Flavia Di Bari

Selective use of vandetanib in the treatment of thyroid cancer

Vandetanib is a once-daily orally available tyrosine kinase inhibitor that works by blocking RET (REarranged during Transfection), vascular endothelial growth factor receptor (VEGFR-2, VEGFR-3), and epidermal growth factor receptor and to a lesser extent VEGFR-1, which are important targets in thyroid cancer (TC). It is emerging as a potentially effective option in the treatment of advanced medullary thyroid cancer (MTC) and in dedifferentiated papillary thyroid cancer not responsive to radioiodine. The most important effect of vandetanib in aggressive MTC is a prolongation of progression-free survival and a stabilization of the disease. Significant side effects have been observed with the vandetanib therapy (as fatigue, hypertension, QTc prolongation, cutaneous rash, hand-and-foot syndrome, diarrhea, etc), and severe side effects can require the suspension of the drug. Several studies are currently under way to evaluate the long-term efficacy and tolerability of vandetanib in MTC and in dedifferentiated papillary TC. The efficacy of vandetanib in patients with MTC in long-term treatments could be overcome by the resistance to the drug. However, the effectiveness of the treatment could be ameliorated by the molecular characterization of the tumor and by the possibility to test the sensitivity of primary TC cells from each subject to different tyrosine kinase inhibitor. Association studies are evaluating the effect of the association of vandetanib with other antineoplastic agents (such as irinotecan, bortezomib, etc). Further research is needed to determine the ideal therapy to obtain the best response in terms of survival and quality of life.

Oral liquid levothyroxine solves the problem of tablet levothyroxine malabsorption due to concomitant intake of multiple drugs

ABSTRACT Background: Unlike the tablet (TAB) formulation, liquid L-T4 (LIQ) is directly absorbed in the intestine. The aim of this study was to assess whether LIQ was superior to TAB, such that it would overcome the interference induced by co-ingestion of multiple interfering drugs (ID). Methods: In this prospective cohort study, we recruited 11 patients with apparent reduced TAB absorption due to ≥ 2 ID, and switched them to LIQ while maintaining the daily dose and the co-ingestion of the ID. Serum TSH was assayed at least twice every eight weeks. Results: Serum TSH was significantly lower on LIQ compared with TAB (P < 0.0001), in patients who took L-T4 for either replacement (P = 0.002) or TSH-suppression (P < 0.0001). This difference was evident already at the first measurement post-switch (P = 0.008 or P = 0.03). Regardless of the purpose of L-T4 therapy, patients who took two ID had lower serum TSH on LIQ compared with patients who took three ID (P = 0.0006). Interestingly, 2/3 patients who failed to reach target TSH levels while on LIQ took three ID. Conclusions: LIQ overcomes the concurrent interference exerted by the ingestion of multiple ID. In such cases, switching from TAB to LIQ permits patients to reach target TSH within 8 weeks.

Undertreated hypothyroidism due to calcium or iron supplementation corrected by oral liquid levothyroxine

PurposeThe aim of this study was to assess whether oral liquid levothyroxine would correct tablet levothyroxine malabsorption induced by calcium or iron, two sequestrants of levothyroxine.MethodsNineteen adult hypothyroid patients with tablet levothyroxine malabsorption caused by calcium and/or iron supplements were switched from tablet to liquid levothyroxine at the same dose. Primary outcomes were: (1) significantly lower mean serum thyroid-stimulating hormone with the liquid compared with the tablet formulation, and (2) significantly greater rate of serum thyroid-stimulating hormone less than or equal to 4.12 or 2.5 mU/L.The mean follow-up was 25.2 ± 16.5 weeks.ResultsTSH was lower with liquid levothyroxine compared with tablet levothyroxine (7.48 ± 5.8 vs. 1.95 ± 1.3 mU/L, P < 0.001), both in the calcium group (8.74 ± 7.2 vs. 2.15 ± 1.4, P < 0.001) and iron group (8.74 ± 7.2 vs. 1.68 ± 0.9, P < 0.001). Thyroid-stimulating hormone levels ≤4.12 mU/L in all patients, calcium group and iron group were more frequent post-switch (95, 87 and 100%) compared to pre-switch (26, 22 and 29%, P < 0.001), and so were thyroid-stimulating hormone levels ≤2.50 mU/L (66, 59 and 76% compared to 5, 9 and 0%, P < 0.001). The pattern held comparing the first liquid levothyroxine thyroid-stimulating hormone levels and the first tablet levothyroxine thyroid-stimulating hormone levels or the corresponding rates of thyroid-stimulating hormone levels below the target.ConclusionsLiquid levothyroxine is resistant to the sequestration by calcium or iron. The high rate of thyroid-stimulating hormone normalization already at the first check (6–8 weeks) should avoid frequent adjustments in levothyroxine doses and assays of thyroid-stimulating hormone, with consequent financial savings.

The micropapillary/hobnail variant of papillary thyroid carcinoma: A review of series described in the literature compared to a series from one southern Italy pathology institution

Papillary thyroid carcinoma (PTC) has a good prognosis with a 10-yr survival greater than 90%. Recently, a micro-papillary pattern with hobnail appearance (MPHC) in PTC has been indicated as associated with poor prognosis, but this suggestion is based only on a few cases from geographical areas different from ours. Two-hundred ninety-nine consecutive PTC cases were collected between the years of 1992 and 2014 at our institution. The corresponding histologic sections (at least 6 for each case) were stained with hematoxylin and eosin and reviewed independently by two pathologists to reach a consensus on the identification and quantification of the MPHC. As done in other cohorts, parallel serial sections were stained with antisera for thyroglobulin, epithelial membrane antigen, thyroid-transcription-factor-1 and Ki 67. BRAF gene mutation at codon 600 and RET/PTC1 gene rearrangements were searched. A comparative statistical analysis was done between the present series and previously published series. Of the 295 PTC, 124 (42.5%) were follicular, 104 (35%) classic, 34 (11.5%) sclerosing, 15 (5%) tall cells, 10 (3.4%) Warthin-like, and 8 (2.7%) MPHC. Four MHPC cases (50%) harbored the BRAF V600E variant, while one was positive for RET/PTC1 rearrangement. Our rate of MPHC-PTC (2.7%) is 2X to 8X greater than those reported previously for cohorts from North America + North Italy, Korea and Mexico. MPHC prognosis appears to be better compared to other cohorts, probably due to not only to the lower rate of the vascular invasion, but also to the smaller size of the MPHC-PTC nodule.

Do Not Forget Nephrotic Syndrome as a Cause of Increased Requirement of Levothyroxine Replacement Therapy.

Nephrotic syndrome increases L-thyroxine requirements because of urinary loss of free and protein-bound thyroid hormones. We report 2 hypothyroid patients referred to us because of high serum TSH, even though the L-thyroxine daily dose was maintained at appropriate levels or was increased. The cause of nephrotic syndrome was multiple myeloma in one patient and diabetic glomerulosclerosis in the other patient. As part of the periodic controls for diabetes, urinalysis was requested only in the second patient so that proteinuria could be detected. However, as in the first patient, facial puffiness and body weight increase were initially attributed to hypothyroidism, which was poorly compensated by L-thyroxine therapy. In the first patient, the pitting nature of the pedal edema was missed at the initial examination. An endocrinologist consulted over the phone by the practitioner hypothesized some causes of intestinal malabsorption of L-thyroxine. This diagnosis would have been accepted had the patient continued taking a known sequestrant of L-thyroxine, i.e. calcium carbonate. The diagnostic workup of patients with increasing requirements of L-thyroxine replacement therapy should not be concentrated on the digestive system alone. Careful history taking and physical examination need to be thorough. Endocrinologists should not forget nephrotic syndrome that, in turn, can be secondary to serious diseases.

One-third of an Archivial Series of Papillary Thyroid Cancer (Years 2007–2015) Has Coexistent Chronic Lymphocytic Thyroiditis, Which Is Associated with a More Favorable Tumor-Node-Metastasis Staging

The significance and impact of the coexistence of chronic lymphocytic thyroiditis (CLT) with thyroid cancer is still debated. To verify the influence of CLT on papillary thyroid cancer (PTC), we retrospectively collected 505 PTC cases and analyzed age at diagnosis, sex, size, lymph node status, and staging. We found that CLT was present in 168 PTC (33.3%). Compared with the 337 patients without CLT (non-CLT), CLT patients were younger (44.42 ± 13.72 vs. 47.21 ± 13.76 years, P = 0.03), had smaller tumors (9.39 ± 6.10 vs. 12 ± 9.71 mm, P = 0.002), and lower rate of lymph node metastases (12.5 vs. 21.96%, P = 0.01, OR = 0.508). Tumor-node-metastasis (TNM) staging (T1a through T4) was more favorable for the CLT group compared to the non-CLT group (for instance, T1a = 65.5 vs. 49.8%, T3 = 4.8 vs. 23.4%). This study shows that one in three patients with PTC harbors CLT, which is associated with a more favorable TNM staging, consistently with a favorable outlook of PTC.

Serum Thyrotropin and Phase of the Menstrual Cycle

About one-fifth of patients treated with levothyroxine have serum thyrotropin (TSH) above target concentrations but, in approximately 15% of them, the cause of this TSH insufficient normalization remains unknown. We report the cases of two regularly menstruating women with known thyroid disease who had TSH levels consistently >3 mU/L (and sometimes above target levels) during mid-cycle, but consistently lower serum levels during the follicular and luteal phases of menstrual cycle. A major TSH release by the thyrotrophs in response to high circulating levels of estradiol (E2) at mid-cycle may increase levels of TSH compared to other phases of the cycle. The increased TSH can be misinterpreted as refractory hypothyroidism if the woman is under L-T4 replacement therapy or as subclinical hypothyroidism if the woman is not. Our findings might have important implications for diagnosis and management of thyroid disease, suggesting to request serum TSH measurements outside of the periovulatory days.

Thyroid Autoimmunity and Lichen

Lichen planus (LP) and lichen sclerosus (LS) are cutaneous-mucous diseases with uncertain epidemiology. Current data, which are likely to be underestimated, suggest a prevalence in the general population of 0.1–4% for cutaneous LP, 1.27–2.0% for oral LP, and 0.1–3.3% for LS. While etiology of lichen is still unknown, clinical and histological evidence show an (auto)immune pathogenesis. Association of lichen with autoimmune thyroid disease (AITD) has been investigated in few studies. This association appears better defined in the case of LS, while is more controversial for LP. In both situations, the frequency of the association is higher in females. We review the available literature on the correlation between the different types of lichen and AITD, and the literature on the genetic risk factors which are shared by both conditions. Such data suggest that a common pathogenic mechanism could be the cause for co-occurrence of lichen and AITD, at least in some patients. Additionally, analyzing literature data and in continuity with our previous work on other autoimmune diseases, we suggest that molecular mimicry could trigger both diseases, and thus explain their co-occurrence.

A patient-specific treatment model for Graves’ hyperthyroidism

BackgroundGraves’ is disease an autoimmune disorder of the thyroid gland causedby circulating anti-thyroid receptor antibodies (TRAb) in the serum. TRAb mimics the action of thyroid stimulating hormone (TSH) and stimulates the thyroid hormone receptor (TSHR), which results in hyperthyroidism (overactive thyroid gland) and goiter. Methimazole (MMI) is used for hyperthyroidism treatment for patients with Graves’ disease.MethodsWe have developed a model using a system of ordinary differential equations for hyperthyroidism treatment with MMI. The model has four state variables, namely concentration of MMI (in mg/L), concentration of free thyroxine - FT4 (in pg/mL), and concentration of TRAb (in U/mL) and the functional size of the thyroid gland (in mL) with thirteen parameters. With a treatment parameter, we simulate the time-course of patients’ progression from hyperthyroidism to euthyroidism (normal condition). We validated the model predictions with data from four patients.ResultsWhen there is no MMI treatment, there is a unique asymptotically stable hyperthyroid state. After the initiation of MMI treatment, the hyperthyroid state moves towards subclinical hyperthyroidism and then euthyroidism.ConclusionWe can use the model to describe or test and predict patient treatment schedules. More specifically, we can fit the model to individual patients’ data including loading and maintenance doses and describe the mechanism, hyperthyroidism→euthyroidism. The model can be used to predict when to discontinue the treatment based on FT4 levels within the physiological range, which in turn help maintain the remittance of euthyroidism and avoid relapses of hyperthyroidism. Basically, the model can guide with decision-making on oral intake of MMI based on FT4 levels.

Circulating thyrotropin is upregulated by estradiol

After encountering two women with serum thyrotropin (TSH) levels greater in periovulatory phase than in other days of the menstrual cycle, we hypothesized that TSH levels could be sensitive to changes in circulating estrogens in women. The objective of this study was to evaluate whether serum TSH increases after an induced acute increase of serum estradiol, and compare serum TSH increase with that of prolactin (PRL) which is a classic estradiol-upregulated pituitary hormone. In this retrospective study, we resorted to stored frozen sera from 55 women who had undergone the GnRH agonist (buserelin)-acute stimulation test of ovarian steroidogenesis. This test, that is preceded by dexamethasone administration to suppress adrenal steroidogenesis, had been performed to show an increased buserelin-stimulated response of 17-hydroxyprogesterone, a response that is frequent in polycystic ovary syndrome. Fifty-five women had enough serum volume at pertinent times (first observation early in the follicular phase and all times of the test) to permit assay of serum estradiol, TSH and PRL. Before dexamethasone administration, estradiol averaged 26.4 ± 15.5 pg/ml (reference range 23–139, follicular phase), TSH 1.78 ± 0.86 mU/L (reference range 0.3–4.2) and PRL 409.4 ± 356 mU/L (reference range 70.8–556) (mean ± SD). Serum estradiol, TSH and PRL averaged 47.2 ± 27 pg/ml, 0.77 ± 0.48 mU/L and 246.4 ± 206.8 mU/L just prior to the buserelin injection, but they peaked at 253.4 ± 113.5 pg/ml (nv 83–495, midcycle), 3.30 ± 1.65 mU/L and 540.3 ± 695.2 mU/L after injection. The responses to buserelin of estradiol, TSH and PRL were of wide magnitude. There was a significant correlation between TSH peak and serum estradiol peak, betweeen AUC0-24 h-TSH and AUC0-24 h-estradiol, or between PRL peak and estradiol peak and AUC0-24 h -PRL and AUC0-24 h-estradiol in only a subgroup of women. Therefore, women with estradiol-dependent increase in serum TSH do exist. Reference bands of serum TSH dependent on the phases of the menstrual cycle should be available.