Stephanie Allelein

Clinical presentation, treatment and outcome of anaplastic thyroid carcinoma: results of a multicenter study in Germany

CONTEXT Anaplastic thyroid carcinoma (ATC) is an orphan disease and confers a dismal prognosis. Standard treatment is not established. OBJECTIVE The aim of this study is to describe clinical characteristics, current treatment regimens and outcome of ATC and to identify clinical prognostic markers and treatment factors associated with improved prognosis. DESIGN Retrospective cohort study at five German tertiary care centers. PATIENTS AND METHODS Totally 100 ATC patients diagnosed between 2000 and 2015 were included in the analysis. Disease-specific overall survival (OS) was compared with the Kaplan-Meier method and log-rank test; Cox proportional hazard model was used to identify risk factors. RESULTS The 6-month, 1-year and 5-year disease-specific OS rates were 37, 28 and 5%, respectively. Stage-dependent OS at 6 months was 78, 54 and 18% for stage IVA, B and C, respectively. 29% patients survived >1 year. Multivariate analysis of OS identified age ≥70 years, incomplete local resection status and the presence of distant metastasis as significant risk factors associated with shorter survival. Radical surgery (hazard ratio [HR] 2.20, 95% confidence interval (CI) 1.19-4.09, P = 0.012), external beam radiation therapy (EBRT) ≥40 Gy (HR = 0.34, 0.15-0.76, P = 0.008) and any kind of chemotherapy (CTX) (HR = 11.64, 2.42-60.39, P = 0.003) were associated with longer survival in multivariate analyses adjusted for age and tumor stage. A multimodal treatment regimen was significantly associated with a survival benefit (HR = 1.04, 1.01-1.08, P < 0.0001) only in IVC patients. CONCLUSION Disease-specific OS is still poor in ATC. Treatment factors associated with improved OS provide a rationale to devise treatment pathways for routine care. Collaborative research structures should be aimed to advance treatment of ATC.

Schilddrüsenfunktionsstörungen@@@Thyroid dysfunction

a. Anti-thyroid drugs in the absence of side-effects are not disqualifying. b. i) Class 1 and European Class 3 holders will undergo review with an ophthalmic specialist to ensure satisfactory eye movements and no diplopia. If normal, a fit assessment can be made by the AME, otherwise review by the AMS will be required. An OML may be required. ii) Class 2 certificate holders will undergo review with an AME to ensure satisfactory eye movements and no diplopia.

Measurement of Basal Serum Calcitonin for the Diagnosis of Medullary Thyroid Cancer

Calcitonin (CT), a tumor marker for medullary thyroid cancer (MTC), can be stimulated with pentagastrin or calcium. Because of the unavailability of pentagastrin, basal CT measurement is frequently used for the preoperative diagnosis of MTC. The aim of the study was to define basal serum calcitonin (bCT) cut-off thresholds for diagnosing MTC. Within a retrospective analysis, 114 patients (51 males) were included fulfilling the criteria of an increased preoperative bCT level (>10 pg/ml) and the criteria of an available postoperative histology analysis. Based on a ROC plot analysis, the cut-off values for the diagnosis of MTC vs. non-malignancy (C cell hyperplasia and goiter) were identified. The most precise bCT thresholds for the identification of MTC were ≥46 pg/ml for males (sensitivity: 93.6%, specificity: 95.0%, PPV: 97%, NPV: 90%) and ≥35 pg/ml for females (sensitivity: 87.3%, specificity: 87.5%, PPV: 98%, NPV: 50%). Using these cut-offs, only 6% of male patients were not identified of having MTC, whereas 5% were false positive (having instead C cell hyperplasia). In females, the discrepancy was higher since 13% of female MTC patients were false negative by using the cut-off of ≥35 pg/ml, and 13% had false positive results (suffering from C cell hyperplasia). Gender-specific bCT cut-offs for the identification of MTC vs. C cell hyperplasia and non-malignancy were defined, which can be used in clinical routine. In female patients, however, the accuracy is much lower compared to males.

Epitope-Specific Antitumor Immunity Suppresses Tumor Spread in Papillary Thyroid Cancer

Context Papillary thyroid cancer (PTC) is characterized by a lymphocytic infiltration. PTC patients with lymphocytic infiltration may have a better clinical outcome. Objective Characterization of tumor epitope-specific immunity and correlation analyses with the clinical outcome. Patients 150 PTC patients; 40 Hashimoto thyroiditis (HT) patients; 21 healthy controls; 27,239 healthy whites (for HLA typing). Main Outcome Measures HLA class I restricted thyroperoxidase (TPO) and thyroglobulin (Tg) epitope-specific T cells (tetramer analyses), correlation analyses between HLA class II phenotypes, T cell immunity, and the clinical course. Results The frequency of TPO- and Tg-specific CD8+ T cells in PTC patients was largely increased compared with healthy controls (TPO and Tg, P < 0.005 and P < 0.005) and was similar to those in HT patients. HLA-DQB1*03-positive PTC patients had a significantly lower risk [risk ratio (RR), 0.170; 95% confidence interval (CI), 0.037 to 0.755; P < 0.05] and HLA-DRB1*03-positive and HLA-DQB1*02-positive PTC patients a significantly higher risk (HLA-DRB1*03: RR, 4.400; 95% CI, 1.378 to 14.05; P < 0.05; HLA-DQB1*02: RR, 3.692; 95% CI, 1.102 to 12.38; P < 0.05) for distant metastases, compared with patients with other haplotypes. HLA-DQB1*03-positive PTC patients revealed an increased responsiveness of tumor epitopes in vitro. These tumor epitope-specific CD8+ T cells were also found in lymph node metastases of HLA-DQB1*03-positive PTC patients. Conclusion We demonstrate a tumor epitope-specific immunity in PTC patients and the protective role of HLA-DQB1*03 against metastatic spread. These results have direct implications for new treatment options with immune checkpoint inhibitors.

Increased Numbers of Circulating Tumor Cells in Thyroid Cancer Patients

Circulating tumor cells (CTCs) have been shown to be a valuable prognostic marker for different solid cancers. Within the present study we quantified CTCs in thyroid cancer (TC) patients. Special focus was given to disease-free PTC patients with undetectable serum thyroglobulin (Tg) levels. Altogether, 67 TC patients (33 papillary, 20 follicular, 14 medullary) were included in the study. CTC numbers, which were normalized to 3.3×105 peripheral blood mononuclear cells, were correlated with clinical outcome. TC patients had significantly higher CTC numbers compared to controls. The number of CTCs correlated to the initial tumor stage. Importantly, in comparison to controls, differentiated TC patients with serum Tg levels<0.3 ng/ml (no evidence of tumor recurrence) revealed a significantly higher amount of CTCs, also associated to their former tumor stage. Regarding the tumor-free papillary TC (PTC) patients the number of CTCs additionally correlated to the time point of radioiodine (RI) therapy: PTC patients with RI therapies>8 years before CTC measurement had significantly higher CTC numbers compared to those with RI therapy<8 years ago. We found a clear correlation between the number of CTCs and the tumor stage. Importantly, PTC patients who are in remission may still have increased numbers of CTCs. Follow-up analyses in these patients will reveal whether these data will have a clinical impact.

Excessive Catecholamine Secretion and the Activation of the Renin-Angiotensin-Aldosterone-System in Patients with Pheochromocytoma: A Single Center Experience and Overview of the Literature

Catecholamines stimulate renin-secretion in the juxtaglomerular cells of the kidney and a number of case reports suggest an association between pheochromocytoma and activation of the RAAS. Therefore, it could be asked whether patients suffering from pheochromocytoma with high concentrations of circulating catecholamines present with oversecretion of renin and aldosterone. We identified twelve patients with excessive catecholamine secretion due to pheochromocytoma and compared them to a group of twelve patients with essential hypertension (EH) with regard to the activation of the renin-angiotensin-aldosterone-system (RAAS). The PubMed database was screened for studies that investigate the association between pheochromocytoma and activation of the RAAS. The plasma concentrations of metanephrines (19.9-fold) and normetanephrines (29.5-fold) were significantly higher in the pheochromocytoma group than in the EH group. Renin and aldosterone levels were 1.3-fold and 1.6-fold higher, respectively, as compared to the EH group, whereas the differences were not statistically significant. There was no significant correlation between plasma metanephrine or normetanephrine levels and the plasma renin concentration (rs=0.077, rs=0.049, respectively) in our patients. The data from our institution and from review of literature suggest that an association between pheochromocytoma in the context of high plasma catecholamine levels and activation of the RAAS is present. However, results have not been consistent. Thus, other causes of RAAS-activation should be considered also in the presence of pheochromocytoma or reinvestigation for aldosteronism should be offered to such patients after removal of the catecholamine-producing tumour.

Diagnostik und Therapie der Struma nodosa im Jahr 2017

Screening Bei älteren Menschen wird von einem generellen Screening auf Schilddrüsenknoten abgeraten. Bildgebende Verfahren Mittels Schilddrüsensonografie kann der Knoten in Kategorien mit verschiedenem Malignitätsrisiko eingeteilt werden. Feinnadelpunktion Als sensitivste Untersuchung zur präoperativen Erkennung malignitätsverdächtiger Knoten gilt die Feinnadelpunktion. Molekulargenetik Im Bereich der Molekulargenetik wurden in den letzten Jahren für die Diagnostik erhebliche Fortschritte erzielt; in der Routine findet dies jedoch noch keinen Einsatz. Calcitonin-Bestimmung Der aussagekräftigste basale Grenzwert zur präoperativen Diskriminierung eines medullären Schilddrüsenkarzinoms ist bei Frauen ca. 30 pg/ml und bei Männern ca. 60 pg/ml. Therapie Neue thermoablative Therapieverfahren bei benignen Knoten werden zunehmend durchgeführt, müssen aber weiter evaluiert werden.