scholarly journals A new functional parameter measured at the time of ablation that can be used to predict differentiated thyroid cancer recurrence during follow-up

2007 ◽  
Vol 156 (1) ◽  
pp. 41-47 ◽  
Author(s):  
Robbert B T Verkooijen ◽  
Daphne Rietbergen ◽  
Jan W Smit ◽  
Johannes A Romijn ◽  
Marcel P M Stokkel
Keyword(s):  
Thyroid Cancer ◽  
Tumor Recurrence ◽  
Differentiated Thyroid Cancer ◽  
Cancer Recurrence ◽  
Distant Metastases ◽  
Tumor Stage ◽  
Ablation Therapy ◽  
Initial Stage ◽  
Uptake Rates

Background: This study addresses the questions whether patients with a high risk for recurrent thyroid cancer can be identified at initial stage, i.e. at the time of ablation. Methods: We evaluated tumor recurrence in consecutive patients treated for differentiated thyroid cancer (DTC). Prognostic factors were statistically analyzed. We defined prognostic parameters based on thyroglobulin (Tg) levels, 24-h I-131 uptake rates and TSH values: (a) Tg/TSH, (b) Tg/24-h I-131 uptake value, and (c) Tg/(TSH×24-h I-131 uptake). Results: We included 190 patients (50 male, 140 female; mean age 47 years) with DTC for analysis, 146 without distant metastases and 44 with M1 tumor stage at initial presentation. The mean period of follow-up was 10.4 years (s.d. ± 3.7 years). In 18 out of the 146 DTC patients with M0 disease (12.4%), tumor recurrence was found during follow-up. Although tumor stage, age, and standard biochemical values significantly differ between patients with and without recurrent disease or between patients with M0 and M1 tumor stage, the newly defined parameter Tg/(TSH×24-h I-131 uptake) was the best independent significant prognostic parameter in the assessment whether patients will develop a tumor recurrence during follow-up or not. Conclusion: High Tg/(TSH×24-h I-131 uptake) ratios justify an adjustment of the I-131 activity for ablation therapy. To assess the optimal cut-off value for a dose adjustment, however, further studies are required in more patients, but the initial results are encouraging with respect to improving outcome in DTC patients.

scholarly journals Management of thyroid cancer: United Kingdom National Multidisciplinary Guidelines

2016 ◽  
Vol 130 (S2) ◽  
pp. S150-S160 ◽  
Author(s):  
A L Mitchell ◽  
A Gandhi ◽  
D Scott-Coombes ◽  
P Perros
Keyword(s):  
Thyroid Cancer ◽  
Total Thyroidectomy ◽  
Neck Dissection ◽  
Differentiated Thyroid Cancer ◽  
Distant Metastases ◽  
Central Compartment ◽  
Extrathyroidal Extension ◽  
Papillary Thyroid ◽  
Ultrasound Scanning

AbstractThis is the official guideline endorsed by the specialty associations involved in the care of head and neck cancer patients in the UK. This paper provides recommendations on the management of thyroid cancer in adults and is based on the 2014 British Thyroid Association guidelines.Recommendations• Ultrasound scanning (USS) of the nodule or goitre is a crucial investigation in guiding the need for fine needle aspiration cytology (FNAC). (R)• FNAC should be considered for all nodules with suspicious ultrasound features (U3–U5). If a nodule is smaller than 10 mm in diameter, USS guided FNAC is not recommended unless clinically suspicious lymph nodes on USS are also present. (R)• Cytological analysis and categorisation should be reported according to the current British Thyroid Association Guidance. (R)• Ultrasound scanning assessment of cervical nodes should be done in FNAC-proven cancer. (R)• Magnetic resonance imaging (MRI) or computed tomography (CT) should be done in suspected cases of retrosternal extension, fixed tumours (local invasion with or without vocal cord paralysis) or when haemoptysis is reported. When CT with contrast is used pre-operatively, there should be a two-month delay between the use of iodinated contrast media and subsequent radioactive iodine (I131) therapy. (R)• Fluoro-deoxy-glucose positron emission tomography imaging is not recommended for routine evaluation. (G)• In patients with thyroid cancer, assessment of extrathyroidal extension and lymph node disease in the central and lateral neck compartments should be undertaken pre-operatively by USS and cross-sectional imaging (CT or MRI) if indicated. (R)• For patients with Thy 3f or Thy 4 FNAC a diagnostic hemithyroidectomy is recommended. (R)• Total thyroidectomy is recommended for patients with tumours greater than 4 cm in diameter or tumours of any size in association with any of the following characteristics: multifocal disease, bilateral disease, extrathyroidal spread (pT3 and pT4a), familial disease and those with clinically or radiologically involved nodes and/or distant metastases. (R)• Subtotal thyroidectomy should not be used in the management of thyroid cancer. (G)• Central compartment neck dissection is not routinely recommended for patients with papillary thyroid cancer without clinical or radiological evidence of lymph node involvement, provided they meet all of the following criteria: classical type papillary thyroid cancer, patient less than 45 years old, unifocal tumour, less than 4 cm, no extrathyroidal extension on ultrasound. (R)• Patients with metastases in the lateral compartment should undergo therapeutic lateral and central compartment neck dissection. (R)• Patients with follicular cancer with greater than 4 cm tumours should be treated with total thyroidectomy. (R)• I131 ablation should be carried out only in centres with appropriate facilities. (R)• Serum thyroglobulin (Tg) should be checked in all post-operative patients with differentiated thyroid cancer (DTC), but not sooner than six weeks after surgery. (R)• Patients who have undergone total or near total thyroidectomy should be started on levothyroxine 2 µg per kg or liothyronine 20 mcg tds after surgery. (R)• The majority of patients with a tumour more than 1 cm in diameter, who have undergone total or near-total thyroidectomy, should have I131 ablation. (R)• A post-ablation scan should be performed 3–10 days after I131 ablation. (R)• Post-therapy dynamic risk stratification at 9–12 months is used to guide further management. (G)• Potentially resectable recurrent or persistent disease should be managed with surgery whenever possible. (R)• Distant metastases and sites not amenable to surgery which are iodine avid should be treated with I131 therapy. (R)• Long-term follow-up for patients with differentiated thyroid cancer (DTC) is recommended. (G)• Follow-up should be based on clinical examination, serum Tg and thyroid-stimulating hormone assessments. (R)• Patients with suspected medullary thyroid cancer (MTC) should be investigated with calcitonin and carcino-embryonic antigen levels (CEA), 24 hour catecholamine and nor metanephrine urine estimation (or plasma free nor metanephrine estimation), serum calcium and parathyroid hormone. (R)• Relevant imaging studies are advisable to guide the extent of surgery. (R)• RET (Proto-oncogene tyrosine-protein kinase receptor) proto-oncogene analysis should be performed after surgery. (R)• All patients with known or suspected MTC should have serum calcitonin and biochemical screening for phaeochromocytoma pre-operatively. (R)• All patients with proven MTC greater than 5 mm should undergo total thyroidectomy and central compartment neck dissection. (R)• Patients with MTC with lateral nodal involvement should undergo selective neck dissection (IIa–Vb). (R)• Patients with MTC with central node metastases should undergo ipsilateral prophylactic lateral node dissection. (R)• Prophylactic thyroidectomy should be offered to RET-positive family members. (R)• All patients with proven MTC should have genetic screening. (R)• Radiotherapy may be useful in controlling local symptoms in patients with inoperable disease. (R)• Chemotherapy with tyrosine kinase inhibitors may help in controlling local symptoms. (R)• For individuals with anaplastic thyroid carcinoma, initial assessment should focus on identifying the small proportion of patients with localised disease and good performance status, which may benefit from surgical resection and other adjuvant therapies. (G)• The surgical intent should be gross tumour resection and not merely an attempt at debulking. (G)

scholarly journals Dynamic Risk Stratification for Predicting Treatment Response in Differentiated Thyroid Cancer

2020 ◽  
Vol 9 (9) ◽  
pp. 2708
Author(s):  
Evanthia Giannoula ◽  
Christos Melidis ◽  
Nikitas Papadopoulos ◽  
Panagiotis Bamidis ◽  
Vasilios Raftopoulos ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Risk Stratification ◽  
Treatment Response ◽  
Differentiated Thyroid Cancer ◽  
Early Stage ◽  
Distant Metastases ◽  
Significant Degree ◽  
Whole Body ◽  
Size Grade

Prognosis in Differentiated Thyroid Cancer (DTC) patients is excellent, but a significant degree of overtreatment still exists because of the inability to accurately identify small patient cohorts who experience a more aggressive form of the disease, often associated with certain poor prognostic factors. Identifying these cohorts at an early stage would allow patients at high risk to receive more aggressive treatment while avoiding unnecessary and invasive treatments in those at low risk. Most risk stratification systems include age, tumor size, grade, presence of local invasion, and regional or distant metastases. Here we discuss these common factors as well as their association with treatment response, but also other upcoming markers including histology and multifocality of primary tumor, dose administered and preparation method for Radioiodine Therapy (RAI), Thyroglobulin (Tg), Anti-thyroglobulin Antibodies (Tg-Ab) levels both at initial management and during follow-up, and the presence of previously existing benign thyroid disease. In addition, we examine the role of remnant size and avidity as well as surgeons’ experience in performing thyroidectomies with recurrence rate, discussing its impact on disease prognosis. Our results reveal that treatment response has a statistically significant association with histology, T and M stages, surgeons’ experience, Tg levels and remnant score both during RAI and follow up and Tg-Ab levels during follow-up whole body scan (WBS).

Initial Management and Follow-up of Differentiated Thyroid Cancer in Children

2010 ◽  
Vol 8 (11) ◽  
pp. 1289-1300 ◽  
Author(s):  
Steven G. Waguespack ◽  
Gary Francis
Keyword(s):  
Thyroid Cancer ◽  
Thyroid Hormone ◽  
High Risk ◽  
Differentiated Thyroid Cancer ◽  
Residual Disease ◽  
Distant Metastases ◽  
High Volume ◽  
Increased Risk ◽  
Initial Care

Children with differentiated thyroid cancer (DTC) often present with metastatic disease and have a high risk for recurrence, but rarely die of the disease. This article reviews DTC in children and discusses current approaches to their initial care and follow-up. These recommendations take into account the greater risk for recurrence and lower disease-specific mortality in these patients. Total thyroidectomy and central compartment lymph node dissection are appropriate for most children, but should be performed by a high-volume thyroid surgeon. Radioactive iodine (RAI) should generally be prescribed for those at very high risk for recurrence or known to have microscopic residual disease, and those with iodine-avid distant metastases. RAI should be considered in other patients only after carefully weighing the relative risks and benefits and the aggressiveness of the clinical presentation, because RAI may be associated with an increased risk for second malignancies and an increase in overall morbidity and mortality. All patients should be treated with thyroid hormone suppression, and follow-up should be lifelong. However, the degree of thyroid hormone suppression and frequency of disease surveillance usually decrease over time as patients are determined to be disease-free.

scholarly journals PSMA expression level predicts differentiated thyroid cancer aggressiveness and patient outcome

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Martina Sollini ◽  
Luca di Tommaso ◽  
Margarita Kirienko ◽  
Chiara Piombo ◽  
Marco Erreni ◽  
...  
Keyword(s):  
Patient Outcome ◽  
Thyroid Cancer ◽  
Differentiated Thyroid Cancer ◽  
Distant Metastases ◽  
Cox Models ◽  
Cumulative Score ◽  
Cancer Aggressiveness ◽  
Positive Score ◽  
Psma Expression

Abstract Background Prostate-specific membrane antigen (PSMA) is overexpressed on the endothelial cells of tumor neo-vessels of several solid malignancies, including differentiated thyroid cancer (DTC). We aimed to test the potential role of PSMA as a biomarker for DTC aggressiveness and outcome prediction. We retrospectively screened all patients who underwent thyroidectomy between 1 January 2010 and 31 December 2017 in our institution. Applying the inclusion (histological diagnosis of thyroid cancer and tissue availability) and exclusion criteria (no clinical or follow-up data or diagnosis of medullary thyroid cancer), a cohort of 59 patients was selected. The monoclonal mouse anti-human PSMA antibody was used to stain tissue sections. A 3-point scale was used to score PSMA positivity: 0–5% expression was considered as negative (score 0), 6–50% as moderately positive (score 1), and 51–100% as highly positive (score 2). A cumulative score (0–10%, 11–79%, and 80–100%) was also explored. Univariate and multivariate logistic regression analyses were performed to predict the presence of distant metastases, chosen as endpoint of aggressiveness. The area under the curve (AUC) was calculated. Cox models were built to predict patient outcome in terms of recurrence, iodine refractoriness, and status at last follow-up, which were calculated using the Kaplan-Meier failure function. Results At immunostaining, 12, 25, and 22 patients had scores of 0, 1, and 2, respectively. According to the cumulative score, PSMA expression was ≤ 10% in 17 cases, 11–79% in 31 cases, and ≥ 80% in 11 cases. At multivariate analysis, age, sex, histotype, vascular invasion, T and N parameters, and PSMA positivity were significant predictors of distant metastases. The AUC was 0.92. Recurrence or progression occurred in 19/59 patients. Twelve patients developed radioiodine (RAI) refractoriness, after a median time of 17 months (range 2–32). One patient died of DTC; 46 of the 58 patients alive at last follow-up were disease free. Median DFS was 23 months (range 3–82). The final multivariate model to predict RAI refractoriness included as covariates the stage, high PSMA expression (≥ 80%), and the interaction between moderate PSMA expression (11–79%) and stage. Conclusions PSMA, a marker of neovasculature formation expressed by DTC, contributes in the prediction of tumor aggressiveness and patient outcome.

scholarly journals Time to Separate Persistent From Recurrent Differentiated Thyroid Cancer: Different Conditions With Different Outcomes

2018 ◽  
Vol 104 (2) ◽  
pp. 258-265 ◽  
Author(s):  
Giulia Sapuppo ◽  
Martina Tavarelli ◽  
Antonino Belfiore ◽  
Riccardo Vigneri ◽  
Gabriella Pellegriti
Keyword(s):  
Thyroid Cancer ◽  
Initial Treatment ◽  
Differentiated Thyroid Cancer ◽  
Recurrent Disease ◽  
Treatment Strategies ◽  
Distant Metastases ◽  
Persistent Disease ◽  
Tertiary Referral Center ◽  
N Status

Abstract Context Differentiated thyroid cancer (DTC) has an excellent prognosis, but up to 20% of patients with DTC have disease events after initial treatment, indistinctly defined as persistent/recurrent disease. Objective To evaluate the prevalence and outcome of “recurrent” disease (relapse after being 12 months disease-free) compared with “persistent” disease (present ab initio since diagnosis). Design Retrospective analysis of persistent/recurrent disease in patients with DTC (1990 to 2016) with 6.5 years of mean follow-up. Setting Tertiary referral center for thyroid cancer. Patients In total, 4292 patients all underwent surgery ± 131I treatment of DTC. Main Outcome Measures DTC cure of disease persistence or recurrence. Results A total of 639 of 4292 (14.9%) patients had disease events after initial treatment, most (498/639, 78%) with persistent disease and 141 (22%) with recurrent disease. Relative to patients with recurrent disease, patients with persistent disease were significantly older (mean age 46.9 vs 45.7 years) and with a lower female to male ratio (1.9/1 vs 4.8/1). Moreover, in this group, structured disease was more frequent (65.7% vs 41.1%), and more important, distant metastases were significantly more frequent (38.4% vs 17.0%). At multivariate analysis, male sex (OR = 1.7), age (OR = 1.02), follicular histotype (OR = 1.5), T status (T3; OR = 3), and N status (N1b; OR = 7.7) were independently associated with persistent disease. Only the N status was associated with recurrent disease (N1b; OR = 2.5). Conclusions In patients with DTC not cured after initial treatment, persistent disease is more common and has a worse outcome than recurrent disease. Postoperative status evaluated during first-year follow-up may have important clinical implications for planning tailored treatment strategies and long-term follow-up procedures.

scholarly journals Differentiated Thyroid Cancer in Children and Adolescents: Long Term Outcome and Risk Factors for Persistent Disease

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3732
Author(s):  
Giulia Sapuppo ◽  
Dana Hartl ◽  
Brice Fresneau ◽  
Julien Hadoux ◽  
Ingrid Breuskin ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Differentiated Thyroid Cancer ◽  
Distant Metastases ◽  
American Thyroid Association ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Incomplete Response ◽  
Imaging Results

Background: Pediatric differentiated thyroid cancer (P-DTC) frequently presents with advanced disease. The study aim was to evaluate the outcome of P-DTC and a modified 2015 American Thyroid Association risk classification (ATA-R). Methods: A retrospective study of consecutive P-DTC patients was performed. The ATA-R for P-DTC was used with a cut-off of ≤ 5 N1a for low-risk. The outcome could be excellent response (ER) (thyroglobulin < 1 ng/mL and no evidence of disease (EoD) at imaging), biochemical incomplete response (BIR) (thyroglobulin ≥ 1 ng/mL and no EoD at imaging) or structural incomplete response (SIR) (EoD at imaging). Results: We studied 260 P-DTC (70% females; median age at diagnosis 14 years; 93% total thyroidectomy and 82% lymph node dissection). The ATA-R was low in 30% cases, intermediate in 15% and high in 55%, including 31.5% with distant metastases. Radioiodine treatment was administered in 218 (83.8%), and further radioiodine and surgery was performed in 113 (52%) and 76 (29%) patients, respectively. After a median follow-up of 8.2 years, the outcome was ER in 193 (74.3%), BIR in 17 (6.5%) and SIR in 50 (19.2%). Independent predictors of SIR or BIR at first and last visits were ATA-R intermediate or high. Conclusion: P-DTC has an excellent prognosis. Modified ATA-R is a useful prognostic tool in P-DTC to guide management.

scholarly journals Long-Term Outcomes and Prognoses of Elderly Patients (≥65-Years-Old) With Distant Metastases From Well-Differentiated Thyroid Cancer During Radioiodine Therapy and Follow-Up

2021 ◽  
Vol 11 ◽  
Author(s):  
Zhong-Ling Qiu ◽  
Chen-Tian Shen ◽  
Zhen-Kui Sun ◽  
Hong-Jun Song ◽  
Chuang Xi ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Prognostic Factors ◽  
Elderly Patients ◽  
Differentiated Thyroid Cancer ◽  
Distant Metastases ◽  
Extrathyroidal Extension ◽  
Long Term Outcomes ◽  
Well Differentiated

ObjectiveThe objective of this study was to investigate the clinicopathological characteristics, long-term outcomes, and prognostic factors of elderly patients with distant metastases at initial diagnosis from well-differentiated thyroid cancer (WDTC) during radioactive iodine (131I) treatment and follow-up.MethodsA retrospective review of medical records identified 183 elderly patients with DTC who underwent 131I treatment at our institution between 2006 and 2019.ResultsIn total, 57 elderly WDTC patients with distant metastases were enrolled in this study. After 131I treatment, 32 (56.14%) patients had 131I avidity and 25 (43.86%) had non-131I avidity; 35 (61.40%) cases were classified as radioiodine refractory (RR)-WDTC and 22 (38.60%) as non-RR-WDTC. At the end of follow-up, 25 (43.86%) patients had died and 32 (56.14%) were alive. The 5- and 10-year overall survival (OS) rates were 71.50% and 30.49%, respectively, while the 5- and 10-year disease-specific survival (DSS) rates were 76.89% and 48.71%, respectively. Multivariate analyses showed that gross extrathyroidal extension and RR-DTC were independent prognostic factors for poor OS (P=0.04 and P=0.03, respectively), while gross extrathyroidal extension, extrapulmonary distant metastases, and RR-WDTC were independent prognostic factors for poor DSS at the end of follow-up (P=0.02, P=0.03, and P=0.02, respectively).ConclusionsWDTC with distant metastases at initial diagnosis accounted for 31.15% of all elderly patients with DTC. Gross extrathyroidal extension and RR-DTC were the major factors associated with poor OS; gross extrathyroidal extension, extrapulmonary distant metastases, and RR-DTC were independent prognostic factors for poor DSS in elderly DTC patients with distant metastases.

scholarly journals Evaluation of the 2015 ATA Guidelines in Patients With Distant Metastatic Differentiated Thyroid Cancer

2019 ◽  
Vol 105 (3) ◽  
pp. e457-e465
Author(s):  
Evert F S van Velsen ◽  
Merel T Stegenga ◽  
Folkert J van Kemenade ◽  
Boen L R Kam ◽  
Tessa M van Ginhoven ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Differentiated Thyroid Cancer ◽  
Distant Metastases ◽  
Initial Therapy ◽  
Control Group ◽  
American Thyroid Association ◽  
Excellent Response ◽  
Structural Disease ◽  
Stratification System

Abstract Context Current American Thyroid Association (ATA) Management Guidelines for the treatment of differentiated thyroid cancer (DTC) stratify patients to decide on additional radioiodine (RAI) therapy after surgery, and to predict recurring/persisting disease. However, studies evaluating the detection of distant metastases and how these guidelines perform in patients with distant metastases are scarce. Objective To evaluate the 2015 ATA Guidelines in DTC patients with respect to 1) the detection of distant metastases, and 2) the accuracy of its Risk Stratification System in patients with distant metastases. Patients and Main Outcome Measures We retrospectively included 83 DTC patients who were diagnosed with distant metastases around the time of initial therapy, and a control population of 472 patients (312 low-risk, 160 intermediate-risk) who did not have a routine indication for RAI therapy. We used the control group to assess the percentage of distant metastases that would have been missed if no RAI therapy was given. Results Two hundred forty-six patients had no routine indication for RAI therapy of which 4 (1.6%) had distant metastases. Furthermore, among the 83 patients with distant metastases, 14 patients (17%) had excellent response, while 55 (67%) had structural disease after a median follow-up of 62 months. None of the 14 patients that achieved an excellent response had a recurrence. Conclusions In patients without a routine indication for RAI therapy according to the 2015 ATA Guidelines, distant metastases would initially have been missed in 1.6% of the patients. Furthermore, in patients with distant metastases upon diagnosis, the 2015 ATA Guidelines are an excellent predictor of both persistent disease and recurrence.

Treatment of radioiodine refractory high-differentiated thyroid cancer with lenvatinib.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e17518-e17518
Author(s):  
Ilya Romanov ◽  
Ali Mudunov ◽  
Pavel Isaev ◽  
Yury Bychkov ◽  
Akgul Odzharova
Keyword(s):  
Thyroid Cancer ◽  
Clinical Practice ◽  
Adverse Events ◽  
Arterial Pressure ◽  
Arterial Hypertension ◽  
Differentiated Thyroid Cancer ◽  
Distant Metastases ◽  
Patient Death ◽  
Thyroglobulin Level

e17518 Background:Long time the patients with high-differentiated thyroid cancer with distant metastases had only one type of treatment. It was radioiodine therapy courses and follow-up. In cases of revealed radioiodine (RAI) refractory process we did not have possibilities for treatment this category of patients. Results of trials DECISION and SELECT gave to oncologist new keys for successful treatment. We present our group of RAI refractory thyroid cancer patients, which was treated by Lenvatinib like routine clinical practice. Methods:We have on treatment 8 patients (3-male, 5-female). Histologically – papillary thyroid carcinoma. Provisions of national clinical recommendations were considered as criteria of a RAI-refractory status. Existence of a symptomatic progression of a tumor was main criterion. Results:Six patients received from 7 to 14 month courses of treatment. All these patients are revealed partial response of the tumor lesions by PET-FDG-CT and the dramatically decrease of thyroglobulin level is noted. Two patients stopped treatment after 1 month of therapy. One patient due to destructive pneumonia, other patient – death due to myocardial infarction. Adverse events not related with Lenvatinib. The adverse events were controllable. We noted the expressed arterial hypertension. Before correction of a dose of a drug increase of arterial pressure more than 160/100 mm Hg is noted. Arterial pressure managed to be corrected the combined scheme of therapy (amlodipin, bisoprolol, hydrochlorthiazide). Correction of a dose of lenvatinib is made at 3 patients to 20 mg daily, 2 patient – 14. Conclusions:Introduction of a lenvatinib clinical practice is very successful. But we noted of important accurate expert selection of patients for treatment after establishment of a condition of a RAI-refractory and revealed really symptomatic progression, adequate correction of the adverse effects (arterial hypertension) and well-timed correction of a dose of a lenvatinib.

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