An Animal Model Further Uncovers the Role of Mutant BrafV600E during Papillary Thyroid Cancer Development.

Papillary thyroid carcinomas (PTCs) account for 90% of human thyroid cancer cases, which represent 1% of all cancer cases. They are likely to develop from papillary thyroid microcarcinomas (PTMCs), found in up to 36% of healthy individuals, due to rare progression events (0.01%). Although the prognosis of PTCs is excellent, 5% to 10% of tumors display an unfavorable outcome. About 45% of PTCs exhibit activating BRAFV600E mutations. Rats of the inbred BD strains postnatally exposed to the carcinogen N-ethyl-N-nitrosourea developed PTMCs, which closely resembled their human counterparts judging from their histology, size, and marginal tendency to progress. DNA sequencing revealed mutations in exon 15 of the Braf gene identical to the human BRAFV600E mutation in 82% of the cases. Predominantly a 50:50 ratio of wild-type to mutant Braf alleles was seen regardless of tumor size or animal age, indicating that the Braf mutation is an early, if not the initial, event in rat PTMC development. Surprisingly, most PTMCs carrying a confirmed BrafV600E mutation did not display BrafV600E protein expression. As the BrafV600Egene is supposed to be the driver in PTC development, down-regulation of expression should contribute to the low risk for progression of PTMC. This model system will enable further insights into the molecular mechanisms of PTMC initiation and progression to PTC, further translating into targeted tumor prevention strategies/therapies.

Analysis of risk factors and prognosis in differentiated thyroid cancer with focus on minimal extrathyroidal extension.

AIMS: In contrast to all prior AJCC/TNM classifications for differentiated thyroid cancer (DTC) the 8th edition does not take minimal extrathyroidal extension (M-ETE) into consideration for local tumor staging. We therefore aimed to retrospectively assess the specific impact of M-ETE on the outcome of M-ETE patients treated in our clinic. METHODS: DTC patients with M-ETE and a follow-up time of ≥ 5 years were included and matched with an identical number of patients without M-ETE, but with equal histopathological tumor subtype and size. The frequency of initially metastatic disease among groups was compared using Fisher's exact test, the recurrence rate by virtue of log-rank test. Fisher's exact test and multivariate analysis were used to account for the presence of confounding risk factors. RESULTS: One hundred sixty patients (80 matching pairs) were eligible. With other confounding risk factors being equal, the prevalence of N1-/M1-disease at initial diagnosis was comparable among groups (M-ETE: 42.5 %; no M-ETE: 32.5 %; p = 0.25). No differences with regard to the recurrence rate were shown. However, M-ETE patients were treated with external beam radiation therapy more often (16.3 % vs. 1.3 %; p = 0.004) and received higher median cumulative activities of 131I (10.0 vs. 8.0 GBq; p < 0.001). DISCUSSION: Although having played a pivotal role for local tumor staging of DTC for decades M-ETE did not increase the risk for metastases at initial diagnosis and the recurrence rate in our cohort. Patients with M-ETE had undergone intensified treatment, which entails a possible confounding factor that warrants further investigation in randomized controlled trials.

[Diagnostic principles of thyroid tumors in pathology : Relevant changes due to the current WHO classification]. / Diagnostische Grundlagen von Schilddrüsentumoren in der Pathologie : Relevante Änderungen durch die aktuelle WHO-Klassifikation.

The current edition of the WHO classification of thyroid tumors (2017) contains a number of very relevant changes with considerable consequences for the diagnostic assessment of thyroid specimens. This applies to both the histomorphological examination of surgical specimens and the preoperative fine needle biopsy (FNB). In addition, molecular pathological examinations are becoming increasingly important in the diagnosis of thyroid tumors. Changes affect practically all areas of thyroid tumor diagnostics. Some of these changes have far-reaching consequences that justify a comprehensive commentary and query of the knowledge acquired in the form of this CME article.

Hepatocyte KLF6 expression affects FXR signalling and the clinical course of primary sclerosing cholangitis.

BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC) is characterized by chronic cholestasis and inflammation, which promotes cirrhosis and an increased risk of cholangiocellular carcinoma (CCA). The transcription factor Krueppel-like-factor-6 (KLF6) is a mediator of liver regeneration, steatosis, and hepatocellular carcinoma (HCC), but no data are yet available on its potential role in cholestasis. Here, we aimed to identify the impact of hepatic KLF6 expression on cholestatic liver injury and PSC and identify potential effects on farnesoid-X-receptor (FXR) signalling. METHODS: Hepatocellular KLF6 expression was quantified by immunohistochemistry (IHC) in liver biopsies of PSC patients and correlated with serum parameters and clinical outcome. Liver injury was analysed in hepatocyte-specific Klf6-knockout mice following bile duct ligation (BDL). Chromatin-immunoprecipitation-assays (ChIP) and KLF6-overexpressing HepG2 cells were used to analyse the interaction of KLF6 and FXR target genes such as NR0B2. RESULTS: Based on IHC, PSC patients could be subdivided into two groups showing either low (<80%) or high (>80%) hepatocellular KLF6 expression. In patients with high KLF6 expression, we observed a superior survival in Kaplan-Meier analysis. Klf6-knockout mice showed reduced hepatic necrosis following BDL when compared to controls. KLF6 suppressed NR0B2 expression in HepG2 cells mediated through binding of KLF6 to the NR0B2 promoter region. CONCLUSION: Here, we show an association between KLF6 expression and the clinical course and overall survival in PSC patients. Mechanistically, we identified a direct interaction of KLF6 with the FXR target gene NR0B2.

The mismatch repair system is not affected in medullary thyroid carcinoma independent of stromal desmoplasia or ret proto-oncogene mutation.

INTRODUCTION: Medullary thyroid carcinoma (MTC) is an aggressive neuroendocrine neoplasia of the thyroid with 10 year overall survival of 50% and limited therapeutic options. High tumor mutational burden because of microsatellite instability (MSI) seems to be a predictor of response to immune checkpoint inhibitor therapy in different tumors. Therefor in 2017 the U.S. Food and Drug Administration (FDA) permitted the therapy of solid tumors with proven Microsatellite instability (MSI) with PD1 antibody Pembrolizumab independently of their origin. As little is known about MSI in MTC and new therapeutic strategies would be eligible we tried to find out, if therapy with PD1-inhibitors could be promising. MATERIAL AND METHODS: We performed MSI-analyses of 38 cases of MTC. Included were MTCs with and without stromal desmoplasia and with/without lymph node metastases. We also checked the immunhistochemical expression of PD-L-1 and performed next generation sequencing for genetic alterations. RESULTS: All cases revealed stable conditions of the microsatellites and showed immunohistochemically positive staining of the four mismatch repair proteins. PD-L-1- Immunostaining was negative in all cases. DISCUSSION: Our data show there is no MSI in MTCs, irrespectively of their status of desmoplasia, metastases and/or ret-mutation. Therefore a positive effect of PD1 inhibitors, because of MSI-associated high tumor mutational burden, seems to be unlikely.

[Histopathological diagnosis and differential diagnosis of nonalcoholic fatty liver disease]. / Histopathologische Diagnostik und Differenzialdiagnostik der nichtalkoholischen Fettlebererkrankung.

Fatty liver disease is a rising problem worldwide, particularly due to metabolic syndrome. The current prevalence is 20-30%, but a further increase is expected whereby children will also be increasingly affected. The presence of fat in hepatocytes is known as steatosis or, in the case of nonalcoholic origin, nonalcoholic fatty liver (NAFL). It is basically reversible, but can progress to steatohepatitis (NASH) as an active and progressive form of fatty liver disease due to continuous cell damage. This leads to progressive liver fibrosis up to end-stage liver cirrhosis. The gold standard of diagnosis is liver biopsy, in which obesity, inflammation, and hepatocellular damage (hepatocellular ballooning) are assessed for the distinction between NAFL and NASH. The extent of fibrosis indicates the progress of the disease. Childhood and adult fatty liver diseases differ morphologically, particularly in the location and amount of fat, inflammation, and fibrosis. Alcoholic and nonalcoholic fatty liver disease/steatohepatitis cannot be reliably differentiated by histology. Clinical parameters must also be taken into consideration for the differential diagnosis of other diseases associated with fatty liver. The main therapeutic goal is to reduce insulin resistance, which can be achieved through weight loss and lifestyle changes. Recently, however, drug therapies have also become available as a promising therapeutic option.

[Liver transplantation. Current aspects of pretransplantation diagnosis and rejection]. / Lebertransplantation. Aktuelle Aspekte der Prätransplantationsdiagnostik und Abstoßung.

Liver transplantation is an established treatment option for patients with end-stage liver disease. The therapy management of these patients is interdisciplinary and requires pathologists to have both clinical and immunological knowledge. Continuous advances in treatment and increasing clinical experience are accompanied by the further development of pathological transplant diagnostics. This article presents and discusses the latest classification of T­cell-mediated rejection (TCMR), antibody-mediated rejection (AMR), and aspects of pretransplant diagnostics.

Case report: Durable complete response of a mucosal melanoma of the rectum after neoadjuvant immunotherapy with ipilimumab plus nivolumab.

Melanoma causes the majority of skin cancer-related deaths. Despite novel therapy options, metastatic melanoma still has a poor prognosis. Immune checkpoint inhibition (ICI) therapy has been shown to prolong overall survival in patients with advanced melanoma, but mucosal melanomas respond less favorably compared to melanomas of cutaneous origin. We report on a patient with a mucosal melanoma of the rectum diagnosed in June 2020. Since a surgical intervention in order to achieve a tumor-free situation would have required an amputation of the rectum, a neo-adjuvant systemic immunotherapy with ipilimumab and nivolumab was initiated. As restaging and colonoscopy after four doses of this combination immunotherapy showed a partial response, the patient decided against the pre-planned surgery and a maintenance therapy with nivolumab was started. Repeated colonoscopy showed a complete response after four doses of nivolumab. After ongoing ICI therapy with nivolumab and no evidence of tumor relapse, immunotherapy was stopped in July 2022 after nearly 2 years of continuous treatment. The patient remained tumor-free during further follow-up. Neo-adjuvant immunotherapy is getting more explored in advanced melanoma. By administering ICI therapy before surgical resection of an essentially operable tumor, a stronger and more diverse immunological response is supposed to be achieved. Our reported case demonstrates that this approach could also be effective in mucosal melanoma despite of its generally lower response to immunotherapy.

Comprehensive biomarker diagnostics of unfavorable cancer of unknown primary to identify patients eligible for precision medical therapies.

PURPOSE: Current guidelines recommend combination chemotherapy for treatment of patients with unfavorable cancer of unknown primary (CUP). Biomarker-guided targeted therapies may offer additional benefit. Data on the feasibility and effectiveness of comprehensive genomic biomarker profiling of CUP in a standard clinical practice setting are limited. METHODS: This analysis included 156 patients with confirmed unfavorable CUP diagnosis according to ESMO guidelines, who were treated at the West German Cancer Center, Essen, Germany, from 2015 to 2021. Clinical parameters and outcome data were retrieved from the electronic hospital information system. Genomic biomarker analyses were performed in formalin-fixed paraffin-embedded tumor tissue whenever possible using the QIAseq Multimodal-Pancancer-Panel. RESULTS: Non-squamous histologies, high tumor burden, and age above 60 years associated with poor survival outcome. Tissue availability restricted comprehensive biomarker analyses to 50 patients (32%), reflecting a major limitation in the real-world setting. In those patients a total of 24 potentially actionable alterations were identified in 17 patients (34% of profiled patients, 11% of total population). The most prevalent biomarkers were high tumor mutational burden and BRCA-mutations. CONCLUSION: In a real-world setting precision medicine for patients with CUP is severely restricted by tissue availability, and a limited spectrum of actionable alterations. Progress for patients may require emphasizing the need for sufficient biopsies, and prospective exploration of blood-based biomarker profiling.

Predictive value of highly sensitive basal versus stimulated thyroglobulin measurement in long-term follow-up of thyroid cancer.

Objective: Recurrence of differentiated thyroid cancer (DTC) is associated with reduced quality of life, and therefore, early identification of patients at risk is urgently needed.Here we investigated the predictive power of various cut-off values of single stimulated thyroglobulin (s-Tg) and single highly sensitive measured, unstimulated thyroglobulin (u-hsTg) measurements close to the end of primary therapy for recurrence-free survival (RFS) in long-term follow-up (>10 years) of patients with DTC. Methods: In DTC patients with adjuvant radioiodine therapy, we assessed retrospectively u-hsTg (6 ± 3 months before s-Tg measurement) and s-Tg measurements (≤24 months after last radioiodine therapy). Positive predictive (PPV)/negative predictive values (NPV) of various cut-off values (s-Tg: 0.5/1.0 ng/mL; u-hsTg: 0.09/0.2 ng/mL) for patient outcomes as well as additional factors associated with disease development were analyzed. Results: In total, 175 patients were retrospectively reviewed (tumor recurrence: n = 14/complete remission: n = 161). Examined cut-off values for s-Tg and u-hsTg showed significant predictive power for RFS (log-rank: all P < 0.001). NPV/PPV for s-Tg were 98.6%/36.4%, respectively (0.5 ng/mL cut-off) and 96.7%/42.9%, respectively (1.0 ng/mL cut-off); those for u-hsTg were 97.3%/35.7%, respectively (0.09 ng/mL cut-off) and 95.2%/85.7%, respectively (0.2 ng/mL cut-off). U-hsTg (P < 0.001) and patient age (P < 0.05) were significantly associated with tumor recurrence. One-third of patients with tumor recurrence in the course initially showed undetectable u-hsTg after completion of primary therapy. Conclusion: With >10 years of follow-up, both s-Tg and u-hsTg have a comparably high predictive power for RFS, while only u-hsTg was significantly associated with a recurrence event.Serial u-hsTg measurements seem warranted since patients with tumor recurrence during follow-up may have an undetectable tumor marker at baseline.

Molecular Markers Are Associated with Onset of Radioiodine Refractoriness in Patients with Papillary Thyroid Carcinoma.

The onset of radioiodine-refractory thyroid carcinoma (RR-TC) is a negative predictor of survival and has been linked to the presence of BRAFV600E mutations in papillary thyroid cancer. We aimed to identify further genetic alterations associated with RR-TC. Methods: We included 38 patients with papillary thyroid cancer who underwent radioiodine imaging and 18F-FDG PET/CT after total thyroidectomy. The molecular profile was assessed by next-generation sequencing. The time to the onset of RR-TC for different genetic alterations was compared using the log-rank test. Results: The median onset to RR-TC was 0.7 and 19.8 mo in patients with and without, respectively, telomerase reverse transcriptase promoter mutations (P = 0.02) and 1.7 and 19.8 mo in patients with and without, respectively, a tumor protein 53 mutation (P < 0.01). This association was not observed for BRAFV600E mutations (P = 0.49). Conclusion: Our data show a significant association between the onset of RR-TC and mutations in telomerase reverse transcriptase promoter and tumor protein 53, indicating the need for a more extensive diagnostic workup in these patients. Certain genetic changes put patients with thyroid cancer at risk of developing cancer spread that does not respond to radioiodine therapy.

Sporadic noninvasive medullary thyroid neoplasm: A desmoplasia-negative unifocal nonmetastatic tumor cured by hemithyroidectomy.

BACKGROUND: The absence of primary tumor desmoplasia, a marker of node metastases, on frozen section may help reduce the extent of surgery without compromising the biochemical cure. We aimed to clarify whether hemithyroidectomy with diagnostic ipsilateral central neck dissection can replace total thyroidectomy with routine central neck dissection in patients with sporadic medullary thyroid cancer. METHODS: We retrospectively evaluated data collected from patients who had undergone primary neck surgery for hypercalcitoninemic sporadic medullary thyroid cancer between January 2017 and December 2022 at one institution. RESULTS: Of the 25 patients we examined, 19 had desmoplasia-negative and 6 desmoplasia-positive primary thyroid tumors on frozen section. The desmoplasia-negative patients had undergone less surgery with fewer nodes removed than the desmoplasia-positive patients (medians of 6 vs 31 nodes, P < .001). The desmoplasia-negative patients had predominantly undergone hemithyroidectomy with ipsilateral central neck dissection. None of the desmoplasia-negative tumors was multifocal (0 of 19 desmoplasia-negative vs 2 of 6 desmoplasia-positive or 0% vs 33%, P = .050) or node-positive (0 of 19 vs 6 of 6 patients or 0% vs 100%; medians of 0 vs 3.5 node metastases; both P < .001). Despite limited surgery, all desmoplasia-negative patients attained and maintained biochemical cure. CONCLUSION: Hemithyroidectomy combined with diagnostic ipsilateral central neck dissection is a viable risk-reducing and curative strategy for desmoplasia-negative and node-negative, nonmetastatic unifocal tumors, for which we propose the term sporadic noninvasive medullary thyroid neoplasm (SNMTP).

SUVmax Above 20 in 18F-FDG PET/CT at Initial Diagnostic Workup Associates with Favorable Survival in Patients with Cancer of Unknown Primary.

Cancer of unknown primary (CUP) is a heterogeneous entity with a limited prognosis. Novel prognostic markers are needed for patient stratification in prospective clinical trials exploring innovative therapies. Methods: In CUP patients treated at the West German Cancer Center Essen, the prognostic value of 18F-FDG PET/CT at the initial diagnostic workup was analyzed by comparing overall survival (OS) in patients who underwent 18F-FDG PET/CT with those who did not. Results: Of 154 patients with a CUP diagnosis, 76 underwent 18F-FDG PET/CT at the initial diagnostic workup. The median overall survival (OS) of the full analysis set was 20.0 mo. Within the PET/CT subgroup, an SUVmax above 20 was associated with significantly superior OS (median OS, not reached vs. 32.0 mo; hazard ratio, 0.261; 95% CI, 0.095-0.713; P = 0.009). Conclusion: Our retrospective work shows that an SUVmax above 20 on 18F-FDG PET/CT at the initial diagnostic workup is a favorable prognostic factor in patients with CUP. This finding deserves further prospective studies for validation.

Unique Finding of a Primary Central Nervous System Neuroendocrine Carcinoma in a 5-Year-Old Child: A Case Report.

Neuroendocrine tumors (NETs) are rare neoplasms predominantly arising in the gastrointestinal-tract or the lungs of adults. To date, only ten cases of primary central nervous system (CNS) NETs have been reported, with just three of them describing a neuroendocrine carcinoma (NECA) and none occurring in a child. We report on a previously healthy 5-year-old boy, who presented with headaches, nausea and vomiting, and was diagnosed with a left cerebellar solid mass with a cystic component. After gross-total resection, histology revealed a neuroendocrine carcinoma. Molecular analysis of the tumor tissue showed a KRAS-splice-site mutation (c451-3C > T). The KRAS-mutation was discovered to be a maternal germline mutation, previously described as likely benign. After extensive search for an extracranial primary tumor, including Ga-68 DOTANOC-PET-CT, the diagnosis of a primary CNS NECA was established, and proton irradiation was performed. Unfortunately, the patient developed an in-field recurrence just 5 weeks after the end of radiotherapy. The tumor was re-resected with vital tumor tissue. Six cycles of chemotherapy were initiated, consisting of cisplatin, carboplatin, etoposide and ifosfamide. The patient remains disease free 22 months after the end of treatment, supporting the beneficial effect of platinum- and etoposide-based chemotherapy for this tumor entity.

Diagnostic Performance of 124I-Metaiodobenzylguanidine PET/CT in Patients with Pheochromocytoma.

123/131I-metaiodobenzylguanidine (MIBG) scintigraphy has shown a high specificity for imaging pheochromocytoma and paraganglioma, but with low sensitivity because of low spatial resolution. 124I-MIBG PET may be able to overcome this limitation and improve the staging of patients with (suspected) pheochromocytoma. Methods: We analyzed the sensitivity, specificity, and positive and negative predictive values of 124I-MIBG PET in 43 consecutive patients with suspected (recurrence of) pheochromocytoma using histopathologic (n = 25) and clinical validation (n = 18) as the standard of truth. Furthermore, we compared the detection rate of 124I-MIBG PET versus contrast-enhanced (CE) CT on a per-patient and per-lesion basis in 13 additional patients with known metastatic malignant pheochromocytoma. Results:124I-MIBG PET/CT was positive in 19 (44%) of 43 patients with suspected pheochromocytoma. The presence of pheochromocytoma was confirmed in 22 (51%) of 43. 124I-MIBG PET/CT sensitivity, specificity, and positive and negative predictive values were 86%, 100%, 100%, and 88%, respectively. 124I-MIBG PET was positive in 11 (85%) of 13 patients with malignant pheochromocytoma. Combined 124I-MIBG PET and CE CT detected 173 lesions, of which 166 (96%) and 118 (68%) were visible on 124I-MIBG PET and CE CT, respectively. Conclusion:124I-MIBG PET detects pheochromocytoma with high accuracy at initial staging and a high detection rate at restaging. Future assessment of 124I-MIBG PET for treatment guidance, including personalized 131I-MIBG therapy, is warranted.

Streptozocin/5-fluorouracil chemotherapy of pancreatic neuroendocrine tumours in the era of targeted therapy.

PURPOSE: The role of streptozocin-based chemotherapy (STZ CTx) in advanced, well-differentiated pancreatic neuroendocrine tumours (PanNET) and the best sequence of treatments in advanced PanNET are unclear. We examined the outcomes after STZ CTx in patients who had been selected according to the current therapeutic guidelines. METHODS: Data from 50 PanNET patients consecutively treated with STZ CTx between 2010 and 2018 were analysed. The endpoints of the study were the objective-response rate (ORR), progression-free survival (PFS), and overall survival (OS). RESULTS: STZ CTx was the first-line treatment in 54% of patients. The PanNET grades were as follows: 6% G1, 88% G2, and 6% well-differentiated G3. The ORR was 38%. Stable disease was the best response in 38% of patients and 24% showed progressive disease. Treatment was discontinued because of toxicity in one patient. Median PFS and OS were 12 (95% confidence interval (CI), 8.5-15.5) and 38 months (95% CI, 20.4-55.6), respectively. In the Kaplan-Meier analysis, the median OS was 89 months (95% CI, 34.9-143.1) for STZ CTx as first-line therapy compared with 22 months (95% CI, 19.3-24.7; p = 0.001, log-rank test) for subsequent lines. Bone metastases negatively impacted survival (HR, 2.71, p = 0.009, univariate analysis, HR, 2.64, p = 0.015, multivariate analysis, and Cox regression). CONCLUSIONS: In patients selected according to current guidelines, PFS, and OS after STZ CTx were lower than previously reported, whereas ORR was unchanged. First-line treatment was positively associated with OS and the presence of bone metastases was negatively associated with OS. Pre-treatment with targeted or peptide-receptor radionuclide therapy did not alter ORR, PFS, or OS.

Enhancing Radioiodine Incorporation into Radioiodine-Refractory Thyroid Cancer with MAPK Inhibition (ERRITI): A Single-Center Prospective Two-Arm Study.

PURPOSE: Restoration of iodine incorporation (redifferentiation) by MAPK inhibition was achieved in previously radioiodine-refractory, unresectable thyroid carcinoma (RR-TC). However, results were unsatisfactory in BRAFV600E-mutant (BRAF-MUT) RR-TC. Here we assess safety and efficacy of redifferentiation therapy through genotype-guided MAPK-modulation in patients with BRAF-MUT or wildtype (BRAF-WT) RR-TC. PATIENTS AND METHODS: In this prospective single-center, two-arm phase II study, patients received trametinib (BRAF-WT) or trametinib + dabrafenib (BRAF-MUT) for 21 ± 3 days. Redifferentiation was assessed by 123I-scintigraphy. In case of restored radioiodine uptake, 124I-guided 131I therapy was performed. Primary endpoint was the redifferentiation rate. Secondary endpoints were treatment response (thyroglobulin, RECIST 1.1) and safety. Parameters predicting successful redifferentiation were assessed using a receiver operating characteristic analysis and Youden J statistic. RESULTS: Redifferentiation was achieved in 7 of 20 (35%) patients, 2 of 6 (33%) in the BRAF-MUT and 5 of 14 (36%) in the BRAF-WT arm. Patients received a mean (range) activity of 300.0 (273.0-421.6) mCi for 131I therapy. Any thyroglobulin decline was seen in 57% (4/7) of the patients, RECIST 1.1 stable/partial response/progressive disease in 71% (5/7)/14% (1/7)/14% (1/7). Peak standardized uptake value (SUVpeak) < 10 on 2[18F]fluoro-2-deoxy-D-glucose (FDG)-PET was associated with successful redifferentiation (P = 0.01). Transient pyrexia (grade 3) and rash (grade 4) were noted in one patient each. CONCLUSIONS: Genotype-guided MAPK inhibition was safe and resulted in successful redifferentiation in about one third of patients in each arm. Subsequent 131I therapy led to a thyroglobulin (Tg) decline in more than half of the treated patients. Low tumor glycolytic rate as assessed by FDG-PET is predictive of redifferentiation success. See related commentary by Cabanillas et al., p. 4164.

Therapeutic Effect of Combined Dabrafenib and Trametinib Treatment of BRAF V600E-Mutated Primary Squamous Cell Carcinoma of the Thyroid: A Case Report.

INTRODUCTION: Primary squamous cell carcinoma (PSCC) of the thyroid is an exceptionally rare malignancy accounting for <1% of all primary thyroid cancers. Therapy is multimodal including surgery, radiotherapy, and chemotherapy but with no consensus for management and therapy. Here, we describe a case of a male patient who presented with a BRAF V600E-mutated PSCC of the thyroid gland showing response to combined dabrafenib and trametinib therapy over a period of >12 months. CASE PRESENTATION: A 78-year-old male patient presented with a 3-week history of dysphonia and dyspnoea. Laryngoscopy revealed a mechanical obstruction by a right-sided, subglottical mass, which on cervical ultrasound was highly suggestive of anaplastic thyroid carcinoma. Additional workup including esophagogastroduodenoscopy showed compression of the oesophagus but no oesophageal infiltration by the tumour. Immunohistochemistry displayed CK19-positive cells indicating epithelial origin of the tumour. CK5/6 and P40 immunohistochemistry confirmed the morphological impression of squamous cell differentiation while staining with thyroid markers TTF-1 and TPO was negative and PAX8 showed a nuclear positive signal. Based on immunohistopathology, presence of TP53 and BRAF V600E mutations, and exclusion of metastatic squamous cell carcinoma of other origin, the diagnosis of a PSCC of the thyroid was established. As an individualized treatment concept, we decided to advocate combined BRAF V600E targeting by the multikinase inhibitors dabrafenib and trametinib. This led to drastic improvement in patient's quality of life without severe side effects over a period of >12 months. CONCLUSION: In this case, molecular diagnosis allowed a highly individualized treatment concept with combined dabrafenib and trametinib therapy.

Functional Characterization of Olfactory Receptors in the Thyroid Gland.

Olfactory receptors (ORs) are almost ubiquitously expressed in the human body. However, information about their functions in these tissues is lacking. To date, no functional characterization of expressed ORs in the human thyroid has been performed. In this study, we detected and compared the expression of OR2H2 and OR2W3 in healthy and malignant cell lines and their corresponding tissues, respectively. We demonstrated that stimulation of ORs by their specific ligand resulted in a transient increase in intracellular calcium and cAMP concentrations. In the case of OR2H2, the downstream signaling cascade analysis revealed that adenylate cyclase (AC) and phosphoinositide phospholipase C (PLC) were involved. Furthermore, OR2H2 and OR2W3 activation affected migration, proliferation, and invasion. These are the first insights that ORs influence physiology-relevant processes in the healthy and malignant thyroid.

Continued Discontinuation of TKI Treatment in Medullary Thyroid Carcinoma - Lessons From Individual Cases With Long-Term Follow-Up.

Background: The tyrosine kinase inhibitors (TKI) vandetanib and cabozantinib are approved as targeted therapies in advanced medullary thyroid carcinoma (MTC) with symptoms or high tumour burden. Only recently, toxicity in long-time TKI usage was analysed. However, little is known about the impact of TKI discontinuation on MTC disease course after longer-term therapy. Here, we report our experience in a series of 7 MTC patients with vandetanib treatment of up to 87 months followed by discontinuation for concerns of toxicity or due to side-effects. The discontinuation of TKI therapy is a relevant clinical scenario. To our knowledge we present the largest single center series on an important aspect of TKI management. Methods: Retrospective analysis of MTC patients with continued discontinuation of vandetanib treatment in a tertiary referral endocrine tumour centre. Analysis included a review of patients' records for TKI indication, and treatment response as well indications for continued TKI discontinuation and follow-up by clinical assessment, calcitonin and CEA doubling times as well as imaging (ultrasound, CT). Results: Seven MTC patients [6 sporadic MTC, 1 Multiple Endocrine Neplasie Type 2a (MEN2a)] with previous vandetanib treatment (median: 41 months; range 7-87 months) and continued TKI discontinuation were identified out of 161 analysed MTC files. TKI treatment was initiated due to high tumour burden and symptoms or RECIST (Response Evaluation Criteria In Solid Tumors) progression in all patients. Two patients (29%) remained stable after discontinuation of vandetanib until now (follow-up of 47 and 61 months). Both patients had been on TKI therapy for 73 and 58 months. Five patients (71%) developed progressive disease after TKI discontinuation. In 2 patients, vandetanib was restarted after 45 and 52 months resulting again in disease control. One patient was enrolled in a new RET kinase inhibitor trial after 45 months of vandetanib discontinuation. Two patients declined restart of treatment due to mental health issues leading to discontinuation of vandetanib in the first place (after 7 and 38 months of treatment) and both patients died of rapidly progressive disease. At time points of tumour progression, calcitonin-doubling time (CDT) was < 2 years in all patients. Conclusion: This case series suggests that discontinuation of long-term vandetanib treatment with documented stable disease does not automatically result in rapid disease progression but may be followed by prolonged "TKI free" stable disease in individual patients. Analysis of calcitonin and CDT during discontinuation is indicated as it will unmask tumour progression earlier than imaging. Restart with the same TKI is possible in case of progression.