Ignite Creation Date:
2024-05-06 @ 7:36 PM
Last Modification Date:
2024-10-26 @ 3:10 PM
Study NCT ID:
NCT06067594
Status:
COMPLETED
Last Update Posted:
2023-10-06
First Post:
2023-09-28
Brief Title:
Calcitonin in Needle Wash Using Electrochemiluminescence Method For Diagnosis Of Medullary Thyroid Carcinoma
Sponsor:
Austral University Argentina
Organization:
Austral University Argentina
Study Overview
Official Title:
Optimizing Diagnostic Accuracy of Fine Needle Aspiration Biopsy Calcitonin Measurements in Detecting Medullary Thyroid Carcinoma
Status:
COMPLETED
Status Verified Date:
2023-10
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Medullary thyroid carcinoma MTC is a tumor originating from parafollicular C cells of the thyroid 1 Representing 1 to 7 of all thyroid carcinoma cases 2 3 4 It can occur in two clinical forms the sporadic or non-hereditary in 75-80 of patients and the hereditary form in the remaining 20-25 It can be part of different clinical syndromes depending on the organs involved Multiple Endocrine Neoplasia type 2A MEN2A Multiple Endocrine Neoplasia type 2B MEN2B and Familial Medullary Thyroid Carcinoma FCM whose clinical expression is only CMT A distinctive characteristic of this tumor is its capacity to secrete calcitonin CT which measured in serum sanctions suspicion of this pathology 5-8 leading to diagnostic studies to confirm CMT For the preoperative diagnosis of thyroid nodules ultrasound-guided fine-needle aspiration cytology FNAC is a useful and safe procedure however its sensitivity to exclude CMT is low 9-15 In 2015 a meta-analysis of 15 studies 16 found that the accuracy of FNAC in diagnosing CMT was around 50 For this reason other studies have indicated that the measurement of calcitonin in the fine-needle lavage aspirate fluid of thyroid nodules CT-guided FNAC which have suspected medullary carcinoma can significantly improve the accuracy in the diagnosis of MTC 17 -19 Therefore clinical practice guidelines recommend its determination in patients with suspected MTC 12 The diagnostic importance of pre-surgical medullary carcinoma lies mainly in two points first it changes the surgical approach of the patients and second it allows one to rule out associated pathologies such as hyperparathyroidism and pheochromocytoma which are associated when the entity is hereditary The performance of CT-guided FNAC by the chemiluminescent CL method has been widely disseminated However to the best of our knowledge to date there are no data available on the appropriate cut-off value of CT-guided FNAC with calcitonin electrochemiluminescence ECL immunometric assay method As previously stated it is of particular interest to determine the calcitonin cut-off point in needle washing by electrochemiluminescence method that allows diagnosing medullary carcinoma Clarifying this point allows improving the approach to patients in whom medullary carcinoma is suspected This work seeks to determine the cut-off point of CT-guided FNAC for the diagnosis of CMT with the ECL assay method
Detailed Description:
Investigative Question
In daily practice what value of calcitonin in needle washing by electrochemiluminescent method allows the diagnosis and localization of medullary carcinoma in patients with thyroid nodules with suspected medullary carcinoma Primary Objective To determine the cut-off point of calcitonin in fine needle washing of puncture aspiration of thyroid nodules CT-guided FNA for diagnosis and localization of medullary carcinomaSample Size Fifty patients with medullary carcinoma and 105 controls will be included For each case two controls will be selected matched by age sex and non-medullary nodular pathology In order to estimate the prevalence of medullary carcinoma in patients of the population studiedin whom calcitonin is routinely determined with an accuracy of - 2 and a confidence levelof 95 it is necessary to study 105 patients according to the formula Study Design Observational case-control study patients with medullary carcinoma versus patients without medullary carcinoma The decision of this design model was due to the low prevalence of medullary carcinoma in the population of patients with thyroid nodules Methodology The manuscript followed STARD guidelines for reporting observational and diagnostic studies Location and Time Period This multicenter study will be carried out in Argentina including variables obtained from 01032018 to May 31 2022Coordinating Institution- Hospital Universitario Austral Dr Cavallo Andrea- Other study centers invited to participate Sanatorio Las Lomas San Isidro and the-Hospital Alta Complejidad Formosa Dr Andrea Cavallo will be the principal investigator in the three centers PatientsA prospective database of patients with punctured thyroid nodules and with serum determination of calcitonin according to the annex presented as an annex will be carried out Patients 18 years of age with nodular or multinodular goiter who are undergoing surgery with normal or elevated serum calcitonin andor with suspected CMT due to RET mutation from 312018 to 5312022 will be selected according to inclusion criteria Patients who do not have a remaining puncture sample without serum calcitonin not referred to surgery or those who are lost upon follow-up will be excluded The study will be carried out in the Endocrinology Service Endocrinology area of the Hospital Universitario Austral Pilar Hospital Alta Complejidad Formosa and Sanatorio Las Lomas San Isidro Selection Criteria for Cases and Controls Cases Patients who meet the above inclusion and exclusion criteria and have adiagnosis of medullary carcinoma by histology Controls Patients who meet the above inclusion and exclusion criteria and do not havea diagnosis of medullary carcinoma by histologyFor the control group patients will be randomly selected in a 12 ratio adults with nodular or multinodular goiter without hypercalcitoninemia who have surgical criteria FNA will be performed according to ATA recommendations and with residual sample of FNA washing fluid for calcitonin It is estimated to include a sample of 100 patients in the control group Study Variables-Primary Results The diagnosis of medullary carcinoma is defined according to guidelines of the American Society of Pathologists that uses the Pathological Anatomy service as a diagnostic basis DATA COLLECTION AND PROCEDURES In all three institutions the diagnostic work-up of a thyroid nodule includes the combination of personal and family history physical examination evaluation of thyroid function and thyroid US FNAB is performed following the ATA guidelines recommendations The data will be obtained from the medical records of the patients according to authorization requested for the creation of the database through observation record sheets in Excel Microsoft Serum calcitonin test CT is measured with the same commercially available ECLIA method at the three participating institutions The determination of calcitonin was carried out on a Cobase601 autoanalyzer with the Elecsys Calcitonin test Roche Diagnostics an electrochemiluminescent immunoassay ECLIA As reported by the manufacturer this test has a detection limit of 05 pgml a referenceinterval of up to 98 pgml for women and 143 pgml for men and a measuring range from 05to 200000 pgml Standardization of serum calcitonin sampling and needle washing in the three institutions The harmonization of the pre-analytical stage for serum calcitonin determination was ensured in all three centers This involved morning blood extraction an 8-hour fasting period and the collection of fresh serum following laboratory-specific centrifugation protocols Fresh samples were promptly processed All centers utilized the same assay for analysis Evaluation of nodules by ultrasound All nodules are routinely analyzed in terms of size echogenicity number margin structure solid mixed or cystic presence of microcalcifications and vascularity According to the ultrasound characteristics of the American Thyroid Society ATA Fine needle aspiration FNA nodule biopsy FNA is performed on each patient as long as ATA guideline criteria is met In case of suspicion of medullary carcinoma in search of a nodule or medullary focus FNA will be performed on all non-cystic or spongiform nodules larger than 08 cm Cytological Analysis The cytological study will be carried out by expert pathologists biased to the value of serum Routine Fine Needle Aspiration Cytology FNAC procedure A 23G gauge needle is used under ultrasound guidance After the smear the remaining syringe and needle used for washing will be rinsed with 05 ml of normal saline The aspirate will be subjected to calcitonin measurement all determinations are made in residual fluid sample from the FNA and will be processed immediately Definition of hypercalcitoninemia in serum Female patients with calcitonin levels 98 pgml and male patients with calcitonin levels 143 pgml To confirm hypercalcitoninemia all patients must have at least two serum determinations it is routinely performed in daily clinical practice as recommended by clinical practice guidelines The following variables will be verified a Inclusion date b Sexc Age d Presentation nodular or multinodular goiter e Number of nodules location f Thyroid function hypothyroidism hyperthyroidism Hashimotos thyroiditis g Description of thyroid nodule echogenicity margins consistency location presence of calcifications size h Type of thyroid carcinoma differentiated medullary anaplastic and its variants Medullary carcinoma was ruled out if Ctn was 98 pgmL for women and 143 pgmL for men those patients with calcitonin levels 98 pgmL for women and 143 pgmL for men and 50 pgmL were considered as harbouring a low risk for MTC those with calcitonin 50 pgmLl and 100 pgmL with a moderate risk and those with calcitonin 100 with a high risk for MTC 25 In all cases of hypercalcitoninemia other causes of non-medullary hypercalcitoninemia were ruled-out first We repeated serum calcitonin two times throughout the study to minimize the risk of false positives and false negatives attributable to the biochemical test we conducted a comprehensive medical history assessment to identify any underlying conditions that could be responsible for elevated calcitonin levels This assessment involved using a designed checklist for medications and diseases To evaluate these conditions we requested laboratory tests clinical signs FNA and pathological examinationsFNAC result bethesda and cytological description for each punctured nodulePathological anatomy result TNM and stageSerum calcitoninCalcitonin in lavage of each punctured nodule To obtain anatomical cytological and anatomopathological correlates each surgical piece was analysed according to the ultrasound data of each patient Biochemical determinations TSH T4l antithyroid antibodies calcium Vit D PTH urea creatinine clearance hepatogram blood count thyroglobulinMortality at last visit Anatomo-pathological analysis It will be carried out according to standardized norms in case of doubts or discrepancies they will be resolved internally by three pathologists from each institution To correlate nodulespinal focus an ultrasound correlation with nodule numbering cytology calcitonin in lavage and histology will be performed in all patients Possible Biases and Confounding Variables Selection bias To avoid this bias in the selection of cases and controls subjects are followed and treated under the same standards of care o Cases and controls will be selected by the investigator of the research study already defined above To avoid biochemical determination bias all determinations will be made using the same procedure and with the same brand of device Statistical Analysis Plan For descriptive analysis continuous variables will be expressed as mean and standard deviation or median and interquartile range IQR depending on the observed distribution The continuous variables were compared by Students Test for independent samples one-factor ANOVA or the Mann-Whitney test in case of not complying with the assumptions of normality To compare qualitative variables the independence test Chi-squared will be used A clinically relevant cutoff point will be selected to calculate sensitivity specificity NPV and PPV and their respective 95 CIs In all cases a significance level of less than 5 will be used from the statistical tests applied to reject the hypothesis The sample will be divided into two groups those with hypercalcitoninemia and patients without hypercalcitoninemia that will constitute the control group ETHICAL ASPECTS The protocol will be sent to the Research Ethics Committee REC or Teaching and Research Committee for review and approval Clinical research will comply with the ethical guidelines indicated in the Declaration of Helsinki of the World Medical Association in the International Ethical Guidelines for Biomedical Research of the Council for International Organizations of Medical Sciences and in the UNESCO Declaration on Bioethics and Human Rights the information cannot be associated outside of scientific reasons with a specific person or person determinable All data obtained from the study will be handled confidentially and will be available for monitoring if requested by REC participants If it is necessary to make modifications to what is written in the protocol during the development of the research new approval will be requested from the REC The REC can actively monitor the study ensuring compliance with laws and principles of research ethics A waiver of informed consent is expected for participating patients beyond that already obtained during medical procedures according to routine practice since punctures will be performed in nodules larger than 08 cm in search of spinal focus in those with hypercalcitoninemia and in addition data will be collected from their medical records according to the request for approval of the creation of the database presented as an annex This study has no external funding The selection and inclusion of institutions data analysis and the results of the different stages of this project will be carried out by the research team described above Expected Results The determination of the calcitonin cut-off point in needle lavage in patients with thyroid nodules from the general population for the diagnosis of medullary carcinoma is clinically relevant data Its determination in this population is seldom studied due to the low incidence of medullary carcinoma in the population of patients with nodular pathology determining it will allow improvement of the management of patients in daily clinical practice Therefore the results are expected to be extremely important for medical science around the world As mentioned above there is no work in world literature that determines the cut-off point for calcitonin in lavage in the general population of patients with thyroid nodules for the diagnosis ofm medullary carcinoma The determination of calcitonin in needle wash is a simple non-invasive low-cost method and the results are very precise and its modulation through the use of a cut-off point has the potential to guide which patients would and would not benefit from a surgical procedure We believe that this research question will be answered through this multicenter case control study
In daily practice what value of calcitonin in needle washing by electrochemiluminescent method allows the diagnosis and localization of medullary carcinoma in patients with thyroid nodules with suspected medullary carcinoma Primary Objective To determine the cut-off point of calcitonin in fine needle washing of puncture aspiration of thyroid nodules CT-guided FNA for diagnosis and localization of medullary carcinomaSample Size Fifty patients with medullary carcinoma and 105 controls will be included For each case two controls will be selected matched by age sex and non-medullary nodular pathology In order to estimate the prevalence of medullary carcinoma in patients of the population studiedin whom calcitonin is routinely determined with an accuracy of - 2 and a confidence levelof 95 it is necessary to study 105 patients according to the formula Study Design Observational case-control study patients with medullary carcinoma versus patients without medullary carcinoma The decision of this design model was due to the low prevalence of medullary carcinoma in the population of patients with thyroid nodules Methodology The manuscript followed STARD guidelines for reporting observational and diagnostic studies Location and Time Period This multicenter study will be carried out in Argentina including variables obtained from 01032018 to May 31 2022Coordinating Institution- Hospital Universitario Austral Dr Cavallo Andrea- Other study centers invited to participate Sanatorio Las Lomas San Isidro and the-Hospital Alta Complejidad Formosa Dr Andrea Cavallo will be the principal investigator in the three centers PatientsA prospective database of patients with punctured thyroid nodules and with serum determination of calcitonin according to the annex presented as an annex will be carried out Patients 18 years of age with nodular or multinodular goiter who are undergoing surgery with normal or elevated serum calcitonin andor with suspected CMT due to RET mutation from 312018 to 5312022 will be selected according to inclusion criteria Patients who do not have a remaining puncture sample without serum calcitonin not referred to surgery or those who are lost upon follow-up will be excluded The study will be carried out in the Endocrinology Service Endocrinology area of the Hospital Universitario Austral Pilar Hospital Alta Complejidad Formosa and Sanatorio Las Lomas San Isidro Selection Criteria for Cases and Controls Cases Patients who meet the above inclusion and exclusion criteria and have adiagnosis of medullary carcinoma by histology Controls Patients who meet the above inclusion and exclusion criteria and do not havea diagnosis of medullary carcinoma by histologyFor the control group patients will be randomly selected in a 12 ratio adults with nodular or multinodular goiter without hypercalcitoninemia who have surgical criteria FNA will be performed according to ATA recommendations and with residual sample of FNA washing fluid for calcitonin It is estimated to include a sample of 100 patients in the control group Study Variables-Primary Results The diagnosis of medullary carcinoma is defined according to guidelines of the American Society of Pathologists that uses the Pathological Anatomy service as a diagnostic basis DATA COLLECTION AND PROCEDURES In all three institutions the diagnostic work-up of a thyroid nodule includes the combination of personal and family history physical examination evaluation of thyroid function and thyroid US FNAB is performed following the ATA guidelines recommendations The data will be obtained from the medical records of the patients according to authorization requested for the creation of the database through observation record sheets in Excel Microsoft Serum calcitonin test CT is measured with the same commercially available ECLIA method at the three participating institutions The determination of calcitonin was carried out on a Cobase601 autoanalyzer with the Elecsys Calcitonin test Roche Diagnostics an electrochemiluminescent immunoassay ECLIA As reported by the manufacturer this test has a detection limit of 05 pgml a referenceinterval of up to 98 pgml for women and 143 pgml for men and a measuring range from 05to 200000 pgml Standardization of serum calcitonin sampling and needle washing in the three institutions The harmonization of the pre-analytical stage for serum calcitonin determination was ensured in all three centers This involved morning blood extraction an 8-hour fasting period and the collection of fresh serum following laboratory-specific centrifugation protocols Fresh samples were promptly processed All centers utilized the same assay for analysis Evaluation of nodules by ultrasound All nodules are routinely analyzed in terms of size echogenicity number margin structure solid mixed or cystic presence of microcalcifications and vascularity According to the ultrasound characteristics of the American Thyroid Society ATA Fine needle aspiration FNA nodule biopsy FNA is performed on each patient as long as ATA guideline criteria is met In case of suspicion of medullary carcinoma in search of a nodule or medullary focus FNA will be performed on all non-cystic or spongiform nodules larger than 08 cm Cytological Analysis The cytological study will be carried out by expert pathologists biased to the value of serum Routine Fine Needle Aspiration Cytology FNAC procedure A 23G gauge needle is used under ultrasound guidance After the smear the remaining syringe and needle used for washing will be rinsed with 05 ml of normal saline The aspirate will be subjected to calcitonin measurement all determinations are made in residual fluid sample from the FNA and will be processed immediately Definition of hypercalcitoninemia in serum Female patients with calcitonin levels 98 pgml and male patients with calcitonin levels 143 pgml To confirm hypercalcitoninemia all patients must have at least two serum determinations it is routinely performed in daily clinical practice as recommended by clinical practice guidelines The following variables will be verified a Inclusion date b Sexc Age d Presentation nodular or multinodular goiter e Number of nodules location f Thyroid function hypothyroidism hyperthyroidism Hashimotos thyroiditis g Description of thyroid nodule echogenicity margins consistency location presence of calcifications size h Type of thyroid carcinoma differentiated medullary anaplastic and its variants Medullary carcinoma was ruled out if Ctn was 98 pgmL for women and 143 pgmL for men those patients with calcitonin levels 98 pgmL for women and 143 pgmL for men and 50 pgmL were considered as harbouring a low risk for MTC those with calcitonin 50 pgmLl and 100 pgmL with a moderate risk and those with calcitonin 100 with a high risk for MTC 25 In all cases of hypercalcitoninemia other causes of non-medullary hypercalcitoninemia were ruled-out first We repeated serum calcitonin two times throughout the study to minimize the risk of false positives and false negatives attributable to the biochemical test we conducted a comprehensive medical history assessment to identify any underlying conditions that could be responsible for elevated calcitonin levels This assessment involved using a designed checklist for medications and diseases To evaluate these conditions we requested laboratory tests clinical signs FNA and pathological examinationsFNAC result bethesda and cytological description for each punctured nodulePathological anatomy result TNM and stageSerum calcitoninCalcitonin in lavage of each punctured nodule To obtain anatomical cytological and anatomopathological correlates each surgical piece was analysed according to the ultrasound data of each patient Biochemical determinations TSH T4l antithyroid antibodies calcium Vit D PTH urea creatinine clearance hepatogram blood count thyroglobulinMortality at last visit Anatomo-pathological analysis It will be carried out according to standardized norms in case of doubts or discrepancies they will be resolved internally by three pathologists from each institution To correlate nodulespinal focus an ultrasound correlation with nodule numbering cytology calcitonin in lavage and histology will be performed in all patients Possible Biases and Confounding Variables Selection bias To avoid this bias in the selection of cases and controls subjects are followed and treated under the same standards of care o Cases and controls will be selected by the investigator of the research study already defined above To avoid biochemical determination bias all determinations will be made using the same procedure and with the same brand of device Statistical Analysis Plan For descriptive analysis continuous variables will be expressed as mean and standard deviation or median and interquartile range IQR depending on the observed distribution The continuous variables were compared by Students Test for independent samples one-factor ANOVA or the Mann-Whitney test in case of not complying with the assumptions of normality To compare qualitative variables the independence test Chi-squared will be used A clinically relevant cutoff point will be selected to calculate sensitivity specificity NPV and PPV and their respective 95 CIs In all cases a significance level of less than 5 will be used from the statistical tests applied to reject the hypothesis The sample will be divided into two groups those with hypercalcitoninemia and patients without hypercalcitoninemia that will constitute the control group ETHICAL ASPECTS The protocol will be sent to the Research Ethics Committee REC or Teaching and Research Committee for review and approval Clinical research will comply with the ethical guidelines indicated in the Declaration of Helsinki of the World Medical Association in the International Ethical Guidelines for Biomedical Research of the Council for International Organizations of Medical Sciences and in the UNESCO Declaration on Bioethics and Human Rights the information cannot be associated outside of scientific reasons with a specific person or person determinable All data obtained from the study will be handled confidentially and will be available for monitoring if requested by REC participants If it is necessary to make modifications to what is written in the protocol during the development of the research new approval will be requested from the REC The REC can actively monitor the study ensuring compliance with laws and principles of research ethics A waiver of informed consent is expected for participating patients beyond that already obtained during medical procedures according to routine practice since punctures will be performed in nodules larger than 08 cm in search of spinal focus in those with hypercalcitoninemia and in addition data will be collected from their medical records according to the request for approval of the creation of the database presented as an annex This study has no external funding The selection and inclusion of institutions data analysis and the results of the different stages of this project will be carried out by the research team described above Expected Results The determination of the calcitonin cut-off point in needle lavage in patients with thyroid nodules from the general population for the diagnosis of medullary carcinoma is clinically relevant data Its determination in this population is seldom studied due to the low incidence of medullary carcinoma in the population of patients with nodular pathology determining it will allow improvement of the management of patients in daily clinical practice Therefore the results are expected to be extremely important for medical science around the world As mentioned above there is no work in world literature that determines the cut-off point for calcitonin in lavage in the general population of patients with thyroid nodules for the diagnosis ofm medullary carcinoma The determination of calcitonin in needle wash is a simple non-invasive low-cost method and the results are very precise and its modulation through the use of a cut-off point has the potential to guide which patients would and would not benefit from a surgical procedure We believe that this research question will be answered through this multicenter case control study
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None