Recent Results in Cancer Research最新文献

{"title":"Long-Term Follow-Up in Medullary Thyroid Carcinoma Patients.","authors":"Friedhelm Raue, Karin Frank-Raue","doi":"10.1007/978-3-031-80396-3_11","DOIUrl":"https://doi.org/10.1007/978-3-031-80396-3_11","url":null,"abstract":"<p><p>After surgery, patients with MTC (medullary thyroid carcinoma) should be assessed for the presence of residual disease, the localization of metastases, and the identification of progressive disease. Postoperative staging is used to separate low-risk patients from high-risk patients with MTC. In addition to the TNM system, further histological staging with Ki67, mitotic count, tumor necrosis, and molecular analysis of somatic RET mutations is helpful for the stratification of patients in different prognostic categories. The number of lymph node metastases and involved compartments as well as postoperative Ctn (calcitonin) and CEA (carcinoembryonic antigen) levels should also be documented. Postoperative nonmeasurable Ctn levels are associated with a favorable outcome. In patients with basal serum Ctn levels less than 150 pg/ml following thyroidectomy, persistent or recurrent disease is almost always confined to lymph nodes in the neck. If the postoperative serum Ctn level exceeds 150 pg/ml, patients should be evaluated by imaging procedures, including neck and chest CT (computed tomography), contrast-enhanced MRI, US of the liver, bone scintigraphy, MRI of the bone and positron emission tomography (PET)/CT. One can estimate the growth rate of MTC metastases from sequential imaging studies using response evaluation criteria in solid tumors (RECIST) that document increases in tumor size over time and by measuring serum levels of Ctn or CEA over multiple time points to determine the tumor marker doubling time. One of the main challenges remains finding effective adjuvant and palliative options for patients with metastatic disease. Patients with persistent or recurrent MTC localized to the neck and slightly elevated Ctn levels following thyroidectomy might be candidates for neck reoperations depending on the extent of the tumor. Once metastases appear, the clinician must decide which patients require therapy, balancing the frequently slow rate of tumor progression associated with a good quality of life and suggesting active surveillance against the limited efficacy and potential toxicities of local and systemic therapies. Considering that metastatic MTC is incurable, the management goals are to provide locoregional disease control, palliate symptoms such as diarrhea, palliate symptomatic metastases causing pain or bone fractures, and control metastases that threaten life through bronchial obstruction or spinal cord compression. This can be achieved by palliative surgery, EBRT (external beam radiation therapy) or systemic therapy using multikinase inhibitors (MKIs) targeting RET or selective RET inhibitors requiring genetic testing prior to the initiation of therapy.</p>","PeriodicalId":39880,"journal":{"name":"Recent Results in Cancer Research","volume":"223 ","pages":"267-291"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143659088","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epidemiology, Clinical Presentation, and Diagnosis of Medullary Thyroid Carcinoma.","authors":"Friedhelm Raue, Karin Frank-Raue","doi":"10.1007/978-3-031-80396-3_4","DOIUrl":"https://doi.org/10.1007/978-3-031-80396-3_4","url":null,"abstract":"<p><p>Medullary thyroid carcinoma (MTC) is a rare neuroendocrine tumor originating from thyroid C cells that produces mainly calcitonin (Ctn) and is used as a tumor marker. MTC can occur either sporadically (75%) or in a hereditary variant (multiple endocrine neoplasia type 2, MEN2) due to germline mutations in the RET proto-oncogene. The discovery of MTC in a patient has several diagnostic implications involving a specific strategy, preoperative evaluation of the tumor marker Ctn and the extent of the disease, classification of MTC as sporadic or hereditary using germline RET testing, screening for associated endocrinopathies in hereditary MTC, and somatic RET testing in sporadic MTC. Elevated Ctn is a highly sensitive and specific tumor marker for the diagnosis and follow-up of MTC. Ctn is directly related to the tumor mass. In patients with nodular thyroid disease, MTC can be diagnosed by Ctn determination. Ctn is an indicator of tumor burden. Patients with confirmed sporadic or hereditary MTC should undergo total thyroidectomy. Depending on the preoperative Ctn value, additional dissection of the lymph nodes in the central and lateral neck compartments should be performed. In MEN 2 patients diagnosed by RET mutation analysis, the timing of prophylactic thyroidectomy depends on the specific RET mutation and Ctn level.</p>","PeriodicalId":39880,"journal":{"name":"Recent Results in Cancer Research","volume":"223 ","pages":"93-127"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143659078","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Systemic Therapies for Advanced Medullary Thyroid Carcinoma.","authors":"Marco Ruiz Santillan, Ramona Dadu, Robert F Gagel, Elizabeth G Grubbs, Mimi I Hu","doi":"10.1007/978-3-031-80396-3_12","DOIUrl":"https://doi.org/10.1007/978-3-031-80396-3_12","url":null,"abstract":"<p><p>Medullary thyroid carcinoma (MTC) is a rare disease that is indolent in the majority of patients. In a subset of patients, the cancer is more aggressive with symptomatic or progressive disease metastasizing to cervical neck structures, lungs, liver, and/or bones. Definitive cure for metastatic MTC remains elusive. Understanding oncogenic pathways and molecular drivers of disease have led to development and approval of multikinase and highly-specific RET inhibitors for the management of progressive MTC. RET mutations are the most common drivers in MTC, followed by mutually exclusive RAS mutations. Cabozantinib and vandetanib, multikinase inhibitors (MKIs) that exert their therapeutic effect mainly through antiangiogenesis by targeting the vascular endothelial growth factor receptor, have mild anti-RET activity. Despite conveying clinical responses in MTC, MKIs have significant off-target activity causing marked toxicities limiting their effectiveness. Potent and selective RET inhibitors, selpercatinib and pralsetinib, demonstrate significant efficacy in RET-altered cancers and more tolerable side effect profiles than MKIs. However, durable responses can be limited by the acquisition of mutations which confer drug resistance to available treatments. Thus, development of more effective treatments for advanced, progressive MTC remains an urgent priority. In this chapter, we describe the current spectrum of systemic therapies for MTC, their limitations, and ongoing investigations.</p>","PeriodicalId":39880,"journal":{"name":"Recent Results in Cancer Research","volume":"223 ","pages":"293-307"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143659103","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pheochromocytoma in MEN2.","authors":"Matti L Gild, Kimchi Do, Venessa H M Tsang, Lyndal J Tacon, Roderick J Clifton-Bligh, Bruce G Robinson","doi":"10.1007/978-3-031-80396-3_8","DOIUrl":"https://doi.org/10.1007/978-3-031-80396-3_8","url":null,"abstract":"<p><p>Pheochromocytomas (PCs) are rare neuroendocrine tumors found in 20-50% of MEN2 patients. MEN2-related PCs are more often bilateral, identified at a younger age and have a low metastatic potential. They secrete epinephrine as the predominant catecholamine, along with its metabolite metanephrine, and lesser amounts of norepinephrine and normetanephrine. The advent of molecular diagnostic tools has enhanced the identification and stratification of these tumors, revealing a strong genotype-phenotype correlation which is crucial for screening and managing patients. Evaluation involves a combination of structural (CT/MRI) and functional imaging. MIBG remains helpful for PC assessment but novel PET ligands (¹⁸F-DOPA, ⁶⁸Ga-DOTATATE, ¹⁸F-FDG) aid in the detection of extra-adrenal paragangliomas, recurrence, and metastatic disease. The treatment paradigm has shifted toward personalized medicine, incorporating genetic insights to tailor interventions, particularly surgical approaches and novel therapeutics such as radiolabeling of somatostatin analogs with lutetium and tyrosine kinase inhibitors.</p>","PeriodicalId":39880,"journal":{"name":"Recent Results in Cancer Research","volume":"223 ","pages":"211-235"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143659094","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hereditary Medullary Thyroid Cancer: Genotype-Phenotype Correlation.","authors":"Karin Frank-Raue, Friedhelm Raue","doi":"10.1007/978-3-031-80396-3_7","DOIUrl":"https://doi.org/10.1007/978-3-031-80396-3_7","url":null,"abstract":"<p><p>Multiple endocrine neoplasia type 2 (MEN2) is an autosomal dominant hereditary cancer syndrome caused by germline variants in the REarranged during Transfection (RET) proto-oncogene. MEN2 is caused by autosomal dominant gain-of-function mutations in the RET proto-oncogene. There are two clinically distinct types of MEN2 syndrome, termed MEN2A and MEN2B. MEN2A is associated with medullary thyroid carcinoma (MTC) and the less frequent occurrence of pheochromocytoma, primary hyperparathyroidism, or both, rarely with cutaneous lichen amyloidosis or Hirschsprung's disease. MEN2B is associated with MTC, pheochromocytoma, and other noncancerous abnormalities, such as Marfanoid habitus and ganglioneuromas of the intestines. Specific RET mutations suggest a predilection toward a particular phenotype and clinical course with strong genotype-phenotype correlation. Based upon these genotype-phenotype correlations, RET mutations are stratified into three risk levels, i.e., highest, high, and moderate risk, based on the age of onset and the penetrance of the MTC. Children in the highest risk category develop MTC within the first year of life and should undergo thyroidectomy in their first year, perhaps even in their first months of life. In children in the high-risk category, ultrasound of the neck and calcitonin (Ctn) measurement should be performed prior to thyroidectomy. Thyroidectomy should typically be performed at 5 years of age or earlier, depending on the presence of elevated serum Ctn levels. However, heterogeneity in disease expression and progression within these groups varies considerably. To personalize disease management, the decision regarding the age of prophylactic thyroidectomy is no longer based upon genotype alone but is currently driven by additional clinical data, the most important being serum Ctn levels. In the moderate-risk group, the timing of thyroidectomy is particularly dependent on the Ctn level. Personalized management also includes decisions about the best age to begin biochemical screening for pheochromocytoma and primary hyperparathyroidism.</p>","PeriodicalId":39880,"journal":{"name":"Recent Results in Cancer Research","volume":"223 ","pages":"183-209"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143659081","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Histopathology of C Cells and Medullary Thyroid Carcinoma.","authors":"José Manuel Cameselle-Teijeiro, Manuel Sobrinho-Simões","doi":"10.1007/978-3-031-80396-3_2","DOIUrl":"https://doi.org/10.1007/978-3-031-80396-3_2","url":null,"abstract":"<p><p>C cells are the neuroendocrine cell component of the thyroid gland that embryologically arise from the pharyngeal endoderm. Normal C cells are concentrated in the upper two-thirds of both lateral lobes, appear singly or in small groups dispersed in, among or peripherally to the follicles, and are involved in the production of calcitonin. Reactive C-cell hyperplasia should be differentiated from proliferation of atypical C cells (neoplastic C-cell hyperplasia) which is considered an intraepithelial neoplasia of C cells/medullary carcinoma in situ, a precursor lesion associated to familial medullary thyroid carcinoma (MTC). MTC typically exhibits a lobular and/or trabecular growth pattern with amyloid deposits; however, due to its great histological variability, immunohistochemical positivity for calcitonin, carcinoembryonic antigen, calcitonin-gene-related peptide, insulinoma-associated protein 1, and/or other markers is necessary to confirm diagnosis. Investigation of germline RET proto-oncogene mutation is mandatory to identify familial MTC. Somatic RET mutations or fusions as well as RAS mutations in cytological and/or biopsy samples may represent therapeutic targets. Mixed medullary and follicular-derived cell carcinoma is a heterogeneous group of tumors which needs to be distinguished from collision tumors.</p>","PeriodicalId":39880,"journal":{"name":"Recent Results in Cancer Research","volume":"223 ","pages":"9-50"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143659085","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Primary Hyperparathyroidism in MEN2 Syndromes.","authors":"Katerina Saltiki, Maria Alevizaki","doi":"10.1007/978-3-031-80396-3_9","DOIUrl":"https://doi.org/10.1007/978-3-031-80396-3_9","url":null,"abstract":"<p><p>One of the components of the classical form of MEN2 syndromes is primary hyperparathyroidism (PHP). It occurs in 20-30% of the typical MEN2A syndrome. Recently, the prevalence in ret gene carriers is rarer possibly due to the increased recognition of cases who have familial MTC only. PHP is diagnosed more frequently in association with the exon 11, 634 mutation of the ret gene-so there is phenotype/genotype correlation. The clinical manifestations of PHP in MEN2 are usually mild and the peak age of diagnosis is after the third decade. The treatment is surgical excision of the enlarged gland(s). Although there can be multigland disease in the parathyroids, it is frequently the case that both hyperplasia and adenoma may coexist, or even a single adenoma may be found during the investigation and finally during the operation. Patients with MEN2 syndromes should be screened for PHP with serum calcium measurements. The intensity of the screening should be higher in those carrying the ret mutations most frequently associated with this manifestation.</p>","PeriodicalId":39880,"journal":{"name":"Recent Results in Cancer Research","volume":"223 ","pages":"237-246"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143659097","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"What Is New in Diagnostics and Management of Medullary Thyroid Carcinoma.","authors":"Friedhelm Raue, Karin Frank-Raue","doi":"10.1007/978-3-031-80396-3_1","DOIUrl":"https://doi.org/10.1007/978-3-031-80396-3_1","url":null,"abstract":"<p><p>Medullary thyroid carcinoma (MTC) is a rare neoplasm originating from parafollicular C cells. It secretes calcitonin (Ctn), a highly sensitive and specific tumor marker, which allows for early diagnosis and defines postoperative cure or persistence/recurrence of MTC. Germline mutations in the RET proto-oncogene are responsible for the development of MTC in MEN2. Somatic RET mutations modify the behavior of MTC and are a target for systemic therapy with selective RET inhibitors. Recent advances in preoperative immunohistochemistry and molecular diagnostics in biopsies achieved by fine needle aspiration significantly improves diagnosis and allows classification in low and high risk MTC with important implications for treatment and prognosis. This personalized approach enables a less aggressive surgery in low risk MTC patients, reduces the incidence of complications and improves quality of life. Risk stratification in MEN2 patients based on genotype-phenotype correlation of the different RET mutations allows cure by personalized thyroidectomy. Postoperative imaging in patients with persistent or recurrent MTC with PET/CT using different radiopharmaceuticals proved to be sensitive and accurate in detecting MTC recurrences/metastases and assesses their biological and clinical aggressiveness. Molecular genetic classification of tumors enables personalized systemic therapies with multikinase inhibitors or selective RET inhibitors in patients with advanced metastasized and progressive disease. Despite the recent progress in diagnosis and treatment, confirmation of these new procedures and standardization of these approaches in MTC are required.</p>","PeriodicalId":39880,"journal":{"name":"Recent Results in Cancer Research","volume":"223 ","pages":"1-8"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143659111","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Calcitonin as Biomarker for the Medullary Thyroid Carcinoma.","authors":"Yoon Ju Bae, Michael Schaab, Jüergen Kratzsch","doi":"10.1007/978-3-031-80396-3_6","DOIUrl":"https://doi.org/10.1007/978-3-031-80396-3_6","url":null,"abstract":"<p><p>Calcitonin (CTN) is a polypeptide hormone consisting of 32 amino acids with a disulfide bridge between position 1 and 7 that is mainly produced by the C-cells of thyroid gland. The measurement of CTN concentrations in blood reflects C-cell activity and is performed in general by immunoassay methods. However, there are analytical, physiological, pharmacological, and pathological factors that can influence results of serum CTN values. Due to the influence of these factors there is a high variability in assay-dependent cutoffs used to discriminate between MTC, C-cell hyperplasia (CCH) and the absence of the pathological impairment of C cells. There is a lot of evidence that the measurement of serum CTN concentrations in patients with thyroid nodules can lead to an earlier diagnosis of MTC or CCH than the exclusive use of imaging procedures and/or fine needle aspiration cytology. Basal CTN concentrations higher than 60-100 pg/mL are highly indicative for the diagnosis MTC. In the range between cutoff and 60 pg/mL CTN, both MTC and HCC may be a relevant diagnosis. Procalcitonin (PCT) and CTN appear to have a comparable diagnostic capability to diagnose MTCs. However, \"positive\" PCT values more than 50 pg/mL may be reached also in subclinical infections and will lead, therefore, to an overdiagnosis of the tumor. Calcium-stimulated serum CTN concentrations higher than cutoff values could improve diagnostics of MTC but a lack of replicable cutoff values in different studies favors the use of only basal values, currently.</p>","PeriodicalId":39880,"journal":{"name":"Recent Results in Cancer Research","volume":"223 ","pages":"155-182"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143659074","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Thyroid C-Cell Biology and Oncogenic Transformation.","authors":"Rozita Bagheri-Yarmand, Elizabeth G Grubbs, Marie-Claude Hofmann","doi":"10.1007/978-3-031-80396-3_3","DOIUrl":"https://doi.org/10.1007/978-3-031-80396-3_3","url":null,"abstract":"<p><p>The thyroid parafollicular cell, or commonly named \"C-cell,\" functions in serum calcium homeostasis. Elevations in serum calcium trigger release of calcitonin from the C-cell, which in turn functions to inhibit absorption of calcium by the intestine, resorption of bone by the osteoclast, and reabsorption of calcium by renal tubular cells. Oncogenic transformation of the thyroid C-cell is thought to progress through a hyperplastic process prior to malignancy with increasing levels of serum calcitonin serving as a biomarker for tumor burden. The discovery that Multiple Endocrine Neoplasia, type 2 is caused by activating mutations of the RET gene serves to highlight the RET-RAS-MAPK signaling pathway in both initiation and progression of medullary thyroid carcinoma. Thyroid C-cells are known to express RET at high levels relative to most cell types, therefore aberrant activation of this receptor is targeted primarily to the C-cell, providing one possible cause of tissue-specific oncogenesis. The role of RET signaling in normal C-cell function is unknown though calcitonin gene transcription appears to be sensitive to RET activation. Beyond RET the modeling of oncogenesis in animals and screening of human tumors for candidate gene mutations has uncovered mutation of RAS family members and inactivation of RB1 regulatory pathway as potential mediators of C-cell transformation. More recently, the integration of multiple biological layers of omics studies has uncovered new pathways of oncogenesis. A growing understanding of how RET interacts with these pathways, both in normal C-cell function and during oncogenic transformation, will help in the development of novel molecular targeted therapies.</p>","PeriodicalId":39880,"journal":{"name":"Recent Results in Cancer Research","volume":"223 ","pages":"51-91"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143659109","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}