Radiopeptide transmitted internal irradiation of non-iodophil thyroid cancer and conventionally untreatable medullary thyroid cancer using

AIM: Differentiated thyroid carcinomas (DTC) and medullary thyroid carcinomas (MTC) overexpress somatostatin receptor subtypes (sstr). The aim of this pilot study was to evaluate the tumour response of thyroid carcinomas to targeted irradiation with the radiolabelled somatostatin analogue [90Y]-1,4,7,10-tetra-azacyclododecan-4,7,10-tricarboxy-methyl-1-yl-acetyl-D-Phe1-Tyr3-octreotide ([90Y]-DOTA-D-Phe1-Tyr3-octreotide, or 90Y-DOTATOC) which has a high affinity to subtype 2 and a low affinity to subtype 5. It shows no affinity to sstr1, sstr3 and sstr4. PATIENTS AND METHODS: Twenty patients (mean age 58 years; 50% female, 50% male) with thyroid cancer were included (medullary thyroid cancer (MTC), 12 patients; differentiated thyroid cancer (DTC), seven patients; papillar carcinoma (PC), four patients; follicular carcinoma (FC), three patients; anaplastic carcinoma (AC), one patient). All patients had been therapy resistant and had progressive disease before 90Y-DOTATOC therapy. The dose applied was between totals of 1700 MBq x m(-2) to 7400 MBq x m(-2) 90Y-DOTATOC, administered in one to four injections at intervals of 6 weeks. In the case of tumour progression under therapy, treatment was terminated. RESULTS: The overall antitumour effect (objective response and stable disease) was 35%; in MTC 42%, in DTC 29%, and in AC 0%. The objective overall response rate was 0%. A stable disease was achieved in 35% (7/20), and progressive disease was found in 65% (13/20). The median time to progression was 8 months, with a median follow-up of 15 months. The treatment was very well tolerated. There were no grade III/IV haematological or renal toxicities. CONCLUSION: Targeted radiotherapy using 90Y-DOTATOC is able to stop tumour progression in a small number of patients and therefore may be an alternative treatment option for resistant disease. More significant tumour responses in thyroid and medullary thyroid cancer may be obtained by using radiopeptides with pan-somatostatin characteristics.     

68Ga DOTANOC PET/CT detects medullary thyroid cancer relapse at bone level

A patient with a history of radical thyroidectomy for medullary thyroid carcinoma (MTC) was studied by 68Ga [DOTA,1-Nal3]octreotide PET/CT for suspected relapse. PET/CT documented a focal area of somatostatin receptors expression at bone level. Although 68Ga DOTA-peptides PET has been successfully used for the detection of neuroendocrine tumors, its role in MTC patients is still under evaluation. In fact, although deriving from the neural crest, MTC cells may show a variable expression of somatostatin receptors. This case shows that PET/CT with DOTANOC may be a useful complementary imaging modality in patients with well-differentiated MTC.     

Technetium-99m-sestamibi uptake by recurrent Hurthle cell carcinoma of the thyroid.

Technetium-99m-sestamibi has been reported to localize in various tumors. Scintigraphic results for a patient with recurrent Hurthle cell carcinoma of the thyroid whose tumor was imaged with both 99mTc-sestamibi and 201TI, but not with 131I, are presented.     

Comparison of In-111 octreotide and Tc-99m (V) DMSA scintigraphy in the detection of medullary thyroid tumor foci in patients with elevated levels of tumor markers after surgery.

PURPOSE: In this retrospective study, the authors evaluated the utility of In-111 octreotide (OctreoScan) and Tc-99m (V) DMSA scintigraphy for the localization of recurrent metastatic tumor foci in patients with medullary thyroid cancer (MTC) and compared the findings with those of conventional radiologic imaging methods. METHODS: The scintigraphic images were compared with computed tomography (CT) and magnetic resonance imaging (MRI) and ultrasonography (US) in 14 patients (8 men, 6 women; age range, 22 to 74 years) with elevated calcitonin and carcinoembryonic antigen levels after total thyroidectomy. All scintigraphic image findings were evaluated qualitatively as mild uptake (+) and moderate to marked uptake (++). RESULTS: In-111 octreotide may be superior to Tc-99m (V) DMSA for the detection of tumor foci of patients with MTC on a patient basis (78.5% versus 57.1%) and on a lesion basis (44.1% versus 30.2%). The sensitivity rate for In-111 octreotide (78.5%) was also similar to that of CT and MRI on a patient basis. Conversely, the combined use of Tc-99m (V) DMSA and In-111 octreotide revealed the best sensitivity rate (85.7%) on a patient basis, whereas the combined use of CT and MRI showed the best sensitivity rate (81.3%) on a lesion basis. CONCLUSIONS: These findings suggest that In-111 octreotide is superior to Tc-99m (V) DMSA and has a similar sensitivity rate to CT and MRI for the diagnosis of recurrent or metastatic MTC. Although the combined use of In-111 octreotide and Tc-99m (V) DMSA was most sensitive, the combined use of CT and MRI with radionuclide imaging methods may better detect more metastatic tumor foci.     

Thyrotoxicosis: a rare presenting symptom of Hurthle cell carcinoma of the thyroid

Hurthle cell carcinoma of the thyroid is a rare type of thyroid neoplasm. The most common clinical presentation is a single palpable thyroid nodule. The neoplasm typically presents as a nonfunctioning or cold nodule on a Tc-99m sodium pertechnetate or radioiodine thyroid scan. We report a case of Hurthle cell carcinoma of the thyroid in a woman presenting with thyrotoxicosis. The Tc-99m thyroid scan was also interesting in that the nodule was a hot or hyperfunctioning area, resulting in a rare scintigraphic finding in a rare tumor. Clinicopathologic aspects and related issues are further discussed.     

Thyroid scintigram in familial medullary carcinoma of the thyroid gland

Findings on thyroid scintigram were compared with results of thyroid palpation and size and location of C-cell disease in 68 thyroid lobes of 35 patients with familial medullary thyroid carcinoma (MTC) and high basal or stimulated plasma calcitonin values. Rectilinear scans showed cold nodules in 24 (35%) of 68 lobes. In three lobes, the cold nodules did not coincide with MTC (2 macrofollicular adenomas, 1 colloid goiter). Thus, the true positive rate for rectilinear scans was 31%. Palpation identified nodules in 20 lobes (29%), but the true positive rate was only 26%. Patients with MTC have high basal or stimulated calcitonin values long before the tumor is detectable by scan or even later by palpation. When the tumors were large enough to be seen on thyroid scans, the most frequently encountered single pattern was that of symmetrically located cold nodules in the middle of otherwise normal thyroid lobes. This pattern, if encountered in a thyroid scan, should raise the suspicion of MTC.     

Tumor uptake of 68Ga-DOTA-Tyr3-octreotate: animal PET studies of tumor flow and acute somatostatin receptor modulation in the CA20948 rat model

IntroductionFactors determining the in vivo uptake of radiolabeled somatostatin analogs by neuroendocrine tumors are poorly known. The aim is to evaluate in vivo tumor perfusion and regulation of somatostatin receptors (sstr) following acute exposure to octreotide, in an animal model of neuroendocrine tumor.MethodsH₂¹⁵O flow studies were performed in 8 CA20948 tumor-bearing rats and another 36 rats underwent three [⁶⁸Ga]-DOTA-Tyr³-octreotate imaging sessions at 24-h intervals. After baseline (Day 0) imaging, scanning was repeated on Day 1 after octreotide injection (175 μg/kg), with a variable delay: no injection (controls, n=7), coinjection (n=6), and octreotide injection 20 min (n=7), 2 h (n=8) and 4 h (n=8) before imaging. Repeat images without octreotide was performed at Day 2 followed by sacrifice and tumor counting.ResultsH₂¹⁵O studies failed to measure quantitative tumor perfusion in this model. On Day 1, ratio of tumor uptake to Day 0 was 1.2±0.3 in controls; 0.6±0.2 in the coinjection group; 0.9±0.2, 1.1±0.1 and 1.2±0.2 in the other groups, respectively. Uptake in the coinjection group showed a statistically significant reduction of tumor uptake (P<.0001). All groups showed increased uptake on Day 2, without statistical differences between groups. In vivo tumor counts showed good correlation with ex vivo countings (R²=0.946).ConclusionAcute exposure to unlabeled octreotide in this neuroendocrine tumor model results in a rapid recycling or resynthesis of sstr. Positron emission tomography (PET) allowed to reliably assess quantitative uptake of [⁶⁸Ga]-DOTA-Tyr³-octreotate over time in the same animal, but failed in this model to measure tumor perfusion.     

The therapeutic value of SST-A octreotide alone or with adjuvant treatment in patients with advanced medullary thyroid carcinoma and positive (111)In-octreotide scan

Medullary thyroid carcinoma (MTC) as a neuroendocrine tumour arising from C cells of the thyroid gland secrets hormonal peptides; among them, calcitonine (CT) and carcino-embryonic antigen (CEA). These two peptides are used for the diagnosis and treatment response of MTC cases. In patients with advanced MTC, scintigraphy by [(111)In-DTPA-d-phe1]-octreotide is able to detect somatostatin receptors (SSTR) and thus identify regional lymph nodes and/or distal metastases. In this article, we have studied the use of [(111)In-DTPA-d-phe1]-octreotide in the treatment of patients with advanced MTC, and a positive octreotide scan. Twenty-two patients were studied, 16 with persistent MTC and six with relapsed MTC. All patients' tumours were detected by [(111)In-DTPA-d-phe1]-octreotide-scan to be SSTR positive. All patients were treated with the somatostatin analog (SST-A) octreotide, for 3-21 months. Nine patients were treated only with SST-A (Group A). The remaining 13 patients (Group B) received adjuvant treatment as follows: six patients received chemotherapy (Ch), five patients received both Ch and external radiotherapy (eRT) and two patients received only eRT. Results were as follows: Group B patients as compared to Group A patients had about the same objective and biological response. Patients of Group B had relatively better subjective response (less diarrheas and abdominal cramps) versus Group A patients, although this finding was not significant. Group B patients had a longer mean survival time after treatment as compared to Group A patients: 39 months (with a range of 4-72 months) versus 20 months (with a range of 3-60 months) respectively, (P<0.05). Also Group B patients had longer than Group A patients mean total survival time - measured from the start of the disease: 138 (18-270) versus 97 (13-235) months respectively (P<0.05). Based on the above findings, it is the opinion of the authors that patients with advanced MTC and SSTR tumor expression in vivo as indicated by [(111)In-DTPA-d-phe1]-octreotide scanning, when submitted to treatment with SST-A octreotide and adjuvant Ch and/or eRT treatment may have a better treatment response than if submitted to treatment with SST-A octreotide alone. More cases are being studied by us at the present.     

Radiolabeled peptides in diagnosis and tumor imaging: clinical overview

The authors briefly review radiopeptides currently approved for use in the United States. They present a short review of the peptide somatostatin's actions and also note the five somatostatin receptors (SSTRs) to which the peptide and its synthetic analogs octreotide, lanreotide, and vapreotide bind. The many conditions besides neuroendocrine tumors having SSTRs are listed. Labeled octreotide and the other two analogues have a strong affinity for SSTR2 and SSTR5, which thereby produce positive imaging. The various neuroendocrine tumors best imaged by somatostatin receptor scintigraphy (SRS) are discussed, and the exceptions (insulinoma and medullary thyroid carcinoma) are noted to be seen better with labeled VIP and (99m)Tc-dimethylsuccinic acid (DMSA), respectively. SRS and VIP receptor scintigraphy are also noted to image many nonneuroendocrine tumors, which often have appropriate receptors. Several of the currently emerging and very effective new imaging techniques are described. These include (99m)Tc-DMSA for medullary thyroid carcinoma, (18)F dihydroxyphenylalanine positron emission tomography, and C(11) 5-hydroxytryptophan positron emission tomography scanning for all neuroendocrine tumor, but especially carcinoid tumor, metastases. The special role of SRS in identifying gastric carcinoid tumors in hypergastrinemic patients is reviewed. Various pitfalls in interpreting SRS are presented and receptor-enhancing techniques described. Besides use of SRS (mainly Octreoscan, Mallinckrodt Medical, St. Louis, MO) only for detecting and localizing primary tumors and metastases for staging, there are many additional special uses for clinical management of SRS-positive tumors. These include the intraoperative use of the handheld gamma-detecting probe. A brief enumeration is given of the most promising of other non-SST G-protein-coupled receptors and ligands currently under development. Finally, we have posed a number of questions for which answers are needed in the immediate future to facilitate better imaging. Extrapolations of current knowledge and experience with radiolabeled peptide pharmaceutical imaging are converted to reasonable speculations of anticipated future developments in this field.     

奥曲肽及其类似物用于肿瘤治疗的进展

简单综述90Y-奥曲肽、177Lu-奥曲肽在肿瘤治疗中的应用价值。对奥曲肽治疗的原理、在肿瘤及正常组织中的分布、对肾脏功能的影响和保护剂的应用进行介绍,主要治疗的病种包括不摄取131I的分化型甲状腺癌转移灶、Hurthle细胞甲状腺癌、甲状腺髓样癌、来自胃肠胰的神经内分泌肿瘤、小细胞癌、嗜铬细胞瘤等。对应用适合的剂量和未来新的可能用于临床治疗的放射肽和发展方向加以综述。     

甲状腺髓样癌的诊治现状及研究进展

甲状腺髓样癌（MTC）是一种来源于甲状腺滤泡旁细胞的中度恶性肿瘤。目前常用的诊断方法包括降钙素及其他肿瘤标志物（如癌胚抗原）检测、超声、细针穿刺细胞学检查（FNAC）等,但这些方法的特异度均不高,且FNAC对技术的要求较高。MTC的治疗以及时根治性外科手术为主,对于手术难以切除的侵袭性、转移性及复发性病灶应选择综合治疗,但疗效不明确。目前降钙素原及新型分子靶向探针在MTC的诊治方面有了新的突破,但缺乏临床转化的支撑。因此,MTC的诊治目前依然是医学难题,笔者就MTC的诊治现状及研究进展作一综述。     

Identification and evaluation of a new tumor cell-binding peptide, FROP-1.

Peptides are useful tools for the targeted delivery of radionuclides or chemotherapeutic drugs to their site of action within an organism. Given that the peptide receptor is overexpressed at the tumor, therapeutically active doses can be delivered to the tumor with reduced side effects. Because currently known peptides are restricted to a small number of tumors, new molecules and their corresponding receptors have to be identified to enlarge the spectrum of malignancies that can be diagnosed or treated using tumor-targeting peptides. METHODS: A 12-amino-acid peptide phage display system was applied to identify a new peptide binding to follicular thyroid carcinoma cells. The properties of the radiolabeled peptide were assessed in binding, competition, and internalization experiments in a variety of tumor cell lines including FRO82-2 and MCF-7 cells, and the pharmacokinetic behavior of the radiolabeled peptide was evaluated in tumor-bearing mice. Peptide stability was studied in human serum. RESULTS: After 5 selection rounds, the new peptide, FROP-1 (EDYELMDLLAYL), was identified. It showed binding to follicular thyroid carcinoma as well as anaplastic thyroid carcinoma, mammary carcinoma, cervix carcinoma, prostate carcinoma, and cell lines derived from head and neck tumors, and low affinity could be observed to control cells such as human umbilical vein endothelial cells or immortalized keratinocytes. In MCF7 cells, 78% and 86% of the bound activity was internalized after 10 and 60 min of incubation, respectively. Stability experiments in human serum showed the appearance of a degradation product after 15 min. Tumor uptake of the radioactive labeled peptide increased for 45 min in nude mouse models, reaching an accumulation level of approximately 3.6 percentage injected dose (%ID)/g for FRO82-2 tumors or approximately 3.8 %ID/g for MCF-7 tumors. CONCLUSION: The target of FROP-1 is most likely a molecule found generally in tumors, making this peptide highly attractive for diagnostic or therapeutic applications. However, modifications are needed to increase stability and affinity.     

In-111 octreotide scan in a case of a neuroendocrine tumor of unknown origin

Major neuroendocrine tumors contain many somatostatin receptors. This feature allows for the localization of primary tumors and tumor metastases by scintigraphy with the radiolabeled somatostatin analog octreotide. We describe a patient with nonspecific clinical data and ultrasonography and CT that showed an isolated focal lesion in the liver. In-111 octreotide scintigraphy was essential in establishing the diagnosis of liver metastasis from a neuroendocrine tumor confirmed by pathologic findings. Because clinical symptoms recurred, ultrasonography and CT were performed a few months after surgery. Both were negative. However, In-111 octreotide scintigraphy suggested multiple bone metastases and established the diagnosis of bone metastases from a neuroendocrine tumor, which was confirmed by Tc-99m MDP bone scans and MRI.     

Peptide receptor imaging and therapy.

This article reviews the results of somatostatin receptor imaging (SRI) in patients with somatostatin receptor-positive neuroendocrine tumors, such as pituitary tumors, endocrine pancreatic tumors, carcinoids, gastrinomas, and paragangliomas, or other diseases in which somatostatin receptors may also be expressed, like sarcoidosis and autoimmune diseases. [(111)In-DTPA0]octreotide is a radiopharmaceutical that has great potential for helping visualize whether somatostatin receptor-positive tumors have recurred. The overall sensitivity of SRI to localize neuroendocrine tumors is high. In several neuroendocrine tumor types, inclusion of SRI in the localization or staging procedure may be very rewarding in terms of cost effectiveness, patient management, or quality of life. The value of SRI in patients with other tumors, such as breast cancer or malignant lymphomas, or in patients with granulomatous diseases has to be established. The application of radiolabeled peptides may be clinically useful in another way: after the injection of [(111)In-DTPA0]octreotide, surgeons can detect tumor localizations by a probe that is used during the operation. This may be of particular value if small tumors with a high receptor density are present (e.g., gastrinomas). As the success of peptide receptor scintigraphy for tumor visualization became clear, the next logical step was to try to label these peptides with radionuclides emitting alpha or beta particles, or Auger or conversion electrons, and to perform radiotherapy with these radiolabeled peptides. The results of the described studies with 90Y- and (111)In-labeled octreotide show that peptide receptor radionuclide therapy using radionuclides with appropriate particle ranges may become a new treatment modality. One might consider the use of radiolabeled somatostatin analogs first in an adjuvant setting after surgery of somatostatin receptor-positive tumors to eradicate occult metastases and second for cancer treatment at a later stage.     

Scintigraphic detection of recurrence of medullary thyroid cancer

A case of recurrent medullary thyroid cancer (MTC) was evaluated with¹²³I-MIBG,^99mTc(V)-dimercaptosuccinic acid (DMSA), and²⁰¹Tl scintigraphy. This patient had been operated on for MTC in the right thyroid. Recently a left neck mass was noticed, and was suspected of being a. recurrence of MTC based on increased plasma calcitonin (CT) and carcinoembryonic antigen (CEA). He was operated on for the neck mass which revealed MTC, and papillary thyroid cancer was incidentally found in the left thyroid, but the CT and CEA levels remained high, and remaining MTC tumor was suspected. But the location of the tumor was unknown. Although^99mTc(V)-DMSA scintigraphy is generally believed to be superior in sensitivity to¹²³I-MIBG scintigraphy, it did not demonstrate the tumor site but²⁰¹Tl and¹²³I-MIBG did. Furthermore,¹²³I-MEBG scintigraphy has greater specificity for tumors which arise in the neural crest. Judging from the results of this case and cases reported in the literatures, both¹²³I-MIBG and^99mTc(V)-DMSA should be performed in the detection of recurrent MTC.     

Determination of magnetization transfer contrast in tissue: an MR imaging study of brain tumors.

OBJECTIVE. In this study, the magnetization transfer contrast (MTC) on MR images of several brain tumors and the correlation between MTC and tumors' histologic features were investigated. MTC depends on the extent of magnetization transfer, or cross-relaxation, from tissue water protons to macromolecular protons. On the basis of the known increase of the cross-relaxation rate with increasing molecular weight of protein in protein solutions, the hypothesis that changes in MTC correlate directly with the macromolecular composition of various tumors was tested. SUBJECTS AND METHODS. Preoperative MR images were obtained with a 0.1-T MR system in 40 patients with brain tumors. MTC was correlated with the histologic features and the dry weight of the tumors. The tumors studied included astrocytomas (10), acoustic schwannomas (three), meningiomas (12), pituitary adenomas (10), craniopharyngiomas (two), and hemangioblastomas (three). RESULTS. MTC was 0.43 in normal white matter and 0.42 in normal gray matter, and varied from 0.11 to 0.37 in the tumors. The mean MTC in astrocytomas (0.21 +/- 0.09) was smaller than the mean MTC in the gray matter (p = .0001) or in the other solid tumors (0.34 +/- 0.07 to 0.37 +/- 0.09, p < .002). MTC was larger in high-grade than in low-grade astrocytomas (0.28 +/- 0.05 vs 0.14 +/- 0.04, p = .0005). In meningiomas, MTC correlated with the collagen content of the tumor tissue (r = .95, p = .01). The differences in contents of solids between the solid tumor groups were not significant (p > or = .1, NS). CONCLUSION. When the previously demonstrated correlations between solid content and 1/T1 of the types of tumors studied are taken into consideration, the present results suggest a larger relative contribution from hydrodynamic vs cross-relaxation effects in astrocytomas than in benign tumors or in gray matter. The twofold difference in MTC between low- and high-grade astrocytomas probably reflects the amount of nuclear material in the tumor cells. Collagen content determined the differences in MTC among meningiomas. These results indicate that the major determinant of differences in MTC within these tumor groups is the high-molecular-weight tissue macromolecules, suggesting higher specificity for MTC than for T1 in discriminating between tissues on MR images.     

Magnetization transfer contrast of hepatic lesions in breath-hold gradient-echo images of different T1 weighting

Seventeen patients with hepatic lesions [six metastases from colon, breast, and gallbladder carcinoma; one gallbladder carcinoma; five hepatocellular carcinoma; three focal nodular hyperplasia (FNH); one adenoma; and one cyst] were examined by MR breath-hold two-dimensional gradient-echo imaging to assess the potential of magnetization transfer contrast (MTC) for improved conspicuity and classification. Imaging sequences were applied with and without irradiation of off-resonant radiofrequency (RF) prepulses, but other parameters were unchanged. Therefore, quantitative assessment of MTC could be performed. In contrast to former examinations of other researchers, no significant difference of MTC was found between malignant liver lesions and benign lesions as FNH or adenoma. MTC might provide differentiation between hemangioma and cysts versus solid tumors, but MTC is not capable of distinguishing benign and malignant types of solid liver tumors. Effects of unchanged MTC prepulses on signal intensity of normal liver tissue and most lesions were more pronounced for nearly proton density-weighted fast low-angle shot (FLASH) images than for T1-weighted FLASH images, obtained by using higher excitation flip angles. Liver-to-lesion contrast could not be improved clearly by MTC prepulses. The contrast between liver and lesions in the gradient-echo breath-hold images was compared with standard T1- and T2-weighted spin-echo images. Liver-to-lesion contrast in the breath-hold images was found to be inferior to T2-weighted spin-echo images in 14 of 17 cases. Lesion conspicuity in regions near the diaphragm was better in breath-hold images, because problems with marked breathing motion (as in standard imaging) could be avoided.     

Use of SPECT with (99m)Tc-Sestamibi in a patient affected by laryngeal carcinoma and parathyroid adenoma

We report the case of a patient with a laryngeal carcinoma in whom asymptomatic hyperparathyroidism was also detected during the preoperative work-up. A planar (201)Thallium/(99m)Tc-pertecnetate subtraction scintigraphy was performed in order to locate the suspected parathyroid adenoma. The study showed a single area of increased (201)Thallium uptake just above the thyroid isthmus, likely due to the laryngeal tumor. The scintigraphic study was repeated using (99m)Tc-Sestamibi and (99m)Tc-pertechnetate and employing the SPECT technique. Both SPECT studies made it possible to identify correctly the parathyroid adenoma, located inferiorly and in a posterior position to the lower third of the right thyroid lobe. The laryngeal tumor and parathyroid adenoma could be excised in a single surgery session. This case is of interest due to the rarity of the coexistence of two neck tumors and the clear advantage shown by the SPECT technique with (99m)Tc-Sestamibi over the planar technique with 201Thallium.