Theresia Weber

Effect of Parathyroidectomy on Quality of Life and Neuropsychological Symptoms in Primary Hyperparathyroidism

Neuropsychological symptoms are found in a certain number of patients with primary hyperparathyroidism (PHPT). Preoperative and postoperative quality of life, anxiety, and depression are measured to analyze the impact of parathyroidectomy on these symptoms. In this prospective study, 66 patients underwent parathyroidectomy for PHPT and were evaluated pre- and postoperatively with two validated psychometric instruments (HADS, PHQ-9). Health-related quality of life was measured with a 12-item short-form health survey (SF-12). Preoperatively, the median physical component score (SF-12) of 43.0 and mental component score of 43.5 were lower than those of the general population (52.8 and 54.2 points, respectively). One year postoperatively the mental component score increased to 48.6 (p = 0.011), whereas the physical functioning scale scored 45.3 and therefore did not change significantly (p = 0.585). Preoperatively, symptoms of depression were found in 23.4% of the patients, and 15.6% of the patients displayed symptoms of anxiety (HADS). The prevalence of depression was significantly higher in patients with preoperative serum calcium levels > 11.2 mg/dl (2.8 mmol/L) (p = 0.015). Twelve months postoperatively, the overall proportion of patients with anxiety and depression decreased to 7.8% and 15.7%, respectively (p = NS). The severity of depression as measured with the PHQ-9 declined postoperatively as well. In this study, preoperative neuropsychological symptoms were related to the serum calcium levels. Postoperative health-related quality of life improved significantly. Among patients with preoperative symptoms of depression and anxiety, both symptoms were alleviated significantly at the 12-month follow-up. Therefore, surgery for PHPT seems to be effective in reducing neuropsychological morbidity associated with PHPT.

Accurate preoperative localization of parathyroid adenomas with C-11 methionine PET/CT.

Background:Focused unilateral or minimally invasive parathyroidectomy for primary hyperparathyroidism (pHPT) depends on the successful preoperative localization of parathyroid adenomas. The aim of this prospective study was to determine the accuracy of C-11 methionine positron emission tomography/computed tomography (Met-PET/CT), a novel localization procedure for hyperfunctional parathyroid tissue. Methods:Preoperative Met-PET/CT scans of the neck and mediastinum of 102 patients undergoing parathyroidectomy for pHPT were preoperatively evaluated by a radiologist and a nuclear medicine physician and prospectively documented. The results of Met-PET/CT were compared with intraoperative and histopathological findings. Results:pHPT was caused by a single-gland adenoma in 97 patients, whereas 5 patients had multiglandular disease. Met-PET/CT correctly located a single-gland adenoma in 83 of 97 (86%) patients with pHPT (sensitivity 91%). The positive predictive value of Met-PET/CT in localizing a single-gland adenoma was 93%. Of the 5 patients with multiglandular disease, Met-PET/CT identified 2 hyperfunctioning parathyroid glands in 1 patient, 1 gland in 3 individuals, and was negative in the fifth patient (sensitivity 80%). A highly significant correlation was observed between true-positive findings and the size (mean = 1.81 ± 0.84 cm) and weight (mean = 1.50 ± 2.56 g) of parathyroid adenoma, whereas patients with false-negative findings had significantly smaller (mean = 1.09 ± 0.41 cm) and lighter (mean = 0.37 ± 0.29 g) glands (P < 0.001 and P = 0.001, respectively). Conclusions:This study demonstrates the high accuracy of Met-PET/CT in the preoperative localization of parathyroid adenomas in a large series of patients with pHPT.

Impact of Intraoperative Parathyroid Hormone Levels on Surgical Results in Patients with Renal Hyperparathyroidism

The aim of our study was to evaluate the impact of intraoperative parathyroid hormone (PTH) measurement on surgical results in patients with renal hyperparathyroidism (HPT). From December 1999 to February 2004, a series of 95 consecutive patients underwent total parathyroidectomy and intraoperative PTH measurement for renal HPT. Intraoperative PTH was measured before and 15 minutes after parathyroidectomy with the Immulite DPC assay for intact PTH. The median PTH levels before surgery were 133.0 pmol/L, which declined to 5.9 pmol/L at the end of the operation. At follow-up, 91 of 95 (96%) patients presented with normal calcium levels. Persistent renal HPT was seen in three patients, and recurrent HPT was diagnosed in another. In 99% of the patients the intraoperative PTH levels declined more than 50% and in 73% the PTH decay was more than 90%. In 64% of the patients PTH levels dropped into the normal range (< 7.6 pmol/L). Altogether, 97% of the patients with an intraoperative PTH decrease of more than 90% presented with normal PTH levels postoperatively (p = 0.0237), as did all of the patients whose intraoperative PTH dropped into the normal range (p = 0.0432). Intraoperative PTH measurement with a decrease in intraoperative PTH of at least 90% is highly predictive of successful parathyroidectomy and normalization of postoperative calcium and PTH levels.

Differentiated thyroid cancer-personalized therapies to prevent overtreatment.

The concept of individualized therapy is rapidly gaining recognition in the management of patients with differentiated thyroid cancer (DTC). This Review provides an overview of the most important elements of this paradigm shift in DTC management and discusses the implications for clinical practice. In the majority of patients with DTC who have an inherently good prognosis, the extent of surgery, the dosage of 131I therapy and the use of levothyroxine therapy are all aspects suitable for individualization, on the basis of both the stage of disease and the response to treatment. In individuals with advanced disease, newer imaging techniques, advances in 131I therapy and the use of targeted molecular therapies (such as multitargeted kinase inhibitors) have provided new options for the personalized care of patients, for whom until recently no effective therapies were available. Individualized therapies could reduce adverse effects, including the sometimes debilitating hypothyroidism that used to be required before initiation of 131I treatment, and major salivary gland damage, a common and unpleasant side effect of 131I therapy. Highly individualized interdisciplinary treatment of patients with DTC might lead to improved outcomes with reduced severity and frequency of complications and adverse effects. However, in spite of ongoing research, personalized therapies remain in their infancy.

Comparative gene array analysis of progenitor cells from human paired deep neck and subcutaneous adipose tissue.

Brown and white adipocytes have been shown to derive from different progenitors. In this study we sought to clarify the molecular differences between human brown and white adipocyte progenitors cells. To this end, we performed comparative gene array analysis on progenitor cells isolated from paired biopsies of deep and subcutaneous neck adipose tissue from individuals (n = 6) undergoing neck surgery. Compared with subcutaneous neck progenitors, cells from the deep neck adipose tissue displayed marked differences in gene expression pattern, including 355 differentially regulated (>1.5 fold) genes. Analysis of highest regulated genes revealed that STMN2, MME, ODZ2, NRN1 and IL13RA2 genes were specifically expressed in white progenitor cells, whereas expression of LRRC17, CNTNAP3, CD34, RGS7BP and ADH1B marked brown progenitor cells. In conclusion, progenitors from deep neck and subcutaneous neck adipose tissue are characterized by a distinct molecular signature, giving rise to either brown or white adipocytes. The newly identified markers may provide potential pharmacological targets facilitating brown adipogenesis.

Detection of disseminated medullary thyroid carcinoma cells in cervical lymph nodes by cytokeratin 20 reverse transcription-polymerase chain reaction

Local recurrence in differentiated and medullary thyroid carcinoma develops frequently from metastatic infiltration of cervical lymph nodes. Despite an aggressive surgical approach, postoperative calcitonin levels as biochemical evidence for residual cancer cells remain often elevated in patients with medullary thyroid carcinoma. In the present study, we compared the detection rates of disseminated medullary thyroid carcinoma cells in cervical lymph nodes by histopathology with reverse transcription-polymerase chain reaction (RT-PCR) amplification of cytokeratin 20 (CK20) transcripts as a more sensitive but still specific molecular parameter for residual thyroid cancer cells. Forty-two cervical lymph nodes obtained from 7 patients with CK20positive medullary thyroid carcinomas were cut into two halves, one used for conventional histology, the other subjected to RNA extraction and subsequent amplification of cytokeratin 20 transcripts. Matching results for CK20 RT-PCR and histopathology were found in 74% (31/42)of the examined lymph nodes (52% positive results, 48% negative results). Positive CK20 RT-PCR pointed to residual thyroid carcinoma cells in another 19% (8/42), in which no thyroid carcinoma cells were identified by histopathology. Histology and immunohistochemistry,however, identified tumor cells in 7% (3/42) of the analyzed lymph nodes, from which no CK20 transcript could be amplified (false-negative results). These data suggest that CK20 RT-PCR might be more sensitive to detect nodal involvement of CK20 positive medullary thyroid carcinomas than conventional histopathology. In combination with histology, it might help to identify patients with residual disease after surgery.

Impact of FDG-PET computed tomography for surgery of recurrent or persistent differentiated thyroid carcinoma.

Fluorodeoxyglucose-positron emission tomography (FDG-PET)/computed tomography (CT) is able to localize persistent or recurrent disease in differentiated thyroid carcinoma (DTC). The aim of the study was to correlate PET/CT results with precise intraoperative localization of persistent or recurrent papillary and follicular thyroid carcinoma. Patients with differentiated thyroid carcinoma who received FDG-PET scans were prospectively documented. The PET/CT results were correlated with other localization studies (neck ultrasound, ¹³¹I whole-body scan) and accurately compared to intraoperative findings and histopathological examinations. FDG-PET/CT scans were performed in 18 patients, between 16 and 84 years of age, from December 2008 to June 2011. Fourteen patients had papillary thyroid carcinomas and 4 had follicular thyroid carcinomas. All patients had a previous thyroidectomy and radioiodine ablation. Before cervical re-exploration, FDG-PET/CT-positive findings were reported in 14 individuals, whereas 4 PET scans provided no evidence of disease. Intraoperatively, 13 of 14 FDG-PET/CT-positive localizations of recurrent or persistent thyroid carcinomas were verified and confirmed by histopathology (sensitivity 93%). In another patient lymph node metastases of lung cancer were detected intraoperatively. However, FDG-PET/CT underestimated the number of lesions in 5 of 6 patients undergoing systematic lymphadenectomy. No lymph node or soft tissue metastases were found intraoperatively in 3 of the 4 patients with negative FDG-PET scans. A solitary cystic lymph node metastasis was found in the fourth patient but was not detected by FDG-PET/CT (specificity 75%). FDG-PET/CT has high sensitivity and specificity for the detection of persistent or recurrent differentiated thyroid carcinoma. FDG-PET/CT helps to select patients who might benefit from surgery because it provides precise anatomical details.

Clinical impact of two different intraoperative parathyroid hormone assays in primary and renal hyperparathyroidism

BACKGROUND Intraoperative parathyroid hormone (PTH) monitoring predicts successful surgery for primary hyperparathyroidism (pHPT). In renal HPT, intraoperative PTH assays can define whether parathyroid resection is adequate. METHODS Intraoperative PTH was measured with two different immunometric assays (Immulite Turbo DPC and ADVIA Centaur assay) in 91 patients undergoing parathyroidectomy for primary (n=57) and renal (n=34) hyperparathyroidism. PTH was monitored preoperatively, 10, 20, and 30 min after parathyroidectomy and 24 h postoperatively. RESULTS Ten minutes after parathyroidectomy, intraoperative PTH dropped into the normal range (<7.6 pmol/l) in 84% of patients with pHPT and tertiary HPT as measured with the ADVIA Centaur assay (PTH-A), compared with 100% of the samples measured with the Immulite Turbo DPC assay (PTH-I; P=0.0082). Twenty minutes after parathyroidectomy for secondary HPT, intraoperative PTH decreased to the normal range in 100% measured with PTH-I compared with 50% measured with PTH-A (P=0.009). Then, 24 h postoperatively, PTH-I and PTH-A levels were within the normal range in all of the successfully treated patients. Both assays correctly identified six patients with persistent disease and another patient with a double adenoma in pHPT. CONCLUSIONS In patients undergoing parathyroidectomy for primary or renal HPT, PTH levels decreasing to the normal range indicated successful surgery in all of the patients as measured with the PTH-I assay. Comparing the two assays, PTH-I was able to quantify the intraoperative PTH decay more quickly than PTH-A.

Detection of hematogenic and lymphogenic tumor cell dissemination in patients with medullary thyroid carcinoma by cytokeratin 20 and preprogastrin-releasing peptide RT-PCR

Despite an extensive surgical approach only 50% of the patients with medullary thyroid carcinoma (MTC) are biochemically cured. The failure to cure a larger number of patients is a result of the early dissemination of MTC. The present study evaluates two RT‐PCR based assays for the detection of disseminated tumor cells in blood, bone marrow and lymph node samples of patients with MTC. Frozen tissue and blood samples of 19 patients with MTC and 61 cervical lymph nodes of these patients were obtained intraoperatively during thyroidectomy and lymphadenectomy. Preoperative bone marrow samples were obtained from 8 patients with MTC. An expression of CK20 and preproGRP was found in all MTC tissue samples. Using CK20‐PCR, disseminated MTC cells were detected in 67% of the cervical lymph nodes of patients with MTC, compared to 72% involved lymph nodes, detected by preproGRP‐PCR. In 16 of 61 nodes (26%) each PCR‐system detected disseminated tumor cells in histologically tumor‐free lymph nodes. Disseminated tumor cells were detected with CK20‐PCR and preproGRP in 5 of 18 (28%) preoperative blood samples, each. The detection of a hematogenic tumor cell dissemination by preproGRP correlated significantly with the tumor stages (p = 0.019). Circulating MTC cells were found in 3 of 8 bone marrow samples with CK20‐PCR, compared to 1 of 8 samples with preproGRP‐PCR. Both PCR assays are highly sensitive to detect disseminated MTC cells in blood, bone marrow and lymph node samples. Our results of disseminated MTC cells in 26% of histologically tumor‐free cervical lymph nodes and in 28% of the blood samples of patients with MTC might therefore explain the low biochemical cure rates.

Detection and prognostic relevance of cytokeratin 20 in differentiated and anaplastic thyroid carcinomas by RT-PCR

BACKGROUND Metastatic disease in epithelial cancer results from tumor cell dissemination. We investigated an expression of cytokeratin 20 (CK20) by reverse transcriptase-polymerase chain reaction (RT-PCR) in differentiated (DTC) and anaplastic thyroid carcinomas (ATC) and correlated the results with TNM categories and the clinical follow-up. METHODS Tissue and blood samples of 32 patients with papillary (PTC), 17 patients with follicular (FTC), and 7 patients with ATC were obtained during operation and subjected to CK20 RT-PCR. RESULTS An expression of CK20 transcripts was detected in 47% of the tissue samples of PTC, 71% of the FTC, and 14% of the ATC. Patients with CK20-positive FTC had a significantly better outcome than patients with CK20-negative FTCs (P=.0016). Disseminated tumor cells were found in 9 of 22 (41%) blood samples of patients with CK20-positive carcinomas. The detection of CK20 transcripts in peripheral blood correlated with tumor categories. Four of 8 (50%) patients with DTC and circulating tumor cells developed local or distant recurrence compared with 3 of 13 (23%) patients with CK20-positive carcinomas and CK20-negative blood samples. CONCLUSION Our results suggest that CK20 might be a suitable differentiation marker in thyroid carcinomas. In patients with CK20-positive tumors, those with CK20-positive blood samples had a poorer prognosis. We suggest that patients with thyroid cancer with positive CK20 blood samples should be evaluated for further adjuvant therapies after surgery.