Correlation of 18F-sodium fluoride uptake and radiodensity in extraosseous metastases of medullary thyroid carcinoma.

Objective: Although 18F-sodium fluoride (18F-NaF) uptake is frequently observed in extraosseous metastases of medullary thyroid carcinoma (MTC) with calcification, itcan also occur in metastatic sites without visible calcium deposition, leading to the hypothesis that visually undetectable calcium accumulation may be responsible for this uptake. The aim of this study was to indirectly support this hypothesis by analyzing the correlation between the degree of 18F-NaF uptake and radiodensity in extraosseous MTC metastases, since calcium deposition can increase attenuation even when not visually detectable. Subjects and methods: Extraosseous metastatic lesions of 15 patients with MTC were evaluated using 18F-NaF positron-emission tomography (PET)/computed tomography (CT)and segmented by levels of standardized uptake value (SUV). The correlation between mean SUV and mean Hounsfield unit (HU) values was assessed for the entire group of segments and for two subgroups with different mean HU values. Results: Very high correlations were observed between mean SUV and mean HU values for both the entire group of segments and the subgroup with a mean HU value greater than 130 (p = 0.92 and p = 0.95, respectively; p < 0.01). High correlation (p = 0.71) was also observed in the subgroup with mean HU values ranging from 20 to 130 (p < 0.01). Conclusion: The findings of the present study suggest that there is an association between 18F-NaF uptake and calcium deposition in extraosseous metastasesof MTC, supporting the hypothesis that visually undetectable calcium accumulation may be responsible for 18F-NaF uptake in regions without visible calcium deposition.

Beyond the Recommendations of the Clinical Guidelines for Medullary Thyroid Cancer - A Case Report / Más allá de las recomendaciones de las guías clínicas de cáncer medular de tiroides - a propósito de un caso

Medullary thyroid cancer (MTC) is a rare disease from parafollicular C cells. Calcitonin has been suggested as a screening; its levels are proportional to the tumor size and predictive of metastatic disease. We present a case where an early action was taken with lower cut-off points. Male patient, 49 years old. Thyroid ultrasound (US) with a suspicious nodule. Fine Needle Aspiration Biopsy (FNAB) suggests MTC, with pre-operative serum calcitonin (CTN) of 591 pg/mL. Total thyroidectomy with central and bilateral dissection was performed. Biopsy: MTC in left nodule of 26 mm without lymph nodes (LN) metastases. Follow-up with undetectable CTN for six years. After that, CT was 4.7 pg/mL, and carcinoembryonic antigen (CEA) was 1.2 ng/mL. Neck US showed bilateral LN. FNAB of LN does not show recurrence. A progressive rise of markers with doubling time of CTN and CEA was 16 and 51.3 months, respectively. CTN raised until 112 pg/mL. Given the lack of cervical compromise, a neck and lung CT, liver MRI, and bone scintigraphy were ordered despite CTN levels < 150 pg/mL. MRI showed hypervascular hepatic lesions, contrasted with gadoxetic acid. PET Ga68-DOTATATE showed lesions with overexpression of somatostatin receptors in the liver. Surgery was done, and a biopsy confirmed metastases. Conclusions: The clinical guidelines may allow the management of cases; however, they should be used considering each case context. In our patient, if the guidelines had been strictly followed, it would not have been possible to detect liver metastases to achieve a surgical resection with curative intent.

Paciente masculino, 49 años. Ecografía tiroidea con nódulo sospechoso. Biopsia por aspiración con aguja fina (PAAF) sugiere cáncer medular de tiroides (CMT), calcitonina sérica preoperatoria (CTN) de 591 pg/mL. Se realizó tiroidectomía total con disección central y bilateral. Biopsia: CMT en nódulo tiroideo izquierdo de 2,6 cm sin metástasis en 29 ganglios linfáticos (GL). En el seguimiento, CTN sérica indetectable durante 6 años. Posteriormente CTN sérica de 4,7 pg/mL y antígeno carcinoembrionario (CEA) de 1,2 ng/mL. Ecografía cervical de control mostró GL subcentimétricos bilaterales en grupo IV. PAAF de GL sin evidencia de malignidad, con niveles de CTN indetectables en la muestra. El doblaje de CTN y CEA fue 16 y 51,3 meses respectivamente. Dado ausencia de compromiso cervical, se solicitó TC de cuello y tórax, RM hepática y gammagrafía ósea, a pesar de no presentar niveles de CTN > 150 pg/mL. La RM mostró 3 lesiones hepáticas hipervasculares; se complementa con un PET Ga-DOTATATE que mostró 2 lesiones focales con sobreexposición de receptores de somatostatina en el parénquima hepático, con SUVmáx de 6,8 y 7,3. Se realiza cirugía extirpando 5 lesiones; la biopsia confirmó metástasis de CMT. Conclusiones: Las guías clínicas pueden dar orientaciones generales y permitir el manejo de casos basados en la evidencia; sin embargo, siempre deben usarse considerando el contexto de cada caso en particular. Si se hubieran seguido estrictamente las pautas, no habría sido posible detectar las metástasis hepáticas dentro de la ventana de oportunidad para lograr una resección quirúrgica con intención curativa.

Beyond the Recommendations of the Clinical Guidelines for Medullary Thyroid Cancer - A Case Report.

Medullary thyroid cancer (MTC) is a rare disease from parafollicular C cells. Calcitonin has been suggested as a screening; its levels are proportional to the tumor size and predictive of metastatic disease. We present a case where an early action was taken with lower cut-off points. Male patient, 49 years old. Thyroid ultrasound (US) with a suspicious nodule. Fine Needle Aspiration Biopsy (FNAB) suggests MTC, with pre-operative serum calcitonin (CTN) of 591 pg/mL. Total thyroidectomy with central and bilateral dissection was performed. Biopsy: MTC in left nodule of 26 mm without lymph nodes (LN) metastases. Follow-up with undetectable CTN for six years. After that, CT was 4.7 pg/mL, and carcinoembryonic antigen (CEA) was 1.2 ng/mL. Neck US showed bilateral LN. FNAB of LN does not show recurrence. A progressive rise of markers with doubling time of CTN and CEA was 16 and 51.3 months, respectively. CTN raised until 112 pg/mL. Given the lack of cervical compromise, a neck and lung CT, liver MRI, and bone scintigraphy were ordered despite CTN levels < 150 pg/mL. MRI showed hypervascular hepatic lesions, contrasted with gadoxetic acid. PET Ga68-DOTATATE showed lesions with overexpression of somatostatin receptors in the liver. Surgery was done, and a biopsy confirmed metastases. Conclusions: The clinical guidelines may allow the management of cases; however, they should be used considering each case context. In our patient, if the guidelines had been strictly followed, it would not have been possible to detect liver metastases to achieve a surgical resection with curative intent.

A fat containing combined neuroendocrine carcinoma and hepatocellular carcinoma in the liver: A case report.

A 79-year-old man was admitted to our hospital because of increased hepatobiliary enzyme levels. Dynamic computed tomography and magnetic resonance imaging showed a liver tumor measuring 60mm containing fat foci at the cranial aspect of the tumor. We diagnosed the patient with hypovascular hepatocellular carcinoma (HCC) and fat deposition, and performed a caudate lobe resection. Pathology examination revealed two intermingled components: moderately differentiated HCC with fat deposition and neuroendocrine carcinoma (NEC). Primary combined NEC and HCC is extremely rare. To our knowledge, this is the first report of combined NEC and HCC including a fat component. HCC is the most common primary hepatic malignancy with fat. HCC might include fat, even if HCC coexists with another type of cancer. The imaging characteristics of and HCC with another type of cancer vary depending on the amount of each component. We should not simply diagnose such tumors as HCC, but think about the possibilities of HCC with another type of cancer, because there is a fat component.

Combining the American Thyroid Association's Ultrasound Classification with Cytological Subcategorization Improves the Assessment of Malignancy Risk in Indeterminate Thyroid Nodules.

Background: The risk of malignancy (RoM) of indeterminate thyroid nodules (ITNs) shows a high variability in interinstitutional cohorts. The RoM is partially associated with the cytological degree of atypia and the ultrasound (US) pattern. This study evaluated the cancer risk of ITNs by jointly considering the cytological subcategory and the American Thyroid Association (ATA)-based US risk classification. Methods: This study features a retrospective cohort from two Brazilian centers comprising 238 ITNs with confirmed outcomes. US classification, according to ATA-based guidelines, and cytological subcategorization were determined. The cytological subgroups were as follows: (1) nuclear atypia (NA) related to papillary thyroid carcinoma (PTC) but insufficient to categorize the cytology as suspicious for malignancy; (2) architectural atypia without NA (AA); (3) both architectural and nuclear atypia (ANA); (4) oncocytic pattern (OP) without NA; and (5) NA not related to PTC (NANP). NA was divided into three subgroups: nuclear size and shape, nuclear membrane appearance, and/or chromatin aspects. Results: The overall frequency of malignancy was 39.5%. Among the cytological subcategories, the highest RoM was related to the NA (43.9%) and to the ANA (43.5%), followed by AA (29.4%), and OP (9.4%). NA was positively and independently associated with cancer (odds ratio [OR]: 4.5; confidence interval [CI: 1.2-16.6]) as was the occurrence of ANA (OR 6.6 [CI 1.5-29.5]). AA and OP were not independently associated with cancer. Both ATA-based high- and intermediate-risk categories showed an independent association with cancer (OR 6.8 [CI 2.9-15.5] and OR: 2.6 [CI 1.1-5.8], respectively). ITNs with cytological findings of NA or ANA when combined with intermediate US patterns had RoM values of 47.5% and 56.7%, respectively. Both cytological subcategories, when combined with the ATA high-suspicion class reached an RoM >70%. The type of NA with the highest odds for cancer was related to the nuclear membrane (OR 11.5). Conclusions: The RoM of ITNs can reach almost 80% when both NA and ATA-based high-risk US features are present. The presence of such cytological features also increased the RoM in the ATA-based intermediate-risk US category. In addition, AA and OP were not independently related to higher cancer risk. These results strengthen the recommendations for combing cytological subcategorization and US risk classification in the workup for ITNs before the decision of a molecular testing, clinical observation, or diagnostic surgery.

Hallazgos en gammagrafía con análogos de la somatostatina (Tc-99m HYNIC-TOC) en metástasis sobre cuero cabelludo como debut en un tumor neuroendocrino de origen incierto / Findings insomatostatin analogue scintigraphy (99mtc-HYNIC-TOC) in scalp metastasis as debut in a neuroendocrine tumor of uncertain origin / Achados em cintilografia com análogos de somatostatina (Tc-99m HYNIC-TOC) em metástases no couro cabeludo como estréia em um tumor neuroendócrino de origem incerta

Los estudios de medicina nuclear permiten en tumor neuroendocrino (TNE) de origen desconocido la búsqueda del tumor primario y estadificación de la enfermedad

Nuclear medicine studies allow neuroendocrine tumor (NET) of unknown origin to search for the primary tumor and staging the disease

Estudos de medicina nuclear permitem o tumor neuroendócrino (NET) de origem desconhecida para a pesquisa do tumor primário e o estadiamento da doença

Carcinoma adenoneuroendocrino mixto de la ampolla de Vater: reporte de caso / Mixed adenoneuroendocrine carcinoma of the ampulla of Vater: case report

INTRODUCCIÓN: Los carcinomas adenoneuroendocrinos mixtos (MANEC) son tipos de tumores bifásicos, reconocidos morfológicamente ante la presencia de una formación neoplásica constituida de manera simultánea por epitelio glandular y células neuroendocrinas. Dentro del tracto gastrointestinal, estas neoplasias predominan en el estómago o el colon. Solo 19 casos localizados en la ampolla de Vater han sido reportados por la literatura. OBJETIVO: Reportar un caso de MANEC; revisar la epidemiología, pronóstico y tratamiento de estos tumores. MATERIALES Y MÉTODO: Presentación de caso clínico de una paciente con diagnóstico de adenocarcinoma neuroendocrino mixto de la región ampular. DISCUSIÓN: La presentación clínica, el manejo y el pronóstico son similares al del adenocarcinoma ampular. Se diagnostican con el examen histopatológico de la muestra resecada. Ambos componentes deben ser histológicamente malignos, y cada uno de ellos debe representar al menos el 30% de la lesión. CONCLUSIÓN: Los MANEC ampulares son tumores poco comunes a nivel mundial, siendo éste el primer caso reportado en nuestro instituto.

INTRODUCTION: Mixed adenoneuroendocrine carcinomas (MANEC) are types of biphasic tumors, morphologically recognized in the presence of a neoplastic formation constituted simultaneously by glandular epithelium and neuroendocrine cells. Only 19 cases located in the ampulla of Vater have been reported in the literature. Within the gastrointestinal tract, these neoplasms predominate in the stomach or colon. AIM: Report a case of MANEC; review of the epidemiology, prognosis and treatment of these tumors. MATERIALS AND METHOD: Case presentation of a patient diagnosed with mixed adeno-neuroendocrine carcinoma of the ampullary region. DISCUSSION: The clinical presentation, management and prognosis are similar to ampullary adenocarcinoma. These tumors are diagnosed with a histopathological examination of the resected specimen. Both components must be histologically malignant, and each of them must represent at least 30% of the lesion. CONCLUSION: MANEC of the ampulla are rare tumors worldwide, being this case the first reported in our institute.

The 4Ds of ectopic ACTH syndrome: diagnostic dilemmas of a difficult disease.

Cushing's syndrome (CS) is an uncommon condition that leads to high morbidity and mortality. The majority of endogenous CS is caused by excessive ACTH secretion, mainly due to a pituitary tumor - the so-called Cushing's disease (CD) - followed by ectopic ACTH syndrome (EAS), an extra-pituitary tumor that produces ACTH; adrenal causes of CS are even rarer. Several methods are used to differentiate the two main etiologies: specific laboratory tests and imaging procedures, and bilateral inferior petrosal sinus sampling (BIPSS) for ACTH determination; however, identification of the source of ACTH overproduction is often a challenge. We report the case of a 28-year-old woman with clinical and laboratory findings consistent with ACTH-dependent CS. All tests were mostly definite, but several confounding factors provoked an extended delay in identifying the origin of ACTH secretion, prompting a worsening of her clinical condition, with difficulty controlling hyperglycemia, hypokalemia, and hypertension. During this period, clinical treatment was decisive, and measurement of morning salivary cortisol was a differential for monitoring cortisol levels. This report shows that clinical reasoning, experience and use of recent methods of nuclear medicine were decisive for the elucidation of the case.

The 4Ds of ectopic ACTH syndrome: diagnostic dilemmas of a difficult disease

SUMMARY Cushing's syndrome (CS) is an uncommon condition that leads to high morbidity and mortality. The majority of endogenous CS is caused by excessive ACTH secretion, mainly due to a pituitary tumor - the so-called Cushing's disease (CD) - followed by ectopic ACTH syndrome (EAS), an extra-pituitary tumor that produces ACTH; adrenal causes of CS are even rarer. Several methods are used to differentiate the two main etiologies: specific laboratory tests and imaging procedures, and bilateral inferior petrosal sinus sampling (BIPSS) for ACTH determination; however, identification of the source of ACTH overproduction is often a challenge. We report the case of a 28-year-old woman with clinical and laboratory findings consistent with ACTH-dependent CS. All tests were mostly definite, but several confounding factors provoked an extended delay in identifying the origin of ACTH secretion, prompting a worsening of her clinical condition, with difficulty controlling hyperglycemia, hypokalemia, and hypertension. During this period, clinical treatment was decisive, and measurement of morning salivary cortisol was a differential for monitoring cortisol levels. This report shows that clinical reasoning, experience and use of recent methods of nuclear medicine were decisive for the elucidation of the case.

[Neoendocrine carcinoma of the esophagus: report of a case]. / Carcinoma neuroendocrino de esófago: reporte de caso.

Neuroendocrine carcinoma of esophagus represents less than 2% of cases of cancer of the esophagus. This presentation is extremely unusual, as this type of carcinoma typically presents with greater frequency in bronchopulmonary regions. The symptoms are usually associated with esophageal obstruction and include odynophagia, dysphagia and weight loss and are not usually associated with Carcinoid syndrome. The diagnosis requires one or more of the following positive immunohistochemical markers: Chromogranin A, synaptophysin or CD56 positive, as well as the presence of EMA and PANCK positive. We report the case of a male patient with diagnosis of neuroendocrine tumor of esophagus.

[Polymetastatic highly aggressive Small Cell Undifferentiated Neuroendocrine Carcinoma of Ascending Colon]. / Carcinoma neuroendocrino indiferenciado polimetástatico altamente agresivo de células pequeñas de colon ascendente.

Neuroendocrine carcinoma (NEC) of the colon is a rare and very aggressive tumor with poor prognosis. The current case report presents a 53-year-old male with a 6 cm × 10 cm ascending colon carcinoma, causing large intestine obstruction, with simultaneous multiple hepatic metastases and peritoneal carcinomatosis. Surgical resection of the primary tumor was performed, because of the bowel obstruction, to ameliorate the symptoms before the onset of chemotherapy. Histopathology revealed that the tumor was a small-cell undifferentiated NEC. During the post0operative period, the patient presented pulmonary metastases, and on the 36th post-operative day, death occurred due to respiratory failure.

El carcinoma neuroendocrino del colon es un tumor raro y muy agresivo, con mal pronóstico. Se presenta el caso de un hombre de 53 años con un carcinoma de colon ascendente de 6 × 10 cm que causa obstrucción del intestino grueso, con metástasis hepáticas múltiples simultáneas y carcinomatosis peritoneal. Se realizó la resección quirúrgica del tumor primario, debido a la obstrucción intestinal, para mejorar los síntomas antes del inicio de la quimioterapia. La histopatología reveló que el tumor era un carcinoma neuroendocrino indiferenciado de células pequeñas. Durante el posoperatorio, el paciente presentó metástasis pulmonares y el día 36 posoperatorio se produjo la muerte por insuficiencia respiratoria.

Carcinoma neuroendocrino de esófago: reporte de caso / Neoendocrine carcinoma of the esophagus: report of a case

El carcinoma neuroendocrino de esófago representa menos del 2% de casos de cáncer de esófago. Esta forma de presentación es extremadamente inusual, ya que este tipo de carcinoma se suele presentar con mayor frecuencia en zonas broncopulmonares. Los síntomas suelen asociarse a la obstrucción esofágica e incluyen odinofagia, disfagia y pérdida de peso, siendo infrecuente la clínica de síndrome carcinoide. Para el diagnóstico se requiere de uno o más de los siguientes marcadores de inmunohistoquímica positivos: cromogranina A, sinaptofisina o CD56 positivos, así como la presencia de los anticuerpos EMA y PANCK positivos. Se reporta el caso de un paciente varón con diagnóstico de tumor neuroendocrino de esófago.

Neuroendocrine carcinoma of esophagus represents less than 2% of cases of cancer of the esophagus. This presentation is extremely unusual, as this type of carcinoma typically presents with greater frequency in bronchopulmonary regions. The symptoms are usually associated with esophageal obstruction and include odynophagia, dysphagia and weight loss and are not usually associated with Carcinoid syndrome. The diagnosis requires one or more of the following positive immunohistochemical markers: Chromogranin A, synaptophysin or CD56 positive, as well as the presence of EMA and PANCK positive. We report the case of a male patient with diagnosis of neuroendocrine tumor of esophagus.

Comparison of 68Ga PET/CT to Other Imaging Studies in Medullary Thyroid Cancer: Superiority in Detecting Bone Metastases.

Context: Persistent disease after surgery is common in medullary thyroid cancer (MTC), requiring lifelong radiological surveillance. Staging workup includes imaging of neck, chest, abdomen, and bones. A study integrating all sites would be ideal. Despite the established use of gallium-68 (68Ga) positron emission tomography (PET)/CT with somatostatin analogues in most neuroendocrine tumors, its efficacy is controversial in MTC. Objective: Evaluate the efficacy of 68Ga PET/CT in detecting MTC lesions and evaluate tumor expression of somatostatin receptors (SSTRs) associated with 68Ga PET/CT findings. Methods: Prospective study evaluating 30 patients with MTC [group 1 (n = 16), biochemical disease; group 2 (n = 14), metastatic disease]. Patients underwent 68Ga PET/CT, bone scan, CT and ultrasound of the neck, CT of the chest, CT/MRI of the abdomen, and MRI of the spine. 68Ga PET/CT findings were analyzed by disease site as positive or negative and as concordant or discordant with conventional studies. Sensitivity and specificity were calculated using pathological or cytological analysis or unequivocal identification by standard imaging studies. Immunohistochemical analysis of SSTRs was compared with 68Ga PET/CT findings. Results: In both groups, 68Ga PET/CT was inferior to currently used imaging studies except for bone scan. In group 2, 68Ga PET/CT sensitivities were 56%, 57%, and 9% for detecting neck lymph nodes, lung metastases, and liver metastases, respectively, and 100% for bone metastases, superior to the bone scan (44%). Expression of SSTRs, observed in 44% of tumors, was not associated with 68Ga-DOTATATE uptake. Conclusions: 68Ga PET/CT does not provide optimal whole-body imaging as a single procedure in patients with MTC. However, it is highly sensitive in detecting bone lesions and could be a substitute for a bone scan and MRI.

Pediatric Neuroendocrine Carcinoid Tumors: Review of Diagnostic Imaging Findings and Recent Advances.

OBJECTIVE: Although rare, pediatric neuroendocrine tumors including carcinoid tumor have increased in incidence over the past few decades. Despite increased recognition, survival rates have not significantly improved. Earlier detection of these tumors is necessary to improve clinical outcomes. This article discusses imaging approaches for detecting pediatric carcinoid tumors including anatomic imaging methods such as CT and MRI as well as functional imaging methods targeting the somatostatin receptor including 111In-labeled octreotide and newer 68Ga-based radiotracers that may hold promise in hybrid PET/CT or PET/MRI. CONCLUSION: Improvements in functional imaging with novel somatostatin receptor-specific radiotracers along with fused functional and anatomic imaging have substantially improved the clinical detection of carcinoid tumors. Although rare, these tumors are encountered in children, and an awareness of the appropriate use of various imaging methods is essential for pediatric specialists. Further research is needed to ascertain the diagnostic value of newer imaging methods and radiotracer-based treatment approaches, especially in the pediatric population.

Early Detection of Bone Metastasis in Small Cell Neuroendocrine Carcinoma of the Cervix by 68Ga-DOTATATE PET/CT Imaging.

The neuroendocrine small cell carcinoma of the cervix is a rare malignancy that has a poor prognosis due to early lymphatic and hematogenous spread. We herein report a case of a 27- year-old woman who was referred for initial staging of a neuroendocrine small cell carcinoma with previous unremarkable structural imaging. Ga-DOTATATE PET/CT revealed focal uptake at the primary tumor and in a solitary pelvic bone lesion suggestive of metastases that was further confirmed by CT-guided biopsy. Somatostatin receptor PET/CT may be a useful image modality for early detection of metastases to guide treatment in these patients.

Visualization of Lymph Nodal and Hepatic Metastases of Medullary Thyroid Carcinoma on 18F-Fluoride PET/CT.

F-fluoride uptake in soft tissue metastases has been previously described. Herein, we report a case of F-fluoride uptake in lymph nodal and hepatic metastases of medullary thyroid carcinoma. Simultaneous CT showed calcified lesions in these regions.

Serum Thyroglobulin Measured With a Second-Generation Assay in Patients Undergoing Total Thyroidectomy Without Radioiodine Remnant Ablation: A Prospective Study.

BACKGROUND: Follow-up consisting of the measurement of nonstimulated serum thyroglobulin (Tg) combined with neck ultrasonography is recommended for patients with papillary thyroid carcinoma without indication for radioiodine ablation. There is no recommendation of thyrotropin suppression during this follow-up. New-generation Tg assays have been increasingly used, but few studies involve patients submitted only to thyroidectomy and they have several limitations. The objective of this prospective study was to define expected concentrations of nonstimulated Tg measured with a second-generation assay after total thyroidectomy in the absence of tumor. METHODS: Serum Tg was measured using a second-generation assay in 69 patients without tumor and serum thyrotropin between 0.5 and 2 mIU/L, 3, 6, 12, and 24 months after total thyroidectomy. All patients had undetectable anti-Tg antibodies. RESULTS: Serum Tg was undetectable in 44.4%, 57%, 62.5%, and 62.1% of the patients 3, 6, 12, and 24 months after thyroidectomy, respectively, and was ≤0.5 ng/mL in 60.3%, 80%, 90.6%, and 90.9% of patients. All patients had a Tg≤2 ng/mL 6 months after thyroidectomy, and 97% had a Tg≤1 ng/mL 24 months after surgery. There was no case of Tg conversion from undetectable to detectable and none of the patients presented an increase in Tg. CONCLUSIONS: An important decline in serum Tg occurred between 3 and 6 months after total thyroidectomy. One year after surgery, Tg was undetectable in approximately 60% of the patients and was ≤2 ng/mL in all of them.