Neurological adverse events of mitotane in adrenocortical carcinoma: results of a pilot study.

Introduction: Mitotane, the only drug approved by the Food and Drug Administration (FDA) for the treatment of adrenocortical carcinoma, is associated with several side effects including neurotoxicity. The aim of our study is to investigate the relationship between mitotane plasma levels and neurological toxicity. Methods: We have considered five patients affected by adrenocortical carcinoma treated with mitotane. The neurological assessment included a neurological examination, an electroencephalogram, event-related potentials (P300), and a neuropsychological assessment. All of the patients were first considered at the onset of symptoms of neurotoxicity or when mitotanemia levels were above 18 mg/L, for the second time at mitotanemia normalization and subsequently at its further increase, or in case of persistent neurological abnormalities, some months after normalization. Results: At the first neurotoxicity, four patients showed impaired neurological examination, electroencephalogram, and P300; three patients had impaired neuropsychological assessment; one patient, only P300. At mitotanemia normalization, the neurological examination became normal in all patients and electroencephalogram normalized in one patient, improved in another one, continuing to be altered in the other three. P300 latency and neuropsychological assessment normalized in two patients and persisted altered in the patient experiencing long-term mitotane toxicity. At the third evaluation, in the patient with prolonged mitotane toxicity, the normal mitotanemia in the previous 9 months restored P300 and improved the electroencephalogram but not the neuropsychological assessment. In the two patients experiencing a further rise of mitotanemia, neurological examination was normal but P300 and electroencephalogram were altered. Conclusion: The results of our study highlighted the presence of neurophysiological and neuropsychological abnormalities associated with mitotane values above 18 mg/L.

New Insights in PRRT: Lessons From 2021.

Peptide receptor radionuclide therapy (PRRT) using radiolabeled somatostatin analogs has been used for over two decades for the treatment of well-differentiated neuroendocrine tumors (NETs), and the publication of the NETTER-1 trials has further strengthened its clinical use. However, many aspects of this treatment are still under discussion. The purpose of this review is to collect and discuss the new available evidence, published in 2021, on the use of 177Lu-Oxodotreotide (DOTATATE) or 90Y-Edotreotide (DOTATOC) in adult patients with NETs focusing on the following hot topics: 1) PRRT use in new clinical settings, broaden its indications; 2) the short- and long-term safety; and 3) the identification of prognostic and predictive factors. The review suggests a possible future increase of PRRT applications, using it in other NETs, as a neoadjuvant treatment, or for rechallenge. Regarding safety, available studies, even those with long follow-up, supported the low rates of adverse events, even though 1.8% of treated patients developed a second malignancy. Finally, there is a lack of prognostic and predictive factors for PRRT, with the exception of the crucial role of nuclear imaging for both patient selection and treatment response estimation.

Metabolic and Endocrine Toxicities of Mitotane: A Systematic Review.

Despite the pivotal role of mitotane in adrenocortical carcinoma (ACC) management, data on the endocrine toxicities of this treatment are lacking. The aim of this systematic review is to collect the available evidence on the side effects of mitotane on the endocrine and metabolic systems in both children and adults affected by adrenal carcinoma. Sixteen articles on 493 patients were included. Among the adrenal insufficiency, which is an expected side effect of mitotane, 24.5% of patients increased glucocorticoid replacement therapy. Mineralocorticoid insufficiency usually occurred late in treatment in 36.8% of patients. Thyroid dysfunction is characterized by a decrease in FT4, which occurs within 3-6 months of treatment in 45.4% of patients, while TSH seems to not be a reliable marker. Dyslipidemia is characterized by an increase in both LDL-c and HDL-c (54.2%). Few studies have found evidence of hypertriglyceridemia. In males, gynecomastia and hypogonadism can occur after 3-6 months of treatment (38.4% and 35.6%, respectively), while in pre-menopausal women, mitotane can cause ovarian cysts and, less frequently, menstrual disorders. Most of these side effects appear to be reversible after mitotane discontinuation. We finally suggest an algorithm that could guide metabolic and endocrine safety assessments in patients treated with mitotane for ACC.

Case Report: Ipilimumab-Induced Panhypophysitis: An Infrequent Occurrence and Literature Review.

BACKGROUND: Immune checkpoint inhibitors (ICIs), by unleashing the anticancer response of the immune system, can improve survival of patients affected by several malignancies, but may trigger a broad spectrum of adverse events, including autoimmune hypophysitis. ICI-related hypophysitis mainly manifests with anterior hypopituitarism, while the simultaneous involvement of both anterior and posterior pituitary (i.e., panhypophysitis) has rarely been described. CASE PRESENTATION: In June 2015, a 64-year-old man affected by liver metastases of a uveal melanoma was referred to us due to polyuria and polydipsia. Two months prior, he had started ipilimumab therapy (3 mg/kg iv every 21 days). The treatment was well-tolerated (only mild asthenia and diarrhea were reported). A few days before the fourth cycle, the patient complained of intense headaches, profound fatigue, nocturia, polyuria (up to 10 L urine/daily), and polydipsia. Laboratory tests were consistent with adrenal insufficiency, hypothyroidism, and transient central diabetes insipidus. The pituitary MRI showed an enlarged gland with microinfarcts, while the hypophyseal stalk was normal, and the neurohypophyseal 'bright signal' in T1 sequences was not detected. The treatment included dexamethasone (then cortisone acetate at replacement dose), desmopressin, and levothyroxine. Within the next five days, the symptoms resolved, and blood pressure, electrolytes, glucose, and urinalysis were stable within the normal ranges; desmopressin was discontinued while cortisone acetate and levothyroxine were maintained. The fourth ipilimumab dose was entirely administered in the absence of further side effects. CONCLUSION: As ICIs are increasingly used as anticancer agents, the damage to anterior and/or posterior pituitary can be progressively encountered by oncologists and endocrinologists in their clinical practice. Patients on ICIs and their caregivers should be informed about that risk and be empowered to alert the referring specialists early, at the onset of panhypopituitarism symptoms, including polyuria/polydipsia.

A Rare Case of Pituitary Melanoma Metastasis: A Dramatic and Prolonged Response to Dabrafenib-Trametinib Therapy.

Introduction: Pituitary metastases (PM) are rare events and to date only very few cases of melanoma PM have been described in literature up to now. Case Presentation: We describe the clinical history of a 33-year-old male patient who underwent surgical excision of an inter-scapular melanoma in 2008. The subsequent follow-up was negative for ~10 years. In September 2018, due to the onset of a severe headache, the patient underwent a brain magnetic resonance imaging, which showed an expansive mass in the saddle and suprasellar region with a maximum diameter of 17 mm. Pituitary function tests and visual field were normal. Worsening of the headache and the appearance of a left eye ptosis led the patient to surgical removal of the lesion in October 2018. The histological examination unexpectedly showed metastasis of the melanoma. Post-operative hormonal assessment showed secondary hypothyroidism and hypoadrenalism, which were both promptly treated, and a mild hypogonadism. Three months after surgery, a sellar MRI showed a persistent, increased pituitary mass (3 cm of diameter); fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) detected an increased radiopharmaceutical uptake in the sellar region. Due to the persistence of the disease and the evidence of a BRAF V600E mutation, in February 2019, the patient underwent a combined treatment with dabrafenib (a BRAF inhibitor) and trametinib (mitogen-activated extracellular signal-regulate kinase inhibitor). Sellar MRI performed 6 months later showed no evidence of mass in the sellar region. The patient was in a good clinical condition and did not complain of headaches or other symptoms; there were no significant side-effects from the anticancer therapy. After 13 months of treatment, the patient showed no recurrence of the disease on morphological imaging. Anticancer therapy was confirmed, replacement therapies with hydrocortisone and levothyroxine continued and the pituitary-gonadal axis was restored. Conclusion: This is a very interesting case, both for the rarity of the pituitary melanoma metastasis and for the singular therapeutic course carried out by the patient. This is the first case of a pituitary melanoma metastasis with BRAF mutation, successfully treated with the combination of dabrafenib and trametinib after incomplete surgical removal.

Grey-Scale Analysis Improves the Ultrasonographic Evaluation of Thyroid Nodules.

Ultrasonography is the main imaging method for the workup of thyroid nodules. However, interobserver agreement reported for echogenicity and echotexture is quite low. The aim of this study was to perform quantitative measurements of the degree of echogenicity and heterogeneity of thyroid nodules, to develop an objective and reproducible method to stratify these features to predict malignancy.A retrospective study of patients undergoing ultrasonography-guided fine-needle aspiration was performed in an University hospital thyroid center. From January 2010 to October 2012, 839 consecutive patients (908 nodules) underwent US-guided fine-needle aspiration. In a single ultrasound image, 3 regions of interest (ROIs) were drawn: the first including the nodule; the second including a portion of the adjacent thyroid parenchyma; the third, the strap muscle. Histogram analysis was performed, expressing the median, mean, and SD of the gray levels of the pixels comprising each region. Echogenicity was expressed as a ratio: the nodule/parenchyma, the nodule/muscle, and parenchyma/muscle median gray ratios were calculated. The heterogeneity index (HI) was calculated as the coefficient of variation of gray histogram for each of the 3 ROIs. Cytology and histology reports were recorded.Nodule/parenchyma median gray ratio was significantly lower (more hypoechoic) in nodules found to be malignant (0.45 vs 0.61; P = 0.002) and can be used as a continuous measure of hypoechogenicity (odds ratio [OR] 0.12; 95% confidence interval [CI] 0.03-0.49). Using a cutoff derived from ROC curve analysis (<0.46), it showed a substantial inter-rater agreement (k = 0.74), sensitivity of 56.7% (95% CI 37.4-74.5%), specificity of 72.0% (67.8-75.9%), positive likelihood ratio (LR) of 2.023 (1.434-2.852), and negative LR of 0.602 (0.398-0.910) in predicting malignancy (diagnostic odds ratio 3.36; 1.59-7.10). Parenchymal HI was associated with anti-thyroperoxidase positivity (OR 19.69; 3.69-105.23). The nodule HI was significantly higher in malignant nodules (0.73 vs 0.63; P = 0.03) and, if above the 0.60 cutoff, showed sensitivity of 76.7% (57.7-90.1%), specificity of 46.8% (42.3-51.4%), positive LR of 1.442 (1.164-1.786), and negative LR of 0.498 (0.259-0.960).Evaluation of nodule echogenicity and echotexture according to a numerical estimate (nodule/parenchyma median gray ratio and nodule HI) allows for an objective stratification of nodule echogenicity and internal structure.

Association of thyroid diseases with primary extra-thyroidal malignancies in women: results of a cross-sectional study of 6,386 patients.

We here analyzed the prevalence of extra-thyroidal malignancies (EM) in 6,386 female patients affected by different thyroid disease (TD). At first, an age-matched analysis of EM in all patients was performed. We then evaluated EM prevalence in four TD diagnostic categories: non-nodular TD (n = 2,159); solitary nodule (n = 905); multinodular TD (n = 2,871); differentiated thyroid cancers (n = 451). Finally, patients were grouped based on the absence (n = 3,820) or presence of anti-thyroglobulin (TgAb) and/or anti-thyroperoxidase (TPOAb) (n = 2,369), or anti-Thyroid Stmulating Hormone (TSH) receptor autoantibodies (n = 197). A total of 673 EM were recorded. EM prevalence in TD patients was higher compared to the general population (Odds Ratio, OR 3.21) and the most frequent EM was breast cancer (OR 3.94), followed by colorectal (OR 2.18), melanoma (OR 6.71), hematological (OR 8.57), uterus (OR 2.52), kidney (OR 3.40) and ovary (OR 2.62) neoplasms. Age-matched analysis demonstrated that the risk of EM was maximal at age 0-44 yr (OR 11.28), remaining lower, but significantly higher that in the general population, in the 45-59 and 60-74 year age range. Breast and hematological malignancies showed an increased OR in all TD, while other cancers associated with specific TD. An increased OR for melanoma, breast and hematological malignancies was observed in both TPOAb and/or TgAb autoantibody negative and positive patients, while colorectal, uterus, kidney and ovary cancers showed an increased OR only in thyroid autoantibody negative patients. In conclusions, women affected by both benign and malignant TD, especially at a younger age and in absence of thyroid autoimmunity, have an increased risk of developing primary EM, thus requiring a careful follow-up and surveillance.

Thyroid autoimmunity and risk of malignancy in thyroid nodules submitted to fine-needle aspiration cytology.

BACKGROUND: Whether the risk of cancer is increased in patients with chronic autoimmune thyroiditis is a controversial issue. METHODS: Between May 2005 and October 2012, 3777 fine-needle aspiration cytologies (FNACs) were performed on 2562 patients. Serum FT4, thyroid-stimulating hormone (TSH), anti-thyroglobulin antibody (TgAb), and anti-thyroperoxidase antibody (TPOAb) were determined. RESULTS: Patients with suspicious cytology were younger and presented smaller maximum lesion diameter. In patients with TgAb positivity, suspicious cytology was detected more frequently (9.4%) than patients without TgAb (5.7%; p = .04). No significant difference was recorded between benign and suspicious cytology in the positive TPOAb rate. Risk factors for suspicious cytology were younger age (odds ratio [OR], 0.94), smaller maximum diameter (0.95), single lesion (1.85), microcalcifications (3.45), and TgAb (1.74). Mixed solid/fluid content resulted as being a protective factor (0.34). According to multivariate logistic regression analysis, age, mixed content, and microcalcification confirmed significance. CONCLUSION: Thyroid nodule malignancy in patients with Hashimoto thyroiditis is not more frequent than in patients without thyroiditis.

Prevalence of breast cancer in thyroid diseases: results of a cross-sectional study of 3,921 patients.

Results from national cancer registries reveal an association of thyroid cancers with extra-thyroidal malignancies. In this study, we evaluated the prevalence of breast cancer (BC) in women affected by both benign and malignant thyroid diseases (TD) in comparison to the general population. To this end, 3,921 female patients from central and southern regions of Italy were evaluated. Age-matched analysis of the prevalence of BC was carried out after dividing the patients into three diagnostic categories: (1) 1,149 patients with non-nodular TD; (2) 2350 patients with nodular TD; (3) 422 patients affected by differentiated thyroid cancers. Furthermore, the patients were grouped according to the absence (2,344 patients) or presence (1,453 patients) of anti-thyroglobulin (TgAb) and/or anti-thyroperoxidase (TPOAb) or anti-TSH receptor auto-antibodies (124 patients). BC prevalence in TD patients as a whole was significantly higher compared to the general population, with an odds ratio (OR) of 3.33. Age-matched analysis showed that the risk of a BC in TD patients was higher in younger patients (age 0-44 years), with an OR of 15.24, which decreased with increasing age. Patients without thyroid auto-antibodies showed a higher OR for BC (p = 0.0005) than TD patients with TgAb and/or TPOAb. The results demonstrate that women affected by either benign or malignant thyroid disease have a significantly greater risk of BC, which is higher at a younger age. Furthermore, thyroid auto-antibodies appear to be protective against BC. These findings may contribute to the identification of common genetic and environmental factors underlying this disease association.

Intrinsic factors affecting adequacy of thyroid nodule fine-needle aspiration cytology.

OBJECTIVE: To evaluate intrinsic nodule features predictive of an inadequate report in fine-needle aspiration cytology (FNAC). DESIGN: Single-centre cross-sectional study. METHODS: Between May 2005 and April 2011, 3279 ultrasonography-assisted FNACs were carried out and features of nodules recorded prospectively. Univariate logistic regression analyses were performed to estimate the association between nondiagnostic cytology and variables such as age, gender, single nodule, maximum nodule diameter and estimated volume. RESULTS: Inadequate or nondiagnostic samples were reported in 1195 FNACs. All diameters were found to be predictors of nondiagnostic cytology; estimated nodule volume, on the other hand, was not. Nodules with a diameter <10 mm were more frequently nondiagnostic (OR 1.65, 95% CI 1.40-1.94, P < 0.001). Neither micro- nor macrocalcification increased the risk of inadequacy. On the contrary, mixed lesions were more frequently diagnostic (OR 0.68, 95% CI 0.85-0.80, P < 0.001). Solid nodule aspiration was performed more easily on isoechogenic nodules (OR 0.64, 95% CI 0.54-0.77, P < 0.001); the same procedure was more cumbersome on hypoechogenic lesions (OR 1.87, 95% CI 1.62-2.16, P < 0.001). Increased vascularization did not cause a significant increase in the nondiagnostic results. Blurred margins increased the inadequacy rate (OR 1.45, 95% CI 1.24-1.69, P < 0.001), while presence of a hypoechogenic halo decreased it (OR 0.67, 95% CI 0.54-0.82, P < 0.001). CONCLUSIONS: Some ultrasonographic features suggestive of malignancy may be predictive of inadequate cytology. Patients must be notified that the FNA report may be nondiagnostic and that this represents a limitation of the technique related to the structure of lesions.

Interpretation of serum calcitonin in patients with chronic autoimmune thyroiditis.

Calcitonin (CT) is an important clinical marker for the diagnosis and follow-up of medullary thyroid carcinoma, although it is not absolutely specific. Some authors have reported C-cell hyperplasia in a number of thyroid specimens affected by Hashimoto's thyroiditis. The association between thyroiditis and hypercalcitoninemia is still controversial because some authors have reported low CT levels. The aim of this study is to evaluate the basal CT values in patients with and without thyroid autoimmunity. From May 2005 to February 2010, 1073 patients underwent ultrasonography-guided fine-needle aspiration cytology at the Thyroid Center of Sapienza University of Rome, with evaluation of basal serum FT4, FT3, TSH, and antithyroid peroxidase (anti-TPO) antibodies as well as CT levels. Forty-one patients presented a basal CT level above the reference upper limit. The mean serum CT was significantly lower in women than in men (4.28 ± 6.63 vs 7.50 ± 25.50  pg/ml; P<0.01). Basal serum CT was not significantly higher in patients showing anti-TPO Ab positivity (4.71 ± 6.46 vs 4.84 ± 13.11  pg/ml; P>0.05). Importantly, the rate of 'suspicious' CT values (above the 10  pg/ml cutoff) was not significantly different between patients with or without thyroid autoimmunity (3.9 vs 3.0%). Patients with hypercalcitoninemia suffering from chronic autoimmune thyroiditis should undergo the same clinical evaluation procedure as patients do without thyroid autoimmunity.