Low Malignancy Rates in Fine-Needle Aspiration Cytologies in a Primary Care Setting in Germany.

BACKGROUND: Reported results for thyroid nodule fine-needle aspiration (FNA) cytology mainly originate from tertiary centers. However, thyroid nodule FNA cytology is mainly performed in primary care settings for which the distribution of FNA Bethesda categories and their respective malignancy rates are largely unknown. Therefore, this study investigated FNA cytology malignancy rates of a large primary care setting to determine to what extent current evidence-based strategies for the malignancy risk stratification of thyroid nodules are applied and applicable in such primary care settings. METHODS: In a primary care setting, 9460 FNAs of thyroid nodules were retrospectively analyzed from 8380 patients evaluated by one cytologist (I.R.) during a period of two years. The 8380 FNA cytologies were performed by 64 physicians in different private practices throughout Germany in primary care settings. RESULTS: The cytopathologic results were classified according to the Bethesda System as non-diagnostic in 19%, cyst/cystic nodule in 21%, benign (including thyroiditis) in 48%, atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) in 6%, follicular neoplasms/suspicious for follicular neoplasm (FN/SFN) in 4%, suspicious for malignancy (SFM) in 1%, and malignant in 1%. The proportion of patients proceeding to surgery or with a follow-up of at least one year and the observed risks of malignancy were 22%/8% for AUS/FLUS, 69%/17% for FN/SFN, 78%/86% for SFM, and 71%/98% for malignant. For 112 cytologically suspicious and malignant FNAs, there were 102 true positives and 10 false positives, considering histology as gold standard. CONCLUSION: At variance with other data mostly originating from tertiary centers, these data demonstrate low percentages for malignant, SFM, FN/SFN, and AUS/FLUS, and high percentages for cysts/cystic nodules in this primary care setting in Germany. The risks of malignancy for malignant, SFM, AUS/FLUS, and FN/SFN FNA cytologies are according to Bethesda recommendations.

Evaluation of a Two-Year Routine Application of Molecular Testing of Thyroid Fine-Needle Aspirations Using a Seven-Gene Panel in a Primary Referral Setting in Germany.

BACKGROUND: Major differences with respect to the diagnostic performance of a "ruling in" approach in the presurgical diagnosis of indeterminate thyroid fine-needle aspirations (FNAs) have been reported. Therefore, the aim of this prospective multicenter study was to investigate the specific diagnostic impact of mutation testing using a seven-gene panel in a routine primary referral setting analyzing FNAs from endocrinology and nuclear medicine practices in Germany. METHODS: RNA and DNA was extracted from 564 routine air-dried FNA smears obtained from 64 physicians and cytologically graded by one experienced cytopathologist. PAX8/PPARG and RET/PTC rearrangements were detected by quantitative polymerase chain reaction, while BRAF and RAS mutations were detected by pyrosequencing. Molecular data were compared to histology and follow-up >1 year, which were available for 322/348 patients undergoing surgery and 33/74 patients having follow-up. Histology results were obtained from the local routine pathologists who were blinded to the molecular test results. RESULTS: BRAF and RET/PTC mutations were associated with carcinoma in 98% and 100% of samples, respectively. RAS and PAX8/PPARG mutations were associated with carcinoma in 31% and 0% of samples, respectively. Thirty-six percent of the carcinomas were identified by molecular testing in the atypia of undetermined significance/follicular lesion of undetermined significance and follicular neoplasm/suspicious for a follicular neoplasm categories, with malignancy rates of 15% and 17%, respectively. Due to a low percentage of RAS mutation-positive carcinomas in combination with a rather high percentage of RAS mutation-positive benign nodules, the positive predictive values of 41% and 36% in the atypia of undetermined significance/follicular lesion of undetermined significance and follicular neoplasm/suspicious for a follicular neoplasm categories offer only limited diagnostic potential. CONCLUSION: In conclusion, the data suggest that the application of the current seven-gene panel in a routine primary referral setting does not improve the presurgical diagnosis of thyroid FNAs. While the diagnostic relevance of RAS mutations in thyroid tumors needs further investigation, more comprehensive mutation panels with more cancer-specific mutations may improve the presurgical diagnosis of thyroid FNAs.

Repair of a segmental long bone defect in human by implantation of a novel multiple disc graft.

Large segmental defects of the weight bearing long bones are very difficult to reconstruct. Current treatment options are afflicted with several limitations and disadvantages. We describe a novel approach to regenerate a segmental long bone defect in a patient using a multiple disc graft. Decellularized bovine trabecular bone discs were seeded with autologous bone marrow cells and cultured in a perfusion chamber for three weeks. Multiple cell-seeded discs were implanted to close a 72 mm defect of the distal tibia in a 58-year-old woman, and fixed by an intramedullary nail. Bone formation was assessed non-invasively by plain radiographs and 18F-labeled sodium fluoride-based co-registration of positron emission- and computed tomography (PET/CT). Bone was actively formed around the grafted defect as early as six weeks after surgery. Because the tibia was sufficiently stabilized, the patient was able to freely walk with full weight bearing 6 weeks after surgery. The uneventful two-year follow-up and the satisfaction of the patient demonstrated the success of the procedure. Therefore the use of multiple cell-seeded disc grafts can be considered as a treatment alternative for patients with segmental long bone defects.

Use of polyglutamic acids to reduce uptake of radiometal-labeled minigastrin in the kidneys.

UNLABELLED: Uptake of radiolabeled peptides in the kidneys may obscure abdominal tumors in radiopeptide scintigraphy. This problem is much more pronounced in peptide receptor radionuclide therapy (i.e., radiopeptide therapy), possibly leading to renal damage or even failure. Cationic peptide uptake in the kidneys can be reduced by the application of cationic amino acids, such as lysine or arginine. The aim of this study was to develop a suitable method to reduce anionic peptide uptake in the kidneys. (111)In-Diethylenetriaminepentaacetic acid dGlu(1)-minigastrin ((111)In-DTPA-dGlu-Glu-Glu-Glu-Glu-Glu-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH(2)) was chosen as a model compound with a sequence of 6 negatively charged glutamic acids in a chain and an additional aspartic acid. METHODS: TT (human medullary carcinoma cells)-bearing nu/nu mice of the Institute of Cancer Research genotype received intraperitoneal injections of different chain lengths and weights of glutamic acids, aspartic acids, and derivatives of glutamic acids. Uptake in tumors and organs was determined and compared with the values for untreated control mice. RESULTS: Accretion of (111)In-DTPA-dGlu(1)-minigastrin in the kidneys could be reduced by up to 90%. The uptake values for all other organs and the tumors were not affected. These results were obtained with a chain of 5 or more glutamic acids, whereas uptake in kidneys was affected not at all or only slightly with poly-d-glutamic or polyaspartic acids and with Glu(x) (x = 1-4). CONCLUSION: These studies indicated a specific blocking of uptake by Glu(5) sequences in the kidneys. Application of polyglutamic acids is a new, successful method of reducing uptake of negatively charged peptides in the kidneys during radiopeptide therapy.