrounding large vessels (Fig. 3b), which on aspiration cytology proved to be thymic carcinoid. He received chemotherapy and radiotherapy as primary was inoperable. One patient with thymic carcinoid refused for surgery.

All three patients with the bronchial carcinoids underwent surgery with removal of the tumour. In one patient, it was successful, other had recurrence with no localization thereafter, and required bilateral adrenalectomy, and the third patient died of acute respiratory distress syndrome post-operatively. Patient with islet cell carcinoid was subjected to bilateral adrenalectomy and also received chemotherapy as the

Fig. 1a. Contrast enhanced CT scan of the thorax showing mass lesion in the right lung. 1b. Contrast enhanced CT scan of abdomen showing bilateral adrenal enlargement. 1c. MRI of sella showing homogenous pituitary enlargement. 1d. MRI of sella showing regression of pituitary enlargement after curative surgery for bronchial carcinoid.

(a) (b)

(c) (d)


following which she received chemotherapy. Bilateral adrenalectomy was performed in patient with apparent ‘primary’ hepatic carcinoid followed by chemotherapy, somatostatin long acting repository (LAR) and metaiodobenzyl guanidine (MIBG) therapy. Even after extensive search and exploratory laparotomy primary lesion could not be found elsewhere therefore it was more likely to be ‘primary’ hepatic carcinoid. Polypectomy was curative in patient with gut carcinoid, but she also had recurrence and is on ketoconazole therapy. Mean (+ SD) duration of follow up was 42.6+ 19.8 months with range of 0-84 months. Of the 12 patients, eight died and three continue to be in our follow up, while one patient was lost to follow up (Table II).

Discussion

This study presents Cushing’s syndrome due to ectopic corticotropin (ACTH) production by the neuroendocrine tumours arising from the various sites. Unlike Cushing’s disease, with an 8:1 female to male preponderance, this syndrome is more common in men2 as shown in our study as well. Earlier it has been reported that ectopic secretion of ACTH is most often from small cell carcinomas of the lung21. But, later reports3,9 indicate that bronchial carcinoid tumour is the single most common cause. While Medonca

Fig. 2. Nesting pattern of tumour cells with their fibrovascular core with unremarkable crypts and surface epithelium (HE x 140). Inset : Immuno histochemistry showing positive ACTH staining tumour cells HEx240.

Fig. 3a. CT thorax showing mediastinal widening with Hounsefield value of - 40 suggestive of mediastinal lipomatosis. b. CT thorax showing anterior mediastinal mass, after bilateral adrenalectomy.

primary was inoperable. Patient with medullary thyroid carcinoma had liver metastasis. She underwent total thyroidectomy along with bilateral adrenalectomy,


(a)

(b)

et al10 reported most common cause as thymic carcinoid in 3 of 8 (37%) patients, as found in our study as well (Table III), and other well documented cases included medullary thyroid carcinoma3, pheochromocytoma3, medullary paraganglioma11, pancreatic islet cell tumours3, and tumours of the ovary22, cervix22 and prostrate22. A lone case of ectopic ACTH secretion associated with non neoplastic inflammatory mass and cure after its excision has also been described12. The Cushing’s syndrome due to ‘primary’ hepatic carcinoid is very rare and has been reported by us earlier13. We did not observe ECS secondary to small cell carcinoma of the lung probably because of lack of typical Cushingoid features, so these would have been missed by treating physicians and/or rapid downhill course prior to referral to our centre.

Corticotropin (ACTH) secreting carcinoid tumours, usually present with clinical features indistinguishable from pituitary dependent Cushing’s syndrome2. This clinical situation is frequently referred to as ‘occult’ ectopic ACTH syndrome. The reason behind this might be the indolent course of carcinoids and as reported in 44 per cent of patients, the neoplasm was initially occult3. Therefore, the clinical course is often prolonged and the delay to ultimate diagnosis varying up to 15 yr3-13 as also shown in our study with a mean lag time of 18 months.

Most reliable signs of Cushing’s syndrome include the presence of proximal myopathy, easy bruising and thinness and fragility of skin. At least one of these

signs was present in all of these patients. Cuticular atrophy as a sign was present in all of patients, and has been under-reported in other series3. Prevalence of proximal muscle weakness, diabetes mellitus was similar to other series3, while bruising, striae and weight loss were more common in our patients as compared to other studies3. Another clue to diagnosis of ectopic ACTH secretion from carcinoids are clinical manifestations due to simultaneous secretion of other metabolically active substances. Two of the patients had diarrhoea at presentation which may indicate secretion of vasoactive intestinal peptide (VIP) from the carcinoid tumours. Lack of age appropriate pubertal signs in two boys can be explained on the basis of direct suppressive effect of cortisol on pituitary gonadotropes and testis as well. Biochemically, ectopic ACTH syndrome is frequently associated with exceedingly high circulating concentrations of corticotropin23, as seen in our patients. The presence of hypokalemia is another biochemical clue that glucocorticoid excess is mediated by ectopic production of corticotropin24. The apparent reason for the hypokalemia is the saturation of 11-β-hydroxysteroid dehydrogenase type 1 by excessive cortisol, which under normal circumstances protects the mineralocorticoid receptors from the effects of cortisol25. However this generally reflects the prevailing levels of cortisol rather than the specific aetiology. In our series, 5 of the 12 patients had hypokalemia at presentation.

Liddle and associates20 reported that administration of dexamethasone in high-dose (16 mg) did not suppress cortisol in 94 per cent of cases of ECS. Consistent with this, 83.3 per cent of our patients had non-suppressibility to high dose dexamethasone. Nevertheless, suppressibility of cortisol after high dose dexamethasone had been shown in slowly growing bronchial carcinoids thereby rendering them difficult to differentiate from pituitary Cushing’s disease26. Carcinoid tumours are often associated with increased levels of urinary 5-hydroxyindoleacetic acid (5-HIAA), a metabolite of serotonin. However, foregut carcinoids, which include bronchial carcinoids as well do not have increased 5-HIAA levels, as was also seen in our study.

Efforts to identify an ectopic source of ACTH secretion is not always successful as happened in one of our patient (8.3%). This result is similar to that of the other study17. In our study thoracic tumour was the source of ectopic secretion in 66.7 per cent of cases, similar to that reported by others3. Tumours were best localized with CT thorax/abdomen in

Table III. Causes of the ectopic ACTH syndrome

Ilias et al3

Saeger

et al9

Mendonca

et al10

Present study

N 90 13 8 12

Thymic carcinoid 5 1 3 5Bronchial carcinoid 35 4 1 3Appendiceal carcinoid 1 - - -Neuroendocrine tumour 13 - - -Pulmonary tumourlets 1 - - -Gastroinoma 6 - - -Small cell lung cancer 3 1 - -Pheochromocytoma 5 1 1 -Medullary thyroid carcinoma 2 2 1 1Islet carcinoid 1 2 2 1Pancreatic carcinoid 1 2 2 0Prostatic cancer - 1 - -Liver carcinoid - - - 1Colonic carcinoid - - - 1Miscellaneous 1 1 - -Unknown/occult 17 - - -


> 80 per cent of cases. However, in case of failure to localize the ectopic source of ACTH secretion with one modality, multiple imaging techniques should be employed to identify the same. Thus, as suggested by Ilias et al3 CT, MRI and octreotide scan/PET scan all may be required to localize the ectopic source of ACTH secretion. In one of our patient mediastinal widening was interpreted as mediastinal lipomatosis and later after bilateral adrenalectomy, he presented with inoperable thymic carcinoid. Other imaging modalities and/or cytology might have helped to localize the lesion initially. In our study CT/MRI of the sella was normal in all patients, where it was performed, except in one who had pituitary hyperplasia. This might be due to corticotropin releasing hormone (CRH) secretion from the carcinoid, as it regressed after removal of the bronchial carcinoid. However, incidental adenomas of the pituitary gland are present in up to 35 per cent of adults27, thus that hypophysectomy occasionally yields a nonfunctioning pituitary adenoma in patients with ectopic ACTH syndrome, is not surprising. On the contrary, even in the presence of pituitary adenoma in a patient with Cushing’s disease, MRI may not reveal the source in up to 50 per cent of cases. Bilateral inferior petrosal sinus sampling seems to be the most accurate method for distinguishing pituitary from ectopic production of corticotrophin1. A basal inferior petrosal sinus to peripheral blood (IPS: P) ratio of ≥2 and a peak IPS: P ratio of ≥3 is suggestive of pituitary as a source of ACTH production. However, this may be misleading in ectopic CRH producing tumours1. Immunostaining positivity for ACTH on tumour tissue strongly supports the tissue source of its ectopic production.

Surgery is often curative for both the neoplasm and the associated glucocorticoid excess as was performed in 66.7 per cent of cases similar to that of 65 per cent reported by others3. The role of adjuvant radiotherapy, chemotherapy, or both have not been accurately assessed because of the lesser number of cases1. Nevertheless, post-operative radiotherapy may be helpful in preventing local recurrence after excision of an invasive carcinoma1,3. Bilateral adrenalectomy was required in one third of patients either because inoperable primary or because of recurrence. This figure is similar to that reported by Ilias et al3. Of the twelve patients, three continue to be in our follow up with a mortality of 66.7 per cent during mean follow up duration of 42.6 months which is higher than what has been reported earlier (18% in 26 months follow up)3.

This possibly is related to delayed presentation, and irregular follow up.

In conclusion, ectopic ACTH syndrome due to slowly growing tumours like carcinoids usually presents with clinical features indistinguishable from classical Cushing’s. Primary tumour in majority of instances could be localized with CT scan. Single imaging can give false positive results. Surgery with removal of primary tumour is the treatment of choice and is often curative but needs regular surveillance for recurrence.

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Reprint requests: Dr Anil Bhansali, Department of Endocrinology, Postgraduate Institute of Medical Education & Research Chandigarh 160 012, India e-mail: [email protected]

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ectopic cushing's syndrome: experience from a tertiary care centre

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