Kinase Inhibitors in the Treatment of Thyroid Cancer: Institutional Experience.

Although most patients with thyroid cancer have a favorable clinical course, some patients develop a more aggressive type of cancer and exhibit more rapid disease progression with worse prognosis. Those patients usually exhibit mutations of proteins such as tyrosine kinase enzymes that play a significant role in regulation of tumor proliferation and spreading. Development of targeted therapies is based on the inhibition of mutated kinases which are involved in the MAPK signaling pathway. The aim of this study was to present the initial results of clinical experience with kinase inhibitors in patients with metastatic differentiated thyroid cancer (DTC), poorly differentiated thyroid cancer (PDTC), and medullary thyroid cancer (MTC) who exhibited rapid disease progression. A total of 17 adult patients (11 women, mean age 53.3 years) managed for progressive, metastatic disease were included in the study. Twelve patients with DTC and PDTC were previously tested for BRAF mutations, of whom nine that had tumor tissue negative for the BRAF V600E mutation received sorafenib, while three patients with tumors harboring the BRAF V600E mutation were treated with vemurafenib. Patients with MTC were treated with sunitinib, vandetanib, and sorafenib. Two patients with tumors harboring the BRAF mutation treated with vemurafenib showed restoration of radioiodine uptake. Most of patients showed significant improvement in disease status but of limited duration until disease progression. Although there was an improvement in progression-free survival, future research has to achieve a greater and longer-lasting response, probably by utilizing combined targeted therapy.

The most common factors influencing on quality of life of thyroid cancer patients after thyroid hormone withdrawal.

BACKGROUND: The aim of study was to evaluate which factors impact mostly on life-quality of patients with differentiated thyroid carcinoma after thyroid hormone withdrawal. SUBJECTS AND METHODS: 150 patients were enrolled in the study by using Quality of life- Thyroid version questionnaire in which they expressed their physical, psychological, social and spiritual well-being. The answers have been interpreted on a scale from 0 to 10. All patients underwent four weeks levothyroxine withdrawal in preparation for I-131 procedures and thyroglobulin testing. RESULTS: Individual statements on the physical subscale showed that patients had most difficulties with fatigue, intolerance to cold and heat, sleep changes and weight gain, but with higher average values than expected. Fatigue was one of the most common physical difficulties. Female patients had significantly more difficulties than male respondents. Five most expressed psychological difficulties have been stress caused by initial diagnosis, followed by stress caused by surgical treatment, fear of metastases, stress caused by initial radioiodine ablation treatment and fear of cancer recurrence. Generally, results revealed troubles mostly in physical symptoms relating to thyroid hormone withdrawal, as well as psychological distress caused by initial diagnosis. Respondents with higher educational level achieved a significantly higher score than less educated patients (p=0.026, Mann-Whitney U test). Illness was very distressing for their families (median value 1, range: 0 to 10) and they reported insufficient support from others (1, range: 0 to 10), but they did not feel isolated. Family and work consequences were less apparent. CONCLUSION: The results of QOL-Thyroid questionnaire help to identify high-risk areas in patients' lives that are negatively affected by hormone withdrawal. Regarding the wide definition of quality of life, a positive impact on patients' recovery could be achieved by directing attention to most expressed difficulties noted in this questionnaire.

Efficacy of long-term ultrasonography in follow-up of patients with papillary thyroid carcinoma: a case of neck metastasis developed 19 years following primary treatment.

The cases of relapse in papillary thyroid cancer patients who were initially considered low-risk and for many years were without signs of the disease are extremely rare, but exist. This is supported by the clinical case of a patient who underwent a total thyroidectomy due to papillary thyroid cancer and 19 years later metastasis with extracapsular spreading in a presumed thyroid place was revealed. Due to such cases, the importance of long-term ultrasound monitoring is emphasized.

B cell-specific transgenic expression of Bcl2 rescues early B lymphopoiesis but not B cell responses in BOB.1/OBF.1-deficient mice.

Mice deficient for the transcriptional coactivator BOB.1/OBF.1 show several defects in B cell differentiation. Numbers of immature transitional B cells in the bone marrow are reduced and fewer B cells reach the periphery. Furthermore, germinal center B cells are absent and marginal zone (MZ) B lymphocytes are markedly reduced. Increased levels of B cell apoptosis in these mice prompted us to analyze expression and function of antiapoptotic proteins. Bcl2 expression is strongly reduced in BOB.1/OBF.1-deficient pre-B cells. When BOB.1/OBF.1-deficient mice were crossed with Bcl2-transgenic mice, B cell development in the bone marrow and numbers of B cells in peripheral lymphoid organs were normalized. However, neither germinal center B cells nor MZ B cells were rescued. Additionally, Bcl2 did not rescue the defects in signaling and affinity maturation found in BOB.1/OBF.1-deficient mice. Interestingly, Bcl2-transgenic mice by themselves show an MZ B cell defect. Virtually no functional MZ B cells were detected in these mice. In contrast, mice deficient for Bcl2 show a relative increase in MZ B cell numbers, indicating a previously undetected function of Bcl2 for this B cell compartment.

Thyroid remnant ablation in patients with papillary cancer: a comparison of low, moderate, and high activities of radioiodine.

OBJECTIVE: The consensus about optimal activities of I-131 for thyroid remnant ablation has not yet been achieved. The aim of this study was to compare ablation rates obtained with different I-131 activities. PATIENTS AND METHODS: The study included 466 patients divided into four groups according to I-131 activities given after total thyroidectomy for papillary thyroid cancer: group A [168 patients who received 888 MBq (24 mCi)], group B [125 patients who received 1480 MBq (40 mCi)], group C [65 patients who received 1850 MBq (50 mCi)], and group D [108 patients who received 4440 MBq (120 mCi)]. Ablation outcome was assessed by whole-body scan in hypothyroid state 6-9 months after ablation and finally 18-21 months after the treatment. RESULTS: The rate of successful ablation was similar in the group of patients who received 24 and 40 mCi (75 and 71.2%, respectively). The higher rate of ablation was achieved in the groups treated with 50 and 120 mCi of radioiodine (87.69 and 90.74%, respectively). The ablation rates at the first follow-up examinations (59.5, 67.2, 73.9, 80.6%) were lower than at second control study (75.0, 71.2, 87.7, 90.7%) in all groups. Time required for thyroid remnant ablation seems to be >or=18 months. CONCLUSION: Our study indicates that activity of 50 mCi seems to be optimal to achieve a successful ablation rate (approximately 90%). Low I-131 activities are acceptable for lower risk patients because of satisfactory ablation rate (>70%), lower expense, and minimal radiation burden to patients as well as lower radiation exposure to clinical staff. The ablative use of high activities seems neither justified nor optimized.

Screening-detected desmoid tumor of the breast: findings at conventional imaging and digital breast tomosynthesis.

Desmoid tumor of the breast is a rare benign entity that usually is mistaken for carcinoma clinically and radiologically. We report two cases of desmoid tumor of the breast detected by mammography screening using digital breast tomosynthesis (DBT). The larger tumor was detected at both full-field digital mammography (FFDM) and DBT. The smaller desmoid tumor, however, was identified only at tomosynthesis. Mammographic and ultrasonographic findings at diagnostic work-up were consistent with carcinoma of the breast. Preoperative needle biopsies could not conclusively diagnose the lesions. Both patients underwent excisional biopsy and histopathology revealed fibromatosis of the desmoid type.

BOB.1/OBF.1 deficiency affects marginal-zone B-cell compartment.

Marginal-zone (MZ) B cells represent a first line of defense against particulate blood-borne antigens. Together with the B1 cells, they are responsible for the early response against type II T-independent antigens. The molecular pathways controlling the development of MZ B cells are only poorly understood. We found that these cells are virtually absent in mice deficient in the BOB.1/OBF.1 coactivator. Loss of these B cells was demonstrated by the lack of cells showing the appropriate cell surface phenotype but also by histological analyses and tri-nitro-phenol-Ficoll capturing. The lack of these cells is a B-cell-intrinsic defect, as shown by bone marrow complementation experiments. We also show that the expression of BOB.1/OBF.1 in peripheral B cells is required for the development of MZ B lymphocytes. Our analysis of BOB.1/OBF.1-deficient splenic B cells reveals alterations in cell motility, tumor necrosis factor receptor expression, and B-cell receptor (BCR) signaling. These changes could contribute to the loss of MZ B lymphocytes by altering the maturation of the cells. Interestingly, development of and BCR signaling in B1 B cells are completely normal in BOB.1/OBF.1 mutant mice.

The value of 18F-DOPA PET/CT in patients with medullary thyroid carcinoma and increased calcitonin values.

AIM: The aim of this prospective observational study was to examine the benefit of a fluorine-18-L-dihydroxyphenylalanine (F-DOPA) PET/computed tomography (CT) scan in patients with medullary thyroid carcinoma (MTC) in terms of increased calcitonin levels. PATIENTS AND METHODS: Twenty-eight MTC patients after initial total thyreoidectomy with increasing follow-up calcitonin levels suggestive for active disease after negative conventional imaging findings (neck ultrasound or thorax, abdomen, pelvis multislice computed tomography as standard imaging) were scanned using F-DOPA PET/CT from November 2012 to April 2016. The mean calcitonin level was 108.5 (range: 6.7-290) pmol/l and the mean carcinoembryonic antigen level was 15.7 (range: 1.1-221.9) µg/l. The mean follow-up period was 19.7 months. RESULTS: F-DOPA PET/CT was positive in 16 out of 28 (57%) patients, mostly because of metabolically active neck and mediastinal lymph nodes metastases. Previously unknown bone metastases were found in six patients. A positive scan was reported in four patients (25% of positive scans) with a very low calcitonin value of less than 49.9 pmol/l. PET/CT findings led to a change of management and therapy in 16 out of 28 patients, with surgical procedure performed in eight patients, radiotherapy in five patients, and chemotherapy in two patients. CONCLUSION: F-DOPA PET/CT is a clinically useful modality in MTC whenever the calcitonin level is increased. There is a clear trend toward more positive scans with the higher calcitonin values, but patients with moderately elevated calcitonin values should also be taken into consideration for molecular imaging with F-DOPA PET/CT as the tumor burden in these patients is probably low, enabling further therapy to be individualized and consequently more efficient.

Usefulness of low iodine diet in managing patients with differentiated thyroid cancer - initial results.

BACKGROUND: Low iodine diet (LID) is recommended in patients with differentiated thyroid cancer before radioiodine administration. Patients with increased thyroglobulin (Tg) level, but negative (131)I whole body scan present diagnostic and therapeutic dilemma. This study was designed to evaluate the benefit of a two-week LID in patients with elevated serum Tg levels and negative (131)I whole body scans. PATIENTS AND METHODS.: For the impact assessment of two-week LID on radioiodine tissue avidity, radioiodine scans before and after LID were compared. Sixteen patients with serum Tg > 2 µg/L, negative Tg-antibodies, and negative radioiodine scans underwent two-week LID before the (131)I administration. Fourteen patients underwent diagnostic scanning and two patients received radioiodine therapy. Iodine concentration in the morning urine specimens were measured in each patient, a day before and 15(th) day after starting LID. RESULTS: Following self-managed LID, patients were able to significantly reduce their iodine body content by 50% (range 28-65%, p<0,001). 13 patients (82%) accomplished mild iodine deficiency (50-99 µg/L) and one patient (6%) achieved targeted moderate iodine deficient state (<50 µg/L). All diagnostic post-LID scans were negative. Both post-therapy (131)I scans showed radioiodine accumulation outside of normal (131)I distribution (neck region and diffuse hepatic uptake). This study demonstrated that two-week LID is effective way to decrease total body iodine content, although without a visible effect on post-LID diagnostic (131)I scans. CONCLUSIONS: A more stringent dietary protocol and longer iodine restriction period are probably needed to achieve targeted moderate iodine deficiency in patients preparing for (131)I administration. This might result in higher radioiodine avidity of thyroid remnant/metastases.

Mycophenolic acid downregulates inducible nitric oxide synthase induction in astrocytes.

Free radical nitric oxide (NO), generated by inducible nitric oxide synthase (iNOS) in astrocytes and macrophages, has been implicated in CNS inflammatory disorders such as multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE). Mycophenolic acid (MPA), a selective inhibitor of inosine monophosphate dehydrogenase (IMPDH), inhibited interferon-gamma (IFN-gamma) + lipopolysaccharide (LPS)-induced NO production dose-dependently in astrocytes, but not in macrophages. The effect of MPA was not mediated through interference with IMPDH-dependent synthesis of iNOS cofactor BH4 and subsequent suppression of iNOS enzymatic activity, as direct BH4 precursor sepiapterin failed to block the action of the drug. However, MPA markedly inhibited IFN-gamma + LPS-triggered astrocyte expression of mRNA for iNOS and its transcription factor IRF-1, while the expression of tumor necrosis factor-alpha (TNF-alpha) gene was not altered. The observed MPA suppression of NO release and iNOS and IRF-1 induction in astrocytes were efficiently prevented by exogenous guanosine, indicating that the drug acted through reduction of IMPDH-dependent synthesis of guanosine nucleotides. This IRF-1-dependent inhibition of iNOS activation might be partly responsible for the protective effect of MPA in EAE, prompting investigation of its potential use in multiple sclerosis.

CD22 regulates early B cell development in BOB.1/OBF.1-deficient mice.

BOB.1/OBF.1 (also called OCA-B), a B lymphocyte-specific transcriptional coactivator, is recruited to octamer-containing promoters by interacting with the Oct-1 or Oct-2 proteins. BOB.1/OBF.1-deficient mice show impaired secondary immunoglobulin isotype secretion and complete absence of germinal centers. Furthermore, numbers of splenic B cells are reduced due to a developmental block at the transitional B cell stage in the bone marrow. We found that surface expression of CD22 is selectively increased on B lineage cells in the bone marrow of BOB.1/OBF.1-deficient mice. CD22 is known as a negative regulator of B cell receptor signaling. We therefore investigated whether defects in B cell development in the BOB.1/OBF.1-deficient mice might be due to CD22 up-regulation. Mice were generated lacking both genes. In BOB.1/OBF.1xCD22 double-deficient mice, numbers of transitional B cells in the bone marrow were normal. Consequently, double-deficient mice also had normal B to T cell ratios in the spleen. We show that BOB.1/OBF.1(-/-) B cells were incapable to induce BCR-triggered Ca(2+) mobilization. This Ca(2+)-signalling defect was restored in BOB.1/OBF.1xCD22 double-deficient B cells. Nevertheless, double-deficient animals were unable to mount humoral immune responses and to form germinal centers. Finally, we demonstrate that CD22(-/-) splenic B cells proliferate independently of BOB.1/OBF.1 upon stimulation with LPS. These studies suggest that the B cell differentiation defect observed in BOB.1/OBF.1(-/-) mice is BCR-signal dependent. However, the impairment in germinal center formation is caused by a different mechanism.

Reduction of marginal zone B cells in CD22-deficient mice.

CD22 is a B cell-specific member of the immunoglobulin superfamily and binds to sialic acid. CD22 inhibits B cell receptor signaling. Mice deficient for CD22 show a largely normal B cell development. Here, we have performed a detailed analysis of the splenic B cell population and found that the subset of marginal zone (MZ) B cells was selectively reduced in CD22-deficient mice. CD22-deficient mice showed a lack of TNP-ficoll capturing cells in the MZ and a reduced response to TNP-ficoll, particularly when the antigen was applied intravenously. CD22-deficient B cells showed both enhanced motility as well as enhanced chemotaxis to certain chemokines. The altered chemokine responsiveness or the higher signaling capacity of CD22-deficient B cells may lead to the compromised MZ B cell compartment, as both processes have previously been shown to affect MZ composition.