Variations in Radioiodine Therapy in Europe: Decision-Making after Total Thyroidectomy.

The role of radioiodine therapy (RIT) (used as ablation therapy or adjuvant therapy) following total thyroidectomy for differentiated thyroid cancer (DTC) changed. Major revisions of the American Thyroid Association (ATA) Guidelines in 2015 resulted in significant differences in treatment recommendations in comparison to the European Association of Nuclear Medicine (EANM) 2008 guidelines. Recently, we presented the effects on daily practice for RIT among Swiss Nuclear Medicine centres. We now performed a study at the European level and hypothesized that there is also considerable variability among European experts. We performed a decision-tree-based analysis of management strategies from all members of the EANM thyroid committee to map current practice among experts. We collected data on whether or not RIT is administered, on which criteria these decisions are based and collected details on treatment activities and patient preparation. Our study shows discrepancies for low-risk DTC, where "follow-up only" is recommended by some experts, while RIT with significant doses is used by other experts. E.g., for pT1b tumours without evidence of metastases, the level of agreement for the use of RIT is as low as 50%. If RIT is administered, activities of I-131 range from 1.1 GBq to 3.0 GBq. In other constellations (e.g., pT1a), experts diverge from current clinical guidelines as up to 75% administer RIT in certain cases. For intermediate and high-risk patients, RIT is generally recommended. However, dosing and treatment preparation (rhTSH vs. thyroid hormone withdrawal) vary distinctly. In comparison to the Swiss study, the general level of agreement is higher among the European experts. The recently proposed approach on the use of RIT, based on integrated post-surgery assessment (Martinique article) and results of ongoing prospective randomized studies are likely to reduce uncertainty in approaching RIT treatment. In certain constellations, consensus identified among European experts might be helpful in formulating future guidelines.

Higher thyroid hormone levels and cancer.

PURPOSE: This narrative review aims to summarize the relationship between hyperthyroidism, upper reference range thyroid hormone (TH) levels, and cancer, and to address the clinical management of hyperthyroidism in cancer patients. METHODS: A comprehensive search was performed by an independent reviewer through Google Scholar and PubMed Electronic databases. All searches were restricted to English language manuscripts published between 2000 and 2020. RESULTS: Numerous in vitro, in vivo, and population-based studies suggest cancer-stimulating effect of triiodothyronine and thyroxin. THs are presented as mediators for tumor growth, proliferation, and progression. Many population and case-control studies suggest an increased risk of several solid but also hematologic malignancies in relation to hyperthyroidism and upper normal range TH levels. However, results are not unambiguous. In this review, we will summarize population and case-control studies that investigated the relationship between hyperthyroidism, upper reference range TH levels, lower thyrotropin (TSH) levels, lower reference range TSH levels with cancer risk, cancer prognosis, and cancer outcome. The vast majority of evidence suggests an association between clinical and subclinical hyperthyroidism with the risk of developing several types of cancer. Furthermore, hyperthyroidism is also linked with a poorer cancer prognosis. In this review, we will also discuss the diagnosis of hyperthyroidism in patients with pre-existing cancer and cover the management of hyperthyroidism in cancer patients, with special attention on the role of nuclear medicine. CONCLUSIONS: It is crucial to emphasize the importance of the rapid establishment of euthyroidism, and consequently, the importance of radioiodine therapy, as the therapy of choice in most cancer patients. We want to show that in this day and age there still is a high relevance for I-131 to achieve a permanent solution and thus likely reduce the risk of adverse influence of hyperthyroidism on the occurrence of new and course of existing cancer cases.

Assessment of Waldeyer's ring in pediatric and adolescent Hodgkin lymphoma patients-Importance of multimodality imaging: Results from the EuroNet-PHL-C1 trial.

BACKGROUND: In the EuroNet Pediatric Hodgkin Lymphoma (EuroNet-PHL) trials, decision on Waldeyer's ring (WR) involvement is usually based on clinical assessment, that is, physical examination and/or nasopharyngoscopy. However, clinical assessment only evaluates mucosal surface and is prone to interobserver variability. Modern cross-sectional imaging technology may provide valuable information beyond mucosal surface, which may lead to a more accurate WR staging. PATIENTS, MATERIALS, AND METHODS: The EuroNet-PHL-C1 trial recruited 2102 patients, of which 1752 underwent central review including reference reading of their cross-sectional imaging data. In 14 of 1752 patients, WR was considered involved according to clinical assessment. In these 14 patients, the WR was re-assessed by applying an imaging-based algorithm considering information from 18 F-fluorodeoxyglucose positron emission tomography, contrast-enhanced computed tomography, and/or magnetic resonance imaging. For verification purposes, the imaging-based algorithm was applied to 100 consecutive patients whose WR was inconspicuous on clinical assessment. RESULTS: The imaging-based algorithm confirmed WR involvement only in four of the 14 patients. Of the remaining 10 patients, four had retropharyngeal lymph node involvement and six an inconspicuous WR. Applying the imaging-based algorithm to 100 consecutive patients with physiological appearance of their WR on clinical assessment, absence of WR involvement could be confirmed in 99. However, suspicion of WR involvement was raised in one patient. CONCLUSIONS: The imaging-based algorithm was feasible and easily applicable at initial staging of young patients with Hodgkin lymphoma. It increased the accuracy of WR staging, which may contribute to a more individualized treatment in the future.

The role of SPECT/CT in radioembolization of liver tumours.

Radioembolization (RE) with (90)Y microspheres is a promising catheter-based therapeutic option for patients with unresectable primary and metastatic liver tumours. Its rationale arises from the dual blood supply of liver tissue through the hepatic artery and the portal vein. Metastatic hepatic tumours measuring >3 mm derive 80 - 100 % of their blood supply from the arterial rather than the portal hepatic circulation. Typically, an angiographic evaluation combined with (99m)Tc-macroaggregated albumin ((99m)Tc-MAA) scan precedes therapy to map the tumour feeding vessels as well as to avoid the inadvertent deposition of microspheres in organs other than the liver. Prior to administration of (99m)Tc-MAA, prophylactic coil embolization of the gastroduodenal artery is recommended to avoid extrahepatic deposition of the microspheres. SPECT/CT allows direct correlation of anatomic and functional information in patients with unresectable liver disease. SPECT/CT is recommended to assess intrahepatic distribution as well as extrahepatic gastrointestinal uptake in these patients. Pretherapeutic SPECT/CT is an important component of treatment planning including catheter positioning and dose finding. A post-therapy bremsstrahlung (BS) scan should follow RE to verify the distribution of the administered tracer. BS SPECT/CT imaging enables better localization and definition of intrahepatic and possible extrahepatic sphere distribution and to a certain degree allows posttreatment dosimetry. In this paper we address the usefulness and significance of SPECT/CT in therapy planning and therapy monitoring of RE.

Dopamine transporter imaging in autopsy-confirmed Parkinson's disease and multiple system atrophy.

Dopamine transporter single-photon emission computerized tomography can visualize dopaminergic degeneration in Parkinson's disease and multiple system atrophy. Some studies have suggested that dopamine transporter imaging can distinguish these disorders based on a more diffuse and symmetric striatal dopamine transporter binding loss in multiple system atrophy. The present study compared patterns of striatal dopamine transporter distribution in postmortem-confirmed Parkinson's disease and multiple system atrophy. Patients with a postmortem diagnosis of multiple system atrophy (n = 6) or Parkinson's disease (n = 8) who had undergone dopamine transporter imaging were included. Imaging had been performed after a mean disease duration of 3.6 and 4.1 years in multiple system atrophy and Parkinson's disease, respectively. Visual analysis showed bilaterally reduced binding in all patients. Mean overall striatal binding was reduced by 53% in multiple system atrophy and 52% in Parkinson's disease. There was a trend for greater asymmetry of striatal binding in multiple system atrophy compared with Parkinson's disease (23% ± 15% vs 10.5% ± 7%, respectively; P = .071), with 3 multiple system atrophy patients showing more asymmetry of striatal binding than any Parkinson's disease patient. Putamen/caudate binding ratios did not differ between the groups. This is the first study comparing dopamine transporter imaging in autopsy-confirmed multiple system atrophy and Parkinson's disease. Unexpectedly, we found a tendency for greater asymmetry of striatal binding in multiple system atrophy than in Parkinson's disease. Our findings demonstrate that these conditions cannot be differentiated by subregional analysis of striatal dopamine transporter binding.

Second line chemotherapy in patients with enteropathy-associated T cell lymphoma: a retrospective single center analysis.

Enteropathy-associated T cell lymphoma (EATL) is a rare disease with a dismal prognosis. Due to the low efficacy of chemotherapy and the poor performance status of patients failing first line, no data on second line therapy exist. A retrospective analysis of 19 patients with EATL at our institution identified six patients (31%) undergoing second line chemotherapy after CHOP-like regimens. Three patients had progressive disease (PD) during first line therapy, while the other three patients showed relapse after an initial complete remission (CR). The time from the last cycle of first line chemotherapy to second line therapy was 1-62 months. Two patients received ifosfamide, carboplatin and etoposide (ICE), two were given fludarabine and cyclophosphamide (FC) and one each had dexamethasone, cisplatin and cytarabine (DHAP) and cladribine chemotherapy. One patient progressed after one course of cladribine, while two patients developed intestinal perforation and died after one course of ICE and DHAP, respectively. Three patients achieved a CR lasting 4, +7 and +64 months, with two being alive without evidence of disease. Our data again confirm the poor prognosis of patients with EATL. A small subset of patients, however, apparently benefits from initiation of second line chemotherapy.

Bortezomib combined with rituximab and dexamethasone is an active regimen for patients with relapsed and chemotherapy-refractory mantle cell lymphoma.

BACKGROUND: Bortezomib belongs to a new class of anti-cancer agents, the proteasome inhibitors, and has documented activity in multiple myeloma and mantle cell lymphoma. Preclinical studies suggest that bortezomib has synergistic activity with rituximab, which provides a rationale for the exploration of treatment combinations. DESIGN AND METHODS: The activity and safety of bortezomib in combination with rituximab and dexamethasone were investigated in patients with relapsed or chemotherapy-refractory mantle cell lymphoma. A treatment cycle consisted of bortezomib (1.3 mg/m² on days 1, 4, 8, and 11; six 21-day cycles), rituximab (375 mg/m², day 1) and dexamethasone (40 mg orally, days 1 to 4). Responding patients received four consolidating doses of rituximab. Sixteen patients with progressive mantle cell lymphoma after a median of three prior lines of therapy were enrolled. RESULTS: The overall response rate was 81.3% (13 patients), with seven patients achieving a complete response (43.8%). Six of these patients were also negative for disease activity by positron emission tomography scanning. The median progression-free survival and overall survival were 12.1 and 38.6 months, respectively. In patients achieving a complete response, the median progression-free survival and overall survival have not yet been reached. Adverse events (greater than grade II) included thrombocytopenia (37.5%), fatigue (18.8%) and peripheral neuropathy (12.5%). Two patients discontinued bortezomib because of grade III neuropathy. CONCLUSIONS: Bortezomib combined with rituximab and dexamethasone has promising activity and manageable toxicity in patients with heavily pretreated mantle cell lymphoma. Achievement of complete response emerged as an important factor for sustained disease control. This trial was registered at www.clinicaltrials.gov as #NCT00261612.

A simple micro-photometric method for urinary iodine determination.

BACKGROUND: Urinary iodide concentration (UIC) is useful to evaluate nutritional iodine status. In clinical settings UIC helps to exclude blocking of the thyroid gland by excessive endogenous iodine, if diagnostic or therapeutic administration of radio-iodine is indicated. Therefore, this study established a simple test for the measurement of UIC. METHODS: UIC was analyzed in urine samples of 200 patients. Samples were pre-treated at 95°C for 45 min with ammonium persulfate in a thermal cycler, followed by a photometric Sandell-Kolthoff reaction (SK) carried out in microtiter plates. For method comparison, UIC was analyzed in 30 samples by inductivity coupled plasma mass spectro-metry (ICP-MS) as a reference method. RESULTS: Incubation conditions were optimized concerning recovery. The photometric test correlated well to the reference method (SK=0.91*ICP-MS+1, r=0.962) and presented with a functional sensitivity of 20 µg/L. UIC of patient samples ranged from <20 to 750 µg/L (median 110 µg/L); 90% of the urine samples had iodide concentrations below 210 µg/L. CONCLUSION: The modified SK-test takes approximately 90 min for analyses of 20 urine samples compared with 27 h for ICP-MS. The photometric test provides satisfactory results and can be performed with the basic equipment of a clinical laboratory.

Follicular thyroid carcinoma in an iodine-replete endemic goiter region: a prospectively collected, retrospectively analyzed clinical trial.

OBJECTIVE: To determine risk factors for presence of lymph node or distant metastases in patients with follicular thyroid cancer (FTC) at the time of diagnosis and whether there is a relationship between the type of tumor invasion and metastases. SUMMARY BACKGROUND DATA: FTC often presents distant metastases at the initial diagnosis. As distant metastases are independent prognostic factors in a patient's survival, determination of clinicopathologic characteristics for patients who are at higher risk for developing metastases is of greater clinical importance. METHODS: The prognostic significance of gender (male vs. female), age (40 mm), number of lesions (uni- vs. multifocality), type of invasion (minimally invasive vs. widely invasive), and oncocytic changes (with vs. without) were analyzed in 207 patients, according to presence of lymph node and distant metastases at the time of initial surgery. According to the type of invasion, the carcinoma-specific survival and the disease-free survival of minimally invasive (MI) and widely invasive (WI) FTC were estimated and compared. RESULTS: None of the 127 patients with MI growth presented with lymph node metastases but 9.4% distant metastases. Overall risk factors for the presence of lymph node metastases at the initial diagnosis were multifocality (P = 0.02) and widely invasion (P = 0.0001) and for distant metastases age >45 years (P = 0.007), tumor size larger than 40 mm (P = 0.03) and widely invasion (P = 0.0001).WI-FTC patients show larger tumors (P = 0.0001), older age (P = 0.0001), and are presented more frequently in recurrent goiter disease (P = 0.0001). The estimated 10 years carcinoma-specific survival and disease-free survival for MI-tumors were significantly better than for WI-tumors (P = 0.0001). CONCLUSIONS: Total thyroidectomy is recommended in all patients with FTC because of early distant metastases. Patients with WI-FTC need a more aggressive surgical treatment because of higher tendency for lymph node metastases. MI-FTC has an excellent prognosis with no sign of lymph node metastases, which emphasizes a limited need for nodal surgery.

European Perspective on 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: Proceedings of an Interactive International Symposium.

BACKGROUND: The American Thyroid Association (ATA) management guidelines for patients with thyroid nodules and differentiated thyroid cancer (DTC) are highly influential practice recommendations. The latest revision appeared in 2015 ("ATA 2015"). These guidelines were developed predominantly by North American experts. European experts frequently have different perspectives, given epidemiological, technological/methodological, practice organization, and medicolegal differences between the respective regions. SUMMARY: Divergent viewpoints were the focus of an invited symposium organized by the European Association of Nuclear Medicine involving 17 European thyroidologists, four ATA Guidelines Taskforce members, and an audience of 200 international experts. The group discussed the preoperative assessment of thyroid nodules, surgery and the role of pathology, radioiodine (RAI) therapy (RAIT), the assessment of initial therapy and dynamic risk stratification, and the treatment of persistent disease, recurrences, and advanced thyroid cancer. The dialogue resulted in this position paper contrasting European and ATA 2015 perspectives on key issues. One difference pertains to the permissiveness of ATA 2015 regarding lobectomy for primary tumors ≤4 cm. European panelists cited preclusion of RAIT, potential need for completion thyroidectomy, frequent inability to avoid chronic thyroid hormone replacement, and limitations of supportive evidence as arguments against widely applying lobectomy. Significant divergence involved ATA 2015's guidance regarding RAIT. European panelists favored wider use of postoperative RAIT than does ATA 2015. Rationales included the modality's association with favorable patient outcomes and generally limited toxicity, and lack of high-quality evidence supporting withholding RAIT. Additionally, European panelists favored recombinant human thyrotropin (rhTSH) in more settings than does ATA 2015, citing avoidance of hypothyroid morbidity and quality-of-life impairment, without apparent sacrifice in oncologic outcomes. Based on clinical evidence plus theoretical advantages, European experts advocated dosimetric versus fixed-activity RAIT approaches for advanced DTC. European panelists noted that the ATA 2015 risk-stratification system requires information sometimes unavailable in everyday practice. ATA 2015 recommendations regarding RAI-refractory DTC should consider potential palliative benefits of RAIT in patients who also have RAI-susceptible lesions. CONCLUSIONS: European panelists suggested modifications to approximately one-third of ATA 2015 recommendations. Varying European and ATA 2015 perspectives can stimulate analysis and discussion of the literature and performance of primary research to resolve discrepant recommendations and potentially improve patient outcomes.

Osteonecrosis of the jaws and bisphosphonate treatment in cancer patients.

PURPOSE: Osteonecrosis of the jaws is described as an intraoral complication after administration of intravenous nitrogen-containing bisphosphonates. In a retrospective study, patients with osteonecrosis of the jaws after bisphosphonate treatment were evaluated with regard to diagnostic investigations and therapeutic management. PATIENTS AND METHODS: Seventeen patients with osteonecrosis of the jaws after bisphosphonate treatment who were referred to our department between July 2004 and June 2005 were included in this study. Computer tomography, magnetic resonance imaging, scintigraphy, bacteriology and biopsy were used in diagnostic evaluation. All patients were treated surgically. RESULTS: The reasons for bisphosphonate treatment were multiple myeloma in 12 patients, breast cancer with bone metastasis in four patients and histiocytosis X in one patient. Five patients had received intravenous pamidronate and 12 patients zoledronic acid. The median number of treatment cycles for pamidronate was 36 times (range 4-100) in 38 months (range 4-100). Zolendric acid was given 23.5 times (range 5-39) in 26 months (range 5-39). Nine patients had a lesion in the mandible, eight in the maxilla. Clinical symptoms were exposed bone, pain and local inflammation of the mucosa. Computer tomography showed sclerotic areas in the osteonecrosis zone. The biopsy did not show a metastatic lesion. Sequestrectomy and decortication was adequate in the follow-up. CONCLUSION: Nitrogen-containing bisphosphonates appear to be associated with the risk of developing osteonecrosis of the jaws. To reduce this risk, patients should be evaluated by a dentist before beginning treatment with intravenous bisphosphonates.

Inter-Reader Reliability of Early FDG-PET/CT Response Assessment Using the Deauville Scale after 2 Cycles of Intensive Chemotherapy (OEPA) in Hodgkin's Lymphoma.

PURPOSE: The five point Deauville (D) scale is widely used to assess interim PET metabolic response to chemotherapy in Hodgkin lymphoma (HL) patients. An International Validation Study reported good concordance among reviewers in ABVD treated advanced stage HL patients for the binary discrimination between score D1,2,3 and score D4,5. Inter-reader reliability of the whole scale is not well characterised. METHODS: Five international expert readers scored 100 interim PET/CT scans from paediatric HL patients. Scans were acquired in 51 European hospitals after two courses of OEPA chemotherapy (according to the EuroNet-PHL-C1 study). Images were interpreted in direct comparison with staging PET/CTs. RESULTS: The probability that two random readers concord on the five point D score of a random case is only 42% (global kappa = 0.24). Aggregating to a three point scale D1,2 vs. D3 vs. D4,5 improves concordance to 60% (kappa = 0.34). Concordance if one of two readers assigns a given score is 70% for score D1,2 only 36% for score D3 and 64% for D4,5. Concordance for the binary decisions D1,2 vs. D3,4,5 is 67% and 86% for D1,2,3 vs D4,5 (kappa = 0.36 resp. 0.56). If one reader assigns D1,2,3 concordance probability is 92%, but only 64% if D4,5 is called. Discrepancies occur mainly in mediastinum, neck and skeleton. CONCLUSION: Inter-reader reliability of the five point D-scale is poor in this interobserver analysis of paediatric patients who underwent OEPA. Inter-reader variability is maximal in cases assigned to D2 or D3. The binary distinction D1,2,3 versus D4,5 is the most reliable criterion for clinical decision making.

Transformation of MALT lymphoma to pure plasma cell histology following treatment with the anti-CD20 antibody rituximab.

Mucosa associated lymphoid tissue (MALT) lymphoma is a relatively common lymphoma arising from marginal-zone B-cells which are closely related to plasma cells. As opposed to the large majority of plasma cells, MALT lymphoma cells express CD20, and the anti-CD20 antibody rituximab has been reported as active treatment in patients with MALT lymphoma. We present a patient with MALT lymphoma involving stomach and lung which transformed to a pure plasma cell tumor after therapy with rituximab. This observation again supports the close association between the cell of origin of MALT lymphoma and plasma cells, suggesting that "plasmacytoma of the GI-tract" as anecdotally reported may in fact be a MALT lymphoma with extreme plasmacytic differentiation. In addition, our findings suggest that MALT lymphomas with plasmacytic differentiation might have a different 18F-FDG uptake as compared to classical MALT lymphoma.

11C-methionine PET/CT imaging of 99mTc-MIBI-SPECT/CT-negative patients with primary hyperparathyroidism and previous neck surgery.

CONTEXT: (99m)Tc-Methoxy-isobutyl-isonitrile (MIBI) scintigraphy is a standard preoperative localization imaging modality in patients with primary hyperparathyroidism (pHPT). Its accuracy in localizing a hyperactive parathyroid gland after previous cervical surgery is limited. Recently, (11)C-methionine has been introduced as a promising radiotracer for pHPT imaging. Yet, few data exist for this technique in patients with persisting or recurrent pHPT before reoperation. OBJECTIVES: We aimed to investigate the ability of (11)C-methionine positron emission tomography (PET)/computed tomography (CT) to localize a parathyroid disorder after cervical surgery and negative postsurgical (99m)Tc-MIBI single-photon emission CT (SPECT)/CT. DESIGN, SETTING, AND PARTICIPANTS: Fifteen patients (6 males, 9 females; age range, 36-85 years) with pHPT and negative (99m)Tc-MIBI SPECT/CT who had undergone earlier neck surgery because of pHPT and/or thyroid disorder were recruited. Twelve of the 15 patients had thyroidectomy for goiter or differentiated thyroid carcinoma. Ten patients had previous parathyroid surgery for pHPT, and 2 patients had a history of parathyroid carcinoma. Thirteen of 15 patients showed elevated levels of intact PTH at the time of PET/CT imaging, whereas all patients had elevated serum calcium values. MAIN OUTCOME MEASUREMENTS: Pathological results of contrast-enhanced (11)C-methionine PET/CT and surgical results were evaluated. RESULTS: In 6 of 15 patients (11)C-methionine PET/CT showed a hypermetabolic focus in the upper mediastinum in 2 patients, in the thoracic outlet in 1 patient, and in the cervical region in 3 patients. In 9 of the 15 patients, no hyperactive parathyroid gland could be visualized. Reoperation was performed in 5 of 6 patients without surgical complications. One patient refused surgery. In 2 of the 5 patients, a transsternal procedure was performed. Correlating with the (11)C-methionine PET/CT results, a single parathyroid adenoma was found in 4 patients and parathyroid carcinoma metastasis in 1 patient. CONCLUSION: (11)C-Methionine PET/CT is a useful complementary imaging technique to localize parathyroid adenoma or carcinoma in (99m)Tc-MIBI SPECT/CT-negative patients.