Early and long-term responses of intestinal microbiota and metabolites to 131I treatment in differentiated thyroid cancer patients.

BACKGROUND: Multiple high doses of 131I therapy in patients with differentiated thyroid cancer (DTC) might disrupt the balance of gut microbiota and metabolites. This study aimed to investigate the alterations of intestinal bacteria and metabolism over two courses of 131I therapy, explore the interactions, and construct diagnostic models reflecting enteric microecology based on 131I therapy. METHODS: A total of 81 patients were recruited for the first 131I therapy (131I-1st), among whom 16 received a second course (131I-2nd) after half a year. Fecal samples were collected 1 day before (Pre-131I-1st/2nd) and 3 days after (Post-131I-1st/2nd) 131I therapy for microbiome (16S rRNA gene sequencing) and metabolomic (LC-MS/MS) analyses. RESULTS: A total of six microbial genera and 11 fecal metabolites enriched in three pathways were identified to show significant differences between Pre-131I-1st and other groups throughout the two courses of 131I treatment. In the Post-131I-1st group, the beneficial bacteria Bifidobacterium, Lachnoclostridium, uncultured_bacterium_f_Lachnospiraceae, and Lachnospiraceae_UCG004 were abundant and the radiation-sensitive pathways of linoleic acid (LA), arachidonic acid, and tryptophan metabolism were inhibited compared with the Pre-131I-1st group. Compared with the Pre-131I-1st group, the Pre-131I-2nd group exhibited a reduced diversity of flora and differentially expressed metabolites, with a low abundance of beneficial bacteria and dysregulated radiation-sensitive pathways. However, less significant differences in microbiota and metabolites were found between the Pre/Post-131I-2nd groups compared with those between the Pre/Post-131I-1st groups. A complex co-occurrence was observed between 6 genera and 11 metabolites, with Lachnoclostridium, Lachnospiraceae_UCG004, Escherichia-Shigella, and LA-related metabolites contributing the most. Furthermore, combined diagnostic models of charactered bacteria and metabolites answered well in the early, long-term, and dose-dependent responses for 131I therapy. CONCLUSIONS: Different stages of 131I therapy exert various effects on gut microecology, which play an essential role in regulating radiotoxicity and predicting the therapeutic response.

The relationship between the gut microbiota and thyroid disorders.

Disorders of the thyroid gland are common, more prevalent in women than in men, and range from inflammatory to neoplastic lesions. Autoimmune thyroid diseases (AITD) affect 2-5% of the population, while thyroid cancer is the most frequent endocrine malignancy. Treatment for AITD is still restricted to management rather than prevention or cure. Progress has been made in identifying genetic variants that predispose to AITD and thyroid cancer, but the increasing prevalence of all thyroid disorders indicates that factors other than genes are involved. The gut microbiota, which begins to develop before birth, is highly sensitive to diet and the environment, providing a potential mechanism for non-communicable diseases to become communicable. Its functions extend beyond maintenance of gut integrity: the gut microbiota regulates the immune system, contributes to thyroid hormone metabolism and can generate or catabolize carcinogens, all of which are relevant to AITD and thyroid cancer. Observational and interventional studies in animal models support a role for the gut microbiota in AITD, which has been confirmed in some reports from human cohorts, although considerable geographic variation is apparent. Reports of a role for the microbiota in thyroid cancer are more limited, but evidence supports a relationship between gut dysbiosis and thyroid cancer.

The comparison of microbial communities in thyroid tissues from thyroid carcinoma patients.

Thyroid carcinoma is a common endocrine organ cancer associated with abnormal hormone secretion, leading to the disorder of metabolism. The intestinal microbiota is vital to maintain digestive and immunologic homeostasis. The relevant information of the microbial community in the gut and thyroid, including composition, structure, and relationship, is unclear in thyroid carcinoma patients. A total of 93 samples from 25 patients were included in this study. The results showed that microbial communities existed in thyroid tissue; gut and thyroid had high abundance of facultative anaerobes from the Proteobacteria phyla. The microbial metabolism from the thyroid and gut may be affected by the thyroid carcinoma cells. The cooccurrence network showed that the margins of different thyroid tissues were unique areas with more competition; the stabilization of microcommunities from tissue and stool may be maintained by several clusters of species that may execute different vital metabolism processes dominantly that are attributed to the microenvironment of cancer.

The Human Microbiota in Endocrinology: Implications for Pathophysiology, Treatment, and Prognosis in Thyroid Diseases.

The human microbiota is an integral component in the maintenance of health and of the immune system. Microbiome-wide association studies have found numerous diseases associated to dysbiosis. Studies are needed to move beyond correlations and begin to address causation. Autoimmune thyroid diseases (ATD) are one of the most common organ-specific autoimmune disorders with an increasing prevalence, higher than 5% worldwide. Most frequent manifestations of ATD are Hashimoto's thyroiditis and Graves' disease. The exact etiology of ATD remains unknown. Until now it is not clear whether bacterial infections can trigger ATD or modulate the efficacy of treatment and prognosis. The aim of our review is to characterize the microbiota and in ATD and to evaluate the impact of dysbiosis on treatment and prognosis. Moreover, variation of gut microbiome has been associated with thyroid cancer and benign nodules. Here we will characterize the microbioma in benign thyroid nodules, and papillary thyroid cancer to evaluate their implications in the pathophysiology and progression.

Alterations in the gut microbiota and metabolite profiles of thyroid carcinoma patients.

The aim of our study was to investigate the relationship among the gut microbiota community, metabolite profiles and thyroid carcinoma (TC). First, 30 TC patients and 35 healthy controls (HCs) fecal samples were applied to characterize the gut microbial community using 16S rRNA gene sequencing. Differential microbiota compositions were observed, with significant enrichment of 19 and depletion of 8 genera in TC samples compared to those in HCs (Q value <0.05), and some genera were correlated with various clinical parameters, such as lipoprotein A and apolipoprotein B. Furthermore, 6 different genera distinguished TC patients from HCs with the AUC of 0.94. The PICRUSt analysis showed 12 remarkably different metabolic pathways (Q value <0.05). Subsequently, we systematically analyzed the gut microbiota and metabolites in the same TC patients (n = 15) and HCs (n = 15). The characteristics of the gut microbiota community were mostly consistent with the above results (30 TC patients and 35 HCs), and liquid chromatography mass spectrometry analysis was performed to characterize the metabolite profiles. In total, 21 different genera (Q value <0.05) and 72 significantly changed metabolites (VIP > 1.0 and p < 0.05) were observed and correlated to each other. Eight metabolites combined with 5 genera were more effective in distinguishing TC patients from HCs (AUC = 0.97). In conclusion, our study presents a comprehensive landscape of the gut microbiota and metabolites in TC patients, and provides a research direction of the mechanism of interaction between gut microbiota alteration and TC pathogenesis.

Dysbiosis of the gut microbiome is associated with thyroid cancer and thyroid nodules and correlated with clinical index of thyroid function.

PURPOSE: Thyroid cancer and thyroid nodules are the most prevalent form of thyroid endocrine disorder. The balance of gut microbiome is highly crucial for a healthy human body, especially for the immune and endocrine system. However, the relationship between gut microbiome and the thyroid endocrine disorders such as thyroid cancer and thyroid nodules has not been reported yet. METHODS: A cohort of 74 patients was recruited for this study. Among them, 20 patients had thyroid cancer, 18 patients had thyroid nodules, and 36 were matched healthy controls. Gut microbiome composition was analyzed by 16S rRNA (16S ribosomal RNA) gene-based sequencing protocol. RESULTS: We compared the gut microbiome results of 74 subjects and established the correlation between gut microbiome and thyroid endocrine function for both thyroid cancer and thyroid nodules. The results inferred that alpha and beta diversity were different for patients with thyroid tumor than the healthy controls (p < 0.01). In comparison to healthy controls, the relative abundance of Neisseria (p < 0.001) and Streptococcus (p < 0.001) was significantly higher for thyroid cancer and thyroid nodules. Butyricimonas (p < 0.001) and Lactobacillus (p < 0.001) displayed notably lower relative abundance for thyroid cancer and thyroid nodules, respectively. It was also found that the clinical indexes were correlated with gut microbiome. CONCLUSION: Our results indicate that both thyroid cancer and thyroid nodules are associated with the composition of gut microbiome. These results may support further clinical diagnosis to a great extent and help in developing potential probiotics to facilitate the treatment of thyroid cancer and thyroid nodules.

Coinfection of disseminated Talaromyces marneffei and Mycobacteria kansasii in a patient with papillary thyroid cancer: A case report.

RATIONALE: Recently, Talaromyces marneffei (T. marneffei) has been reported in human immunodeficiency virus (HIV)-negative patient with underlying diseases, such as oral cancer, colon cancer, haematological malignancies, connective tissue disease, diabetes mellitus, and corticosteroids or immunosuppressive agents. Similar to HIV-positive ones, such patients were observed with CD4 lymphocytopenia. PATIENT CONCERNS: We reported a case of a 45-year-old woman who was diagnosed with disseminated T. marneffei and Mycobacteria kansasii (M. kansasii) with papillary thyroid cancer as the underlying disease. T-cell subsets counts, CD4 T-cell%, CD8 T-cell%, CD4/CD8 ratio, and NK cell% were all turned out to be normal. DIAGNOSES: Based on bronchoalveolar lavage fluid and skin lesions secretion cultures, blood culture, the patient was diagnosed with disseminated T. marneffei and M. kansasii. Pathological examination reported papillary thyroid cancer with cervical lymph node metastasis. INTERVENTIONS: The patient received the combined and longer antifungal therapy and drug regimens for M. kansasii. She had total thyroidectomy with radical neck dissection to treat the papillary thyroid cancer. OUTCOMES: The patient had a favorable outcome for 19 months without recurrence. LESSONS: T. marneffei could infect non-HIV individuals with underlying disease under the condition of normal T-cell counts. The symptoms were lack of specificity and were more likely to be misdiagnosed. Such patients with unidentified T-cell dysfunction or other unidentified primary immunodeficiency disorders may prone to coinfect with other opportunistic pathogens, such as M. kansasii. Compared with HIV-positive ones, they need combined and much longer antifungal therapy.

What is the effect of radioiodine therapy on Helicobacterpylori infection?

BACKGROUND/AIM: Helicobacter pylori is an important human pathogen associated with gastric and duodenal ulcers, gastric mucosa- associated lymphoid tissue lymphoma, and adenocarcinoma. Radioiodine (RAI) treatment plays an important role in the management of differentiated thyroid cancer and primary hyperthyroidism. It is known that during RAI treatment, a considerable amount is absorbed by the stomach as well. In this study we aimed to reveal any therapeutic impact of RAI on H. pylori infections. MATERIALS AND METHODS: Eighty-seven patients who were hospitalized for RAI treatment were consecutively included in this study. Of those, 76 patients had differentiated thyroid cancer and 11 had primary hyperthyroidism. The urea breath test (UBT) was performed on the day before RAI, and the test was repeated after 2 months. RESULTS: The dose of RAI was 115 ± 3.3 mCi (range: 100-150 mCi) in the patients with malignant disease and 22.7 ± 1.4 mCi (range: 20-30 mCi) in the remaining patients. Among the patients with differentiated thyroid cancer, 44 (57%) had positive and 32 (43%) had negative UBT tests prior to RAI. Four (36%) patients with hyperthyroidism had pretreatment positive UBT tests and 7 (64%) had negative tests. The results of UBT conducted 2 months after RAI therapy were identical in every patient, which means that none of the patients with positive UBT became UBT-negative (P = 1). CONCLUSION: RAI does not have any therapeutic effect on H. Ovlori infection.

Cáncer diferenciado de la tiorides, de la biología molecular a la clínica / Differentiated thyroid cancer, from molecular biology to the clinic

Recent advances in molecular research have made possible to identify intracellular pathways involved in cell proliferation and differentiation processes, and to clarify how functional alterations in these pathways could explain development of differentiated thyroid cancer. This information has direct implications in diagnostic and therapeutic strategies. We present a review of this topic with this integrated vision between molecular findings and clinical management.

Emergency thyroidectomy in infected thyroid cyst due to spontaneous gas forming organisms.

We are reporting a case of a young female, who presented to emergency room with sudden increase in thyroid swelling, high fever and acute respiratory distress. Clinical diagnosis of spontaneous infection of thyroid cyst was made. Operative finding was infection of thyroid cyst with gas formation. Systemic antibiotics and operative intervention by subtotal thyroidectomy led to recovery of the patient.

Extragastric mucosa-associated lymphoid tissue lymphoma showing the regression by Helicobacter pylori eradication therapy.

A 69-year-old man presented with right neck tumour. Primary thyroid MALT lymphoma occurring in Hasimoto's thyroiditis was diagnosed. He was also diagnosed to have gastric cancer with Helicobacter pylori infection. After subtotal gastrectomy by itself, thyroid lymphoma became smaller transiently. Then the patient was treated with H. pylori eradication therapy, resulting in the complete disappearance of lymphoma. Although H. pylori organisms were not detected in the lymphoma tissue by polymerase chain reaction (PCR), it might be implicated in the pathogenesis of extragastric MALT lymphomas.

A possible role for Epstein-Barr virus in tumorigenesis after immunosuppression in cases of renal transplantation.

Eight secondary malignancies developing after renal transplantation were investigated in terms of a possible role of the Epstein-Barr virus (EBV). In five cases, four gastric cancers and one colonic cancer, the presence of EBV was proven by the polymerase chain reaction (PCR), all four gastric lesions being confirmed to have a massive EBV infection by in situ hybridization. Two cases demonstrated monoclonal infection with EBV, as indicated by a single band of the lymphocyte-defined membrane antigen tandem-repeat gene using PCR, and were immunohistochemically positive for the latent membrane protein 1. Our series suggests that gastrointestinal cancer predominates as a secondary malignancy in states of induced severe immunosuppression, and that EBV may play an important role in tumorigenesis as an oncovirus.

Prognostic factors in medullary thyroid carcinoma: evaluation of 741 patients from the German Medullary Thyroid Carcinoma Register.

A retrospective study of 741 patients with medullary thyroid carcinoma diagnosed between 1967 and 1991 was carried out by members of the German Medullary Thyroid Carcinoma Study Group to evaluate prognostic factors. A total of 559 patients (75%) were considered to have sporadic disease, and 182 (25%) had the familial type. The sex ratio (male to female) was 1:1.4 in sporadic disease patients, and the mean age at diagnosis was 45.9 years (range 5-81 years). For familial disease patients the sex ratio was 1:1.1, and the mean age at diagnosis was 33.4 (range 5-77 years). The follow-up time for 630 patients ranged from 1 month to 20.8 years (mean 13.0 years). The overall adjusted survival rate was 86.7% at 5 years and 64.2% at 10 years. In a univariate analysis the stage of disease at diagnosis, age, sex, and type of disease (sporadic, familial) were relevant prognostic factors, with a better prognosis for young female patients with familial disease and diagnosed at an early stage. In a multivariate proportional hazards analysis, the difference in the survival rate of patients with familial disease versus those with the sporadic form disappeared, while prognostic information provided by age and sex was still significant. The poorer prognosis of patients with sporadic medullary thyroid carcinoma may be related to the patients' older age at detection and more advanced tumor stage at diagnosis. There seems to be no difference in biological behavior between tumors of the sporadic and those of the familial type.

C cell hyperplasia and carcinoma developing in sheep with experimentally-induced lymphosarcoma.

Two cases of C cell hyperplasia and one case of C cell carcinoma of the thyroid glands were bilaterally recognized in 11 sheep with experimentally-induced lymphosarcoma. The serum calcium concentration in the C cell carcinoma case was slightly increased above the normal concentration of around 9 mg per dl. Bilateral C cell hyperplasia also developed in the thyroid lobes of the C cell carcinoma case. Immunohistochemically, hyperplastic C cells and tumour cells were positive for calcitonin, calcitonin gene-related peptide, chromogranin A and neurone-specific enolase. No amyloid deposition nor multiple endocrine neoplasia was demonstrated in any of the cases. Ultrastructurally, many secretory granules were observed in the cytoplasm of neoplastic cells constituting the C cell carcinoma and in the hyperplastic C cells.

Thyroid adenocarcinomas secondary to tissue-specific expression of simian virus-40 large T-antigen in transgenic mice.

A hybrid gene comprising the bovine thyroglobulin gene promoter and the coding region for the simian virus-40 large T- and small t-antigens was used to generate 30 transgenic mice by microinjection into the pronuclei of single cell embryos. All animals except three developed, as single primitive pathology, a dramatic enlargement of the thyroid gland. Compression of trachea and esophagus, accompanied by dyspnea, inspiratory stridor, and dysphagia, led to a progressive cachexia and premature death attributed to respiratory failure. Despite the large thyroid volume, T4 levels were abnormally low, and the progression of the syndrome could be delayed by a substitutive treatment with thyroid hormones. The rapid evolution of the disease, leading to the death of most founder transgenic animals before the breeding age, prevented transmission of the transgene to their offspring. Only two transgenic lines are presently surviving. Immunohistochemical analysis of the tissues revealed a specific expression of the simian virus-40 antigens in the thyroid cells. Hyperplasia was already obvious at birth. Older animals displayed moderately to poorly differentiated thyroid adenocarcinomas. Electron microscopy revealed, however, the persistence of cell polarity and the presence of microfollicles between the densely packed cells. Cell lines derived from these large T-expressing thyroids were shown to have lost expression of both thyroglobulin and thyroperoxidase, while expressing low levels of TSH receptors. These transgenic mice could constitute an interesting model of aggressive adenocarcinoma, sharing phenotypical similarities with the anaplastic type of human thyroid tumors.

Malignant lymphoma of the thyroid and Epstein-Barr virus.

We have investigated the specific immune response to Epstein-Barr virus (EBV) of peripheral blood mononuclear cells (PBMC) from patients with malignant lymphoma of the thyroid. Coculture of PBMC and EBV resulted in EBV cell transformation and regression which was assayed by an EBV-induced B cell focus-regression assay technique. The EBV had been isolated from mouthwash samples. The specific immune response to EBV by outgrowth inhibition in PBMC from untreated EBV-seropositive patients with malignant lymphoma was significantly decreased when compared to PBMC from EBV-seropositive healthy subjects (p less than 0.05). This observation is at least consistent with the possibility that B-cell proliferation after continuous or recurrent EBV infection could be a causative factor or may potentiate malignant lymphoma of the thyroid.