Molecular Diagnostics and [18F]FDG-PET/CT in Indeterminate Thyroid Nodules: Complementing Techniques or Waste of Valuable Resources?

Background: An accurate preoperative workup of cytologically indeterminate thyroid nodules (ITN) may rule out malignancy and avoid diagnostic surgery for benign nodules. This study assessed the performance of molecular diagnostics (MD) and 2-[18F]fluoro-2-deoxy-d-glucose ([18F]FDG)-positron emission tomography/computed tomography (PET/CT) in ITN, including their combined use, and explored whether molecular alterations drive the differences in [18F]FDG uptake among benign nodules. Methods: Adult, euthyroid patients with a Bethesda III or IV thyroid nodule were prospectively included in this multicenter study. They all underwent MD and an [18F]FDG-PET/CT scan of the neck. MD was performed using custom next-generation sequencing panels for somatic mutations, gene fusions, and copy number alterations and loss of heterozygosity. Sensitivity, specificity, negative and positive predictive value (NPV, PPV), and benign call rate (BCR) were assessed for MD and [18F]FDG-PET/CT separately and for a combined approach using both techniques. Results: In 115 of the 132 (87%) included patients, MD yielded a diagnostic result on cytology. Sensitivity, specificity, NPV, PPV, and BCR were 80%, 69%, 91%, 48%, and 57% for MD, and 93%, 41%, 95%, 36%, and 32% for [18F]FDG-PET/CT, respectively. When combined, sensitivity and specificity were 95% and 44% for a double-negative test (i.e., negative MD plus negative [18F]FDG-PET/CT) and 68% and 86% for a double-positive test, respectively. Concordance was 63% (82/130) between MD and [18F]FDG-PET/CT. There were more MD-positive nodules among the [18F]FDG-positive benign nodules (25/59, 42%, including 11 (44%) isolated RAS mutations) than among the [18F]FDG-negative benign nodules (7/30, 19%, p = 0.02). In oncocytic ITN, the BCR of [18F]FDG-PET/CT was mere 3% and MD was the superior technique. Conclusions: MD and [18F]FDG-PET/CT are both accurate rule-out tests when unresected nodules that remain unchanged on ultrasound follow-up are considered benign. It may vary worldwide which test is considered most suitable, depending on local availability of diagnostics, expertise, and cost-effectiveness considerations. Although complementary, the benefits of their combined use may be confined when therapeutic consequences are considered, and should therefore not routinely be recommended. In nononcocytic ITN, sequential testing may be considered in case of a first-step MD negative test to confirm that withholding diagnostic surgery is oncologically safe. In oncocytic ITN, after further validation studies, MD might be considered. Clinical Trial Registration: This trial is registered with ClinicalTrials.gov: NCT02208544 (August 5, 2014), https://clinicaltrials.gov/ct2/show/NCT02208544.

The PRolaCT studies - a study protocol for a combined randomised clinical trial and observational cohort study design in prolactinoma.

BACKGROUND: First-line treatment for prolactinomas is a medical treatment with dopamine agonists (DAs), which effectively control hyperprolactinaemia in most patients, although post-withdrawal remission rates are approximately 34%. Therefore, many patients require prolonged DA treatment, while side effects negatively impact health-related quality of life (HRQoL). Endoscopic transsphenoidal resection is reserved for patients with severe side effects, or with DA-resistant prolactinoma. Surgery has a good safety profile and high probability of remission and may thus deserve a more prominent place in prolactinoma treatment. The hypothesis for this study is that early or upfront surgical resection is superior to DA treatment both in terms of HRQoL and remission rate in patients with a non-invasive prolactinoma of limited size. METHODS: We present a combined randomised clinical trial and observational cohort study design, which comprises three unblinded randomised controlled trials (RCTs; PRolaCT-1, PRolaCT-2, PRolaCT-3), and an observational study arm (PRolaCT-O) that compare neurosurgical counselling, and potential subsequent endoscopic transsphenoidal adenoma resection, with current standard care. Patients with a non-invasive prolactinoma (< 25 mm) will be eligible for one of three RCTs based on the duration of pre-treatment with DAs: PRolaCT-1: newly diagnosed, treatment-naïve patients; PRolaCT-2: patients with limited duration of DA treatment (4-6 months); and PRolaCT-3: patients with persisting prolactinoma after DA treatment for > 2 years. PRolaCT-O will include patients who decline randomisation, due to e.g. a clear treatment preference. Primary outcomes are disease remission after 36 months and HRQoL after 12 months. DISCUSSION: Early or upfront surgical resection for patients with a limited-sized prolactinoma may be a reasonable alternative to the current standard practice of DA treatment, which we will investigate in three RCTs and an observational cohort study. Within the three RCTs, patients will be randomised between neurosurgical counselling and standard care. The observational study arm will recruit patients who refuse randomisation and have a pronounced treatment preference. PRolaCT will collect randomised and observational data, which may facilitate a more individually tailored practice of evidence-based medicine. TRIAL REGISTRATION: US National Library of Medicine registry (ClinicalTrials.gov) NCT04107480 . Registered on 27 September 2019, registered retrospectively (by 2 months).

Reactivation of Graves' orbitopathy after rehabilitative orbital decompression.

OBJECTIVE: To present and discuss three cases of apparent reactivation of Graves' orbitopathy (GO) after orbital decompression and to evaluate the incidence of this phenomenon. DESIGN: Observational case series and retrospective follow-up study. PARTICIPANTS: A few weeks after surgery 2 patients with GO (patients 1 and 2), treated at our institution with rehabilitative bony orbital decompression during the static phase of the disease showed clinical and radiologic evidence of reactivated orbitopathy. After this observation, a sample of 249 patients who had consecutively undergone the same treatment for the same reason before the second of the 2 observed patients was selected for this study. METHODS: The records of the selected patients were retrospectively reviewed searching for cases presenting with clinical and radiologic evidence of GO reactivated as a consequence of any type of bony orbital decompression. Patients treated with perioperative systemic glucocorticoids or who had concurrent periorbital diseases, injuries, or surgeries, or who had immunocompromised conditions or a follow-up of < or =2 months, were excluded. MAIN OUTCOME MEASURES: Incidence of reactivation. Clinical history, clinical and radiologic characteristics, treatment modalities, and time course of the reactivation in patients presenting with this phenomenon. RESULTS: Decompression surgery took place between 1994 and 2000. Eleven patients were excluded for having been treated with perioperative glucocorticoids. Only 1 patient (patient 3) presented with reactivation. The incidence of the phenomenon that we regard as reactivation of GO after rehabilitative bony orbital decompression was therefore 1.3% (3/239). In all 3 patients, the reactivation took place a few weeks after surgery, after an early normal convalescence period and could be controlled with systemic immunosuppression or orbital radiotherapy. None of the patients we report developed further episodes of reactivation during the follow-up period (mean, 7.5 years). CONCLUSIONS: Based on its clinical characteristics, we suggest naming our observation delayed decompression-related reactivation and we propose using its acronym DDRR when referring to it. Although DDRR appears to be a rare event, it is important for physicians and patients to be aware of its possible occurrence with rehabilitative decompression surgery.

Early versus late orbital decompression in Graves' orbitopathy: a retrospective study in 125 patients.

PURPOSE: To determine if early rehabilitative orbital decompression in Graves' orbitopathy (GO) leads to a more effective postoperative outcome than the same intervention performed at a later, more likely, fibrotic stage. DESIGN: Retrospective comparative case series. PARTICIPANTS: The medical records of all GO patients treated with a 3-wall orbital decompression at our institution between 1990 and 2000 were reviewed retrospectively. Only patients operated bilaterally for aesthetic rehabilitation, without preoperative diplopia, were included. They were divided into group 1 (duration of GO < 4 years) and group 2 (duration > or = 4 years). METHODS AND MAIN OUTCOME MEASURES: The 2 groups were compared for demographics, smoking habits, preoperative characteristics (immunosuppressive treatments, Hertel values, score in NOSPECS [no signs or symptoms, only signs, soft tissue involvement with symptoms and signs, proptosis, extraocular muscle involvement, corneal involvement, sight involvement] class 2, degree of extraocular muscle enlargement), and surgical outcome (mean reduction of exophthalmos, symmetry of exophthalmos reduction, reduction in upper and lower lid retraction, any persistent periorbital swelling requiring cosmetic eyelid surgery, postdecompression diplopia). RESULTS: The medical records of 125 of 376 patients were selected for this study. There were no differences between group 1 (n = 70) mean GO duration (2.2+/-0.8 years) and group 2 (n = 55) mean GO duration (9.0+/-5.4 years) with respect to demographics, smoking habits, and preoperative characteristics except for the degree of extraocular muscle enlargement, which was significantly greater in group 1 (P = 0.039). There was no difference in surgical outcomes between the 2 groups, with the exception of postdecompression diplopia, which was significantly more frequent in group 1 than in group 2 (29% vs. 13%, P = 0.033). CONCLUSIONS: In GO, early rehabilitative orbital decompression does not improve surgical outcome and is associated with a higher risk of postdecompression diplopia.

The removal of the deep lateral wall in orbital decompression: its contribution to exophthalmos reduction and influence on consecutive diplopia.

PURPOSE: To evaluate the contribution of maximal removal of the deep lateral wall of the orbit to exophthalmos reduction in Graves' orbitopathy and its influence on the onset of consecutive diplopia. DESIGN: Case-control study. METHODS: The medical records of two cohorts of patients affected by Graves' orbitopathy with exophthalmos > or = 23 mm, without preoperative diplopia, were retrieved at random from the pool of patients decompressed for rehabilitative reasons at our institution (01/1990 to 12/2003), and retrospectively reviewed. They had been treated with an extended (cases, group 1, n = 15) or conservative (controls, group 2, n = 15) 3-wall orbital decompression performed through a coronal approach. The deep portion of the lateral wall had been removed in the extended decompression group while preserved in the conservative decompression group. Demographics, preoperative characteristics, and surgical outcome were compared. The difference in mean exophthalmos reduction between groups 1 and 2 was considered to be the contribution of the deep lateral wall to reduction of exophthalmos. RESULTS: Groups 1 and 2 were drawn from a pool of 37 and 335 patients, respectively. Demographics and preoperative characteristics of the two groups were not significantly different. The mean contribution of the deep lateral wall to exophthalmos reduction was 2.3 mm. The onset of consecutive diplopia was not significantly different between the two groups (case n = 2/15, controls n = 5/15; P = .203). Diplopia resolved spontaneously in all the patients of group 1, while all the patients of group 2 required surgery. CONCLUSIONS: Removal of the deep lateral orbital wall as part of a coronal-approach, 3-wall decompression, enhances the degree of exophthalmos reduction without increasing the risk of consecutive diplopia.

[Hypoglycaemia with low insulin levels: what insulin tests do not measure]. / Hypoglykemieën met lage insulinewaarden: wat een insulinebepaling niet meet.

Insulin can be measured by immunochemical methods using polyclonal or monoclonal antibodies. Monoclonal antibodies are specific in the detection of pure human insulin, and may show little to no cross reactivity with pro-insulin or recombinant insulin. Polyclonal antibodies, however, do show such cross reactivity. Most medical laboratories use commercial (monoclonal) methods to measure insulin 75% of which are not capable of detecting pro-insulin or exogenous insulin. This pitfall in diagnostics may lead to prolonged uncertainty for both patient and physician, which we illustrate with two patients. The first patient was a 45-year-old woman with DM type 1 who for years suffered from hypoglycaemic attacks. Factitious hypoglycaemia went undiagnosed because our monoclonal assay did not detect the overdose insulin analogues. The second patient was a 47-year-old woman with recurrent hypoglycaemic attacks. An insulinoma, which produced pro-insulin, was only detected after using polyclonal insulin and specific pro-insulin assays.

[Agranulocytosis/granulocytopenia after long-term use of thiamazole]. / Agranulocytose na langdurig gebruik van thiamazol.

Agranulocytosis/granulocytopenia is a rare side effect of thyreostatics. Earlier publications state that for thiamazole this side effect occurs during the first few months of treatment. In two patients this thiamazole-induced agranulocytosis/granulocytopenia only occurred after years of treatment. A 53-year-old man presented with fever after a visit to Suriname. He had used thiamazole for 12 years for Graves' hyperthyroidism. The second patient, a 31-year-old woman, presented at the emergency department with fever and sore throat after 13 years of intermittent treatment with thiamazole. Both patients had an agranulocytosis/granulocytopenia and leukopenia. This was thought to be a side effect of thiamazole and blood values normalised after cessation of therapy. Both patients were treated empirically with broad-spectrum antibiotics during the agranylocytic period. They then received radioactive sodium iodide. To our knowledge this case report is the first to describe agranulocytosis/granulocytopenia following long-term treatment with thiamazole.

Orbital irradiation for Graves' ophthalmopathy: Is it safe? A long-term follow-up study.

PURPOSE: We evaluated the frequency of long-term complications of orbital irradiation (radiation-induced tumors, cataract, and retinopathy) in comparison with glucocorticoids. DESIGN: We conducted a follow-up study in a cohort of 245 Graves' ophthalmopathy patients who had been treated with retrobulbar irradiation (20 Gy in 2 weeks) and/or oral glucocorticoids between 1982 and 1993 in our institution. Irradiated patients were compared with nonirradiated patients. METHODS: Data on mortality and cause of death were obtained. Living patients were invited to participate in a follow-up study. Possible retinopathy was assessed in a masked fashion and defined as the presence of > or =1 hemorrhages and/or microaneurysms on red-free retina photographs. If >5 lesions were present, patients were categorized as suffering from definite retinopathy. Cataract was assessed using the Lens Opacity Classification System II score. MAIN OUTCOME MEASURES: Mortality, prevalence of retinopathy, prevalence of cataract, and type of cataract. RESULTS: Thirty-seven of the 245 patients had died, none of them from an intracranial tumor. Mortality was similar in the irradiated (27/159 [17%]) and nonirradiated patients (10/86 [12%]; P = 0.264). One hundred fifty-seven of the 208 living patients (75%) consented to participate in a follow-up ophthalmologic investigation; the mean follow-up time (+/- standard deviation) was 11+/-3 years. Possible retinopathy was present in 15% of patients, 22 of the irradiated and 1 of the nonirradiated patients (P = 0.002). In 5 patients (all had been irradiated), definite retinopathy (i.e., >5 retinal lesions) was present. Of these, 3 had diabetes mellitus, and 1 had hypertension. Diabetes was associated with both possible (P = 0.029) and definite (P = 0.005) retinopathy, with a relative risk of 21 (95% confidence interval, 3-179). The prevalence and severity of cataract were similar in the radiotherapy group (29%) and the glucocorticoid group (34%); it should be noted that 88 of 104 of the irradiated patients were also treated with oral glucocorticoids. CONCLUSION: The data suggest that orbital irradiation for Graves' ophthalmopathy is a safe treatment modality, except possibly for diabetic patients.