A novel CCK2/gastrin receptor-localizing radiolabeled peptide probe for personalized diagnosis and therapy of patients with progressive or metastatic medullary thyroid carcinoma: a multicenter phase I GRAN-T-MTC study.
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SUBMITTER: Erba PA
PROVIDER: S-EPMC6347971 | biostudies-literature | 2018 Dec
REPOSITORIES: biostudies-literature
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A novel CCK2/gastrin receptor-localizing radiolabeled peptide probe for personalized diagnosis and therapy of patients with progressive or metastatic medullary thyroid carcinoma: a multicenter phase I GRAN-T-MTC study.
Erba Paola A PA Maecke Helmut H Mikolajczak Renata R Decristoforo Clemens C Zaletel Katja K Maina-Nock Theodosia T Peitl Petra Kolenc PK Garnuszek Piotr P Froberg Alida A Goebel Georg G de Jong Marion M Jabrocka-Hybel Agata A Konijnenberg Mark M Virgolini Irena I Nock Berthold B Lenda-Tracz Wioletta W Pawlak Dariusz D Rangger Christine C Trofimiuk-Müldner Małgorzata M Sowa-Staszczak Anna A Tomaszuk Monika M von Guggenberg Elisabeth E Scarpa Lorenza L Hubalewska-Dydejczyk Alicja A
Polish archives of internal medicine 20181205 12
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Project description:IntroductionMedullary thyroid cancer (MTC) is a rare malignant tumour of the parafollicular C-cells with an unpredictable clinical course and currently suboptimal diagnostic and therapeutic options, in particular in advanced disease. Overexpression of cholecystokinin-2 receptors (CCK2R) represents a promising avenue to diagnostic imaging and targeted therapy, ideally through a theranostic approach.Materials and methodsA translational study (GRAN-T-MTC) conducted through a Phase I multicentre clinical trial of the indium-111 labelled CP04 ([111In]In-CP04), a CCK2R-seeking ligand was initiated with the goal of developing a theranostic compound. Patients with proven advanced/metastatic MTC or short calcitonin doubling time were enrolled. A two-step concept was developed through the use of low- and high-peptide mass (10 and 50 μg, respectively) for safety assessment, with the higher peptide mass considered appropriate for therapeutic application. Gelofusine was co-infused in a randomized fashion in the second step for the evaluation of potential reduction of the absorbed dose to the kidneys. Imaging for the purpose of biodistribution, dosimetry evaluation, and diagnostic assessment were performed as well as pre-, peri-, and postprocedural clinical and biochemical assessment.ResultsSixteen patients were enrolled. No serious adverse events after application of the compound at both peptide amounts were witnessed; transient tachycardia and flushing were observed in two patients. No changes in biochemistry and clinical status were observed on follow-up. Preliminary dosimetry assessment revealed the highest dose to urinary bladder, followed by the kidneys and stomach wall. The effective dose for 200 MBq of [111In]In-CP04 was estimated at 7±3 mSv and 7±1 mSv for 10 μg and 50 μg CP04, respectively. Administration of Gelofusine reduced the dose to the kidneys by 53%, resulting in the organ absorbed dose of 0.044±0.019 mSv/MBq. Projected absorbed dose to the kidneys with the use of [177Lu]Lu-CP04 was estimated at 0.9±0.4 Gy/7.4 GBq. [111In]In-CP04 scintigraphy was positive in 13 patients (detection rate of 81%) with superior diagnostic performance over conventional imaging.ConclusionIn the present study, [111In]In-CP04 was shown to be a safe and effective radiopharmaceutical with promising theranostic characteristics for patients with advanced MTC.
| S-EPMC9852173 | biostudies-literature
Project description:Background: Cytopathological evaluation of thyroid fine-needle aspiration biopsy (FNAB) specimens can fail to raise preoperative suspicion of medullary thyroid carcinoma (MTC). The Afirma RNA-sequencing MTC classifier identifies MTC among FNA samples that are cytologically indeterminate, suspicious, or malignant (Bethesda categories III-VI). In this study we report the development and clinical performance of this MTC classifier. Methods: Algorithm training was performed with a set of 483 FNAB specimens (21 MTC and 462 non-MTC). A support vector machine classifier was developed using 108 differentially expressed genes, which includes the 5 genes in the prior Afirma microarray-based MTC cassette. Results: The final MTC classifier was blindly tested on 211 preoperative FNAB specimens with subsequent surgical pathology, including 21 MTC and 190 non-MTC specimens from benign and malignant thyroid nodules independent from those used in training. The classifier had 100% sensitivity (21/21 MTC FNAB specimens correctly called positive; 95% confidence interval [CI] = 83.9-100%) and 100% specificity (190/190 non-MTC FNAs correctly called negative; CI = 98.1-100%). All positive samples had pathological confirmation of MTC, while all negative samples were negative for MTC on surgical pathology. Conclusions: The RNA-sequencing MTC classifier accurately identified MTC from preoperative thyroid nodule FNAB specimens in an independent validation cohort. This identification may facilitate an MTC-specific preoperative evaluation and resulting treatment.
| S-EPMC9526471 | biostudies-literature
Project description:Background: The concomitant presence of papillary thyroid cancer (PTC) and medullary TC (MTC) is rare. In this multicentric study, we documented the epidemiological characteristics, disease conditions and clinical outcome of patients with simultaneous MTC/PTC. Methods: We collected data of patients with concomitant MTC/PTC at 14 Italian referral centers. Results: In total, 183 patients were enrolled. Diagnosis was mostly based on cytological examination (n = 58, 32%). At diagnosis, in the majority of cases, both PTC (n = 142, 78%) and MTC (n = 100, 54%) were at stage I. However, more cases of stage II-IV were reported with MTC (stage IV: n = 27, 15%) compared with PTC (n = 9, 5%). Information on survival was available for 165 patients: 109 patients (66%) were disease-free for both PTC and MTC at the last follow-up. Six patients died from MTC. Median time to progression was 123 months (95% confidence interval (CI): 89.3-156.7 months). Overall, 45% of patients were disease-free after >10 years from diagnosis (125 months); this figure was 72.5% for PTC and 51.1% for MTC. Conclusions: When MTC and PTC are concurrent, the priority should be given to the management of MTC since this entity appears associated with the most severe impact on prognosis.
| S-EPMC6826384 | biostudies-literature
Project description:AimsTo confirm by means of pentagastrin, a synthetic gastrin agonist, that netazepide is a gastrin/CCK2 receptor antagonist in healthy subjects, and that antagonism persists during repeated dosing.MethodsWe did two studies in which we infused pentagastrin (0.6 μg kg(-1) h(-1) intravenously), aspirated gastric secretion and measured the volume, pH and H(+) secretion rate of the gastric aspirate. First, we did a double-blind, five-way crossover study (n = 10) to assess the effect of single oral doses of netazepide (1, 5, 25 and 100 mg) and placebo on the response to pentagastrin. Then, we did a single-blind, placebo-controlled study (n = 8) to assess the effect of the first and last oral doses of netazepide (100 mg) twice daily for 13 doses on the response to pentagastrin.ResultsNetazepide was well tolerated. After placebo, pentagastrin increased the volume and H(+) secretion rate and reduced the pH of gastric aspirate. Compared with placebo, single doses of netazepide caused dose-dependent inhibition of the pentagastrin response (P < 0.02); netazepide (100 mg) abolished the response. After 13 doses, the reduction in volume and H(+) secretion rate persisted (P < 0.001), but the pH effect was mostly lost.ConclusionsNetazepide is an orally active, potent, competitive antagonist of human gastrin/CCK2 receptors. Antagonism is dose dependent and persists during repeated dosing, despite tolerance to the effect on pH. Further studies are required to explain that tolerance. Netazepide is a tool to study the physiology and pharmacology of gastrin, and merits studies in patients to assess its potential to treat gastric acid-related conditions and the trophic effects of hypergastrinaemia.
| S-EPMC3853528 | biostudies-literature
Project description:AimsTo compare gastric acid suppression by netazepide, a gastrin/CCK2 receptor antagonist, with that by a proton pump inhibitor (PPI), and to determine if netazepide can prevent the trophic effects of PPI-induced hypergastrinaemia.MethodsThirty healthy subjects completed a double-blind, randomized, parallel group trial of oral netazepide and rabeprazole, alone and combined, once daily for 6 weeks. Primary end points were: basal and pentagastrin-stimulated gastric acid and 24 h circulating gastrin and chromogranin A (CgA) at baseline, start and end of treatment, gastric biopsies at baseline and end of treatment and basal and pentagastrin-stimulated gastric acid and dyspepsia questionnaire after treatment withdrawal.ResultsAll treatments similarly inhibited pentagastrin-stimulated gastric acid secretion. All treatments increased serum gastrin, but the combination and rabeprazole did so more than netazepide alone. The combination also reduced basal acid secretion. Rabeprazole increased plasma CgA, whereas netazepide and the combination reduced it. None of the biopsies showed enterochromaffin-like (ECL) cell hyperplasia. Withdrawal of treatments led neither to rebound hyperacidity nor dyspepsia.ConclusionsNetazepide suppressed pentagastrin-stimulated gastric acid secretion as effectively as did rabeprazole. The reduction in basal acid secretion and greater increase in serum gastrin by the combination is consistent with more effective acid suppression. Despite our failure to show rabeprazole-induced ECL cell hyperplasia and rebound hyperacidity, the increase in plasma CgA after rabeprazole is consistent with a trophic effect on ECL cells, which netazepide prevented. Thus, netazepide is a potential treatment for the trophic effects of hypergastrinaemia and, with or without a PPI, is a potential treatment for acid-related conditions.
| S-EPMC4415711 | biostudies-literature
Project description:PurposeCabozantinib, a tyrosine kinase inhibitor (TKI) of hepatocyte growth factor receptor (MET), vascular endothelial growth factor receptor 2, and rearranged during transfection (RET), demonstrated clinical activity in patients with medullary thyroid cancer (MTC) in phase I.Patients and methodsWe conducted a double-blind, phase III trial comparing cabozantinib with placebo in 330 patients with documented radiographic progression of metastatic MTC. Patients were randomly assigned (2:1) to cabozantinib (140 mg per day) or placebo. The primary end point was progression-free survival (PFS). Additional outcome measures included tumor response rate, overall survival, and safety.ResultsThe estimated median PFS was 11.2 months for cabozantinib versus 4.0 months for placebo (hazard ratio, 0.28; 95% CI, 0.19 to 0.40; P < .001). Prolonged PFS with cabozantinib was observed across all subgroups including by age, prior TKI treatment, and RET mutation status (hereditary or sporadic). Response rate was 28% for cabozantinib and 0% for placebo; responses were seen regardless of RET mutation status. Kaplan-Meier estimates of patients alive and progression-free at 1 year are 47.3% for cabozantinib and 7.2% for placebo. Common cabozantinib-associated adverse events included diarrhea, palmar-plantar erythrodysesthesia, decreased weight and appetite, nausea, and fatigue and resulted in dose reductions in 79% and holds in 65% of patients. Adverse events led to treatment discontinuation in 16% of cabozantinib-treated patients and in 8% of placebo-treated patients.ConclusionCabozantinib (140 mg per day) achieved a statistically significant improvement of PFS in patients with progressive metastatic MTC and represents an important new treatment option for patients with this rare disease. This dose of cabozantinib was associated with significant but manageable toxicity.
| S-EPMC4164813 | biostudies-literature
Project description:BackgroundRadiomics strategies exhibit great promise in the context of thyroid nodule diagnosis. This study aimed to compare radiomics features of different sizes of medullary thyroid carcinoma (MTC) and papillary thyroid carcinoma (PTC) tumors and to compare the efficiency of radiomics approaches as a means of differentiating between these tumor types.MethodsIn total, 86 MTC and 330 PTC nodules were divided into the macronodular (>10 mm) and micronodular (⩽10 mm) categories. The radiomics features of these nodules were analyzed to identify independent prognosis factors and evaluate the efficacy of individual and combined indicators as predictors of tumor type.ResultsIn total, 12 radiomics features were found to differ significantly between MTC and PTC macronodules, while 6 differed significantly between MTC and PTC micronodules. Shape 2D_Sphericity, firstorder_Skewness, glrlm_RunLengthNonUniformity, glszm_GrayLevelNonUniformity, and glszm_SizeZoneNonUniformity were features that were independently associated with the differential diagnoses of MTC and PTC macronodules. Receiver operating characteristic (ROC) curve analyses of the efficacy of these 5 single indicators and a combined indicator composed thereof yielded area under the curve (AUC) values of 0.621, 0.678, 0.704, 0.762, 0.747, and 0.824, respectively, with respective sensitivities of 55.3%, 43.0%, 53.1%, 56.3%, 46.9%, and 65.6%, and respective specificity values of 65.6%, 89.1%, 81.6%, 88.8%, 95.0%, and 91.1%. The glrlm_RunEntropy and glszm_SizeZoneNonUniformity features were identified as independent factors associated with the differential diagnoses of MTC and PTC micronodules. Receiver operating characteristic curve analyses of the efficacy of these 2 single indicators and a combined indicator composed thereof yielded respective AUC values of 0.678, 0.678, and 0.771; Sensitivities of 57.0%, 72.7%, and 72.7%; and specificities of 77.3%, 64.2%, and 77.5%.ConclusionsA range of different radiomics features can enable effective differentiation between MTC and PTC nodules of different sizes. Moreover, analyses of combinations of radiomics features yielded diagnostic efficiency values higher than those associated with single radiomics features, highlighting a more reliable approach to diagnosing MTC and PTC tumors.
| S-EPMC9121460 | biostudies-literature
Project description:Medullary thyroid cancer is uncommon and patients typically present with advanced disease. Treatment options for patients with progressive, metastatic medullary thyroid cancer had been limited until recently. Tyrosine kinase inhibitors have garnered increasing interest in this subset of patients. The US Food and Drug Administration recently approved cabozantinib, a tyrosine kinase inhibitor, after promising results were shown in a large Phase III clinical trial. This review summarizes the clinical pharmacology, clinical trials, and safety data for cabozantinib and concludes with a discussion of possible future directions for the treatment of medullary thyroid cancer.
| S-EPMC4043815 | biostudies-literature
Project description:HER2 transmembrane receptor is an important target in immunotherapy treatment of breast and gastroesophageal cancer. Molecular imaging of HER2 expression may provide essential prognostic and predictive information concerning disseminated cancer and aid in selection of an optimal therapy. Radiolabeled low molecular weight peptide ligands are particularly attractive as probes for molecular imaging, since they reach and bind to the target and clear from non-target organs and blood stream faster than bulky antibodies. In this study, we evaluated a potential HER2-imaging probe, an A9 nonapeptide, derived from the trastuzumab-Fab portion. Its cellular uptake was investigated by mass spectrometry analysis of the cytoplasmic cellular extracts. Moreover, based on in-silico modeling, DTPA chelator was conjugated to N-terminus of A9. 111In-labeled A9 demonstrated nanomolar affinity to HER2-expressing BT474 cells and favorable biodistribution profile in NMRI mice. This study suggests that the peptide A9 represents a good lead candidate for development of molecular probe, to be used for imaging purposes and for the delivery of cytotoxic agents.
| S-EPMC5812989 | biostudies-literature
Project description:BackgroundMedullary thyroid carcinoma (MTC) is a rare subtype of thyroid cancer. Other than gain-of-function RET mutations, no other genetic, lifestyle or environmental risk associations have been established for MTC. Several case-control studies and meta-analysis have examined the risk association of different SNPs with MTC in different populations but with contradictory or inconclusive results.MethodsIn a large cohort of 438 Indian MTC cases and 489 gender and ethnicity matched healthy controls from 1000 genome project, a comprehensive risk association of 13 SNPs of three pathways-detoxification, cell cycle regulation and RET was performed along with meta-analysis of RET SNPs.ResultsMultivariate logistic regression analysis identified a protective risk association of CDKN1ASer31Arg SNP with both hereditary (OR 0.26; 95% confidence interval [CI] 0.13-0.55; P < .001) and sporadic MTC (OR 0.53; 95% CI 0.36-0.78; P = .001). An increased risk association was identified for NAT2Y94Y SNP (OR 1.62, 95% CI 1.17-2.25, P = .004) and CDKN2A3'UTR SNP (OR 1.89, 95% CI 1.19-2.98, P = .006) with sporadic MTC and RET S904S with hereditary MTC (OR 2.82, 95% CI 1.64-4.86, P < .001). Meta-analysis of RET SNPs including our cohort identified increased risk association of all four RET SNPs with MTC.ConclusionIn this largest SNP risk association study for MTC and the only risk association study of the 13 most commonly studied MTC associated SNPs in a single cohort of this rare cancer, a significant protective risk association of CDKN1ASer31Arg SNP with MTC was shown for the first time. Meta-analysis identified significant risk association of all four RET SNPs, not observed in previous meta-analysis.
| S-EPMC6792509 | biostudies-literature