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Tumour heterogeneity in the clinic hypothyroidism – What Is Thyroid Cancer?

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David Stewart
Friday, October 6, 2017
  • As expected, in untreated patients, TSH median, 0.

  • Boaventura P. As described above, the genomic landscape, like the clinical and pathologic landscapes that preceded it, is one where tumor heterogeneity is common and important.

  • Many studies focused on the efficacy of LT4 to reduce the volume of solitary nodules in patients residing in nonendemic areas, rather than in patients with multinodular goiter 93 — Br J Cancer —7.

  • Biopsy at set time point depending on tumour type. Single-cell exome sequencing and monoclonal evolution of a JAK2-negative myeloproliferative neoplasm.

Publication types

Systematic identification of genomic markers of drug sensitivity in cancer cells. Elisei, R. Nature Biotechnol.

  • The association of NTIS with cancer was documented in various tumor types including breast cancergastrointestinal cancerslung cancer —central nervous system tumorsmultiple myelomachronic lymphocytic leukemiaand diffuse large cell lymphoma Recently, a strong relationship between serum TSH and risk of thyroid malignancy has been reported.

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  • Evidence that preoperative measurement of serum Tg impacts patient management or outcomes is not yet available.

The diagnostic performance of US assessments of thyroid nodules according to the echogenicity of underlying thyroid parenchyma was calculated, including sensitivity, specificity, positive the clinic value PPVnegative predictive value NPVand accuracy. Does sunitinib-induced hypothyroidism play a role in the activity of sunitinib in metastatic renal cell carcinoma? Know why a new medicine or treatment is prescribed, and how it will help you. Interestingly, Ngan et al. Volume

Cancer Discov. To what extent are the mutations seen in advanced disease already present in the initial cancer? Recent large-scale the clinic sequencing efforts have shed light on the degree of molecular heterogeneity seen in primary tumors across the broad spectrum of human cancers. Recent history Saved searches. Thyroid nodules Enlargement of your thyroid can expand the gland well beyond its normal size and cause a noticeable bulge in your neck. Single-cell exome sequencing to detect single nucleotide mutations is being developed 95 — 97such that molecular characterization using captured CTCs could eventually be possible

Several studies show that intraoperative nerve monitoring is more commonly utilized by higher volume surgeons to facilitate nerve management, and several studies show improved rates of nerve paralysis with the use of neural monitoring in reoperative and complex thyroid surgery— A cytology diagnostic for a primary thyroid malignancy will almost always lead to thyroid surgery. So far, this hypothesis was not supported by experimental data. J Cell Physiol. J Chronic Dis.

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Thress, K. Nat Rev Clin Oncol 15, 81—94 Tumour heterogeneity in the clinic.

Guerra A. Yes, some: You need hypothyroiddism see an endocrinologist. Genomic studies have significantly improved our understanding of heterogeneity, and have pointed to ways in which heterogeneity might be understood and defeated for therapeutic effect. Recognition of intratumour heterogeneity to inform treatment decisions requires test methods that can be applied to clinical tumour samples. Transl Med.

Iin or hyperechoic solid nodule, or partially cystic nodule with eccentric uniformly solid areas without microcalcifications, irregular margin or extrathyroidal extension, or taller than wide shape prompts low suspicion for malignancy Fig. This translated to 1. Table 6. The strong relationship between TSH levels and risk of thyroid cancer has been confirmed in a number of papers published so far 2730 — 3250 — Relationships of uterine and ovarian tumors to pre-existing chronic conditions.

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Mutational heterogeneity in cancer and the search for new cancer-associated on. Wherever significant heterogeneity exists, it serves as a potential threat to the life of the patient. Mass spectrometry imaging of L-[ring- 13 C 6 ]-labeled phenylalanine and tyrosine kinetics in non-small cell lung carcinoma. Deciphering intratumor heterogeneity and temporal acquisition of driver events to refine precision medicine.

Multiregion sequencing, single-cell sequencing, analysis of autopsy samples, and longitudinal analysis of tumour heterogeneity in the clinic hypothyroidism biopsy samples are all emerging technologies with considerable potential to dissect the complex clonal architecture of cancers. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. References 59—61 show that next-generation sequencing technology can be applied to stored formalin-fixed, paraffin-embedded tumour samples in a clinical setting. N-of-1 clinical trial design The N-of-1 clinical-trial design framework has been pursued for non-oncology diseases, most frequently in neuropsychiatric, pulmonary and musculoskeletal conditions 80 ,

ALSO READ: Ryuga Hashimoto S Hypothyroidism

In addition, it is possible that for some drug targets, heterogeneity may not tumour heterogeneity in the clinic hypothyroidism as clinically significant as for others. Metrics details. Some tumors, as TCGA analyses demonstrate, are characterized by high mutational rates and seemingly endless heterogeneity. Sakurada, A. However, there is a growing recognition that intratumour heterogeneity within the same patient is clinically relevant because the status of predictive biomarkers that are used for making clinical decisions may evolve during tumour progression, in particular metastatic dissemination of the primary tumour to a distant organ or for established metastatic disease under the selection pressure of treatment.

Hyperthyroidism was related to a slight increase in the risk of breast cancer compared to the general population SIR 1. In this context, it would be critical to identify the cancer cells that have the potential to contribute to disease progression, in order to develop more effective cancer therapies. However, as much as possible, we tried to separate recommendations on the diagnostic accuracy of a test from therapeutic management based on the test result, with the latter grading being more rigorous and based on longer term outcomes whenever possible. Tetraiodothyronine T4the main hormone synthesized in the thyroid gland, is catalyzed to the Triiodothyronine T3 by specific iodothyronine deiodinases 2. J Clin Invest. Hypothyroidism in pancreatic cancer: role of exogenous thyroid hormone in tumor invasion-preliminary observations.

Associated Data

Shin D, Kim E, Lee E: Role of ultrasonography in outcome prediction in subclinical hypothyroid patients treated with levothyroxine. These may include patients with very low-risk tumors e. Levothyroxine up-regulates P-glycoprotein independent of the pregnane X receptor. Download all slides. Relationships of uterine and ovarian tumors to pre-existing chronic conditions.

Recent Activity. This strategy may be adapted to increase enrolment of patients with tumour types that demonstrate early signals of antitumour activity while excluding those who lack preliminary response. Intratumor heterogeneity and clonal evolution in an aggressive papillary thyroid cancer and matched metastases. Hypothyroidism might be related to breast cancer in post-menopausal women.

Disagreements were resolved by discussion with a third independent reviewer K. J Clin Invest. Lee, V. Hausser J. Thyroid nodules Enlargement of your thyroid can expand the gland well beyond its normal size and cause a noticeable bulge in your neck. Effective assessment of egfr mutation status in bronchoalveolar lavage and pleural fluids by next-generation sequencing.

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Although this framework will not directly lead to regulatory approval, given its exploratory nature, it does provide a platform to determine the differences in the of the same molecular alteration across multiple cancer types. Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. The authors would like to thank Sandra De Dominici for her skilled technical assistance in reviewing the English style and grammar of the manuscript. In instances in which archived tumour tissue is too scant to yield sufficient DNA, or has been exhausted owing to serial evaluations of single markers, then a fresh tumour biopsy would be necessary for genomic profiling.

Ask U. Nevertheless, monitoring heterogeneity of metastatic clones seems eminently rational. Article Google Scholar At the molecular level, genetic and epigenetic heterogeneity can be present [ 14 ]. The publisher's final edited version of this article is available at Nature. Cancer 11—

Fiore et al. Another hypothesis for the causal relationship between HT and PTC is that elevated levels heterogenneity TSH found in hypothyroid patients with HT stimulate follicular epithelial proliferation, thereby promoting the development of papillary carcinoma 71427 Thyroid hormone receptor mediates human MDR1 gene expression-Identification of the response region essential for gene expression. This FNA measurement of Tg is likely valid even in patients with circulating anti-Tg autoantibodies, although one study challenges the validity of this measurement in patients with anti-Tg autoantibodies Effect of thyroid function on MNU-induced mammary carcinogenesis. The utility of serum calcitonin has been evaluated in a series of prospective, nonrandomized studies 50— Thyroid hormones and cancer: clinical studies of hypothyroidism in oncology.

Evidence Acquisition

However, as much as heterogeneit, we tried to separate recommendations on the diagnostic accuracy of a test from therapeutic management based on the test result, with the latter grading tumour heterogeneity in the clinic hypothyroidism more rigorous and based on longer term outcomes whenever possible. Proliferation of some, but not all, cell lines derived from highly aggressive pancreatic adenocarcinoma was suppressed by T3 Level VI contains the thyroid gland, and the adjacent nodes bordered superiorly by the hyoid bone, inferiorly by the innominate brachiocephalic artery, and laterally on each side by the carotid sheaths.

A new risk factor in oesophageal cancer aetiology: hyperthyroidism. The hypothyroidism occurrence of brafve is a rare clonal event in papillary thyroid carcinoma. Cancer 76 : — The risk of malignancy in each of the six diagnostic categories should be independently defined at each cytology center or institution to guide clinicians on risk estimates and help choose appropriate molecular testing for patients with indeterminate cytology. Fine Needle Biopsy A thyroid fine needle biopsy is a simple procedure that can be performed in the physician's office. On clinical grounds, the risk of thyroid malignancy increases with serum TSH concentrations and, even within normal ranges, higher TSH values are associated with a higher frequency and more advanced stage of thyroid cancer. The calculated RR of the presence of PTC in antibody-positive thyroids compared to antibody-negative thyroids was 1.

Tumour heterogeneity in the clinic hypothyroidism repeat Ultrasound study of your Teh better understanding of the molecular basis of thyroid cancers as well as development of more effective cancer therapies has revolutionized the treatment approach in patients with advanced thyroid cancer. Kim K. Suda, K. Buttitta, F. Nodule: If no size change, probably benign. A second search was performed using Pubmed from the date of its inception until March 12, Appendix.

What causes thyroid nodules?

Cancer Metab9 111 Jun Anti-Cancer Drugs. Cited by: 31 articles PMID: Your thyroid gland is located at the base of your neck, just below the Adam's apple. A total of 9 studies were included in our systematic review.

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily. Recurrent EZH1 mutations are a second hit in autonomous thyroid adenomas. Heterogeneeity hormone has been shown to be involved in carcinogenesis via its effects on cell proliferation pathways. Thyroid gland Your thyroid gland is located at the base of your neck, just below the Adam's apple. Gerlinger, M. Figure 4: Application of longitudinal plasma profiling. Large-scale sequencing efforts by TCGA and related organizations almost certainly underestimate the degree of intratumoral heterogeneity.

Cancer Sci. Thyroid nodule at 3. While retesting metastatic sites for growth factor receptors is logical to consider and prudent to perform, there are remarkably few data on the practical outcome of such retesting. Kinde I, et al.

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In the study by Eisenberg et al 39none of the patients with a thyroid carcinoma and HT developed relapse or metastases after 74 months of follow-up. The underlying heterogeneous echogenicity of the thyroid gland significantly lowers the specificity, PPV and accuracy of US in the differentiation of thyroid nodules. Horm Cancer — In retrospect, this approach led to many unnecessary operations, since fewer than 10 percent of the removed nodules proved to be cancerous. This article has been cited by other articles in PMC.

  • T4 may also facilitate cancer progression by interfering with anti-tumor immune responses. Acting via a cell surface receptor, thyroid hormone is a growth factor for glioma cells.

  • Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. Google Scholar.

  • Cell Mol Life Sci.

  • Thyroid Res. Recent preclinical and clinical studies in various cancer types have further shown promising outcomes following chemical reduction of thyroid hormones or inhibition or their binding to the integrin receptor.

  • Cedars-Sinai has a range of comprehensive treatment options.

  • An important limitation of our diagnostic test appraisal system is that it does not specifically examine the clinical utility of a test in improving long-term health outcomes by execution of the test as part of an intended therapeutic strategy unless specifically noted.

Enlargement of your thyroid can expand cinic gland well beyond its normal size and cause a noticeable bulge in your neck. Tumour heterogeneity and the evolutionary trade-offs of cancer. Razvi et al. Mattiuzzi C. Only a small percentage of thyroid nodules are cancerous. The patterns and dynamics of genomic instability in metastatic pancreatic cancer.

Understanding the risks and harms of management of incidental thyroid nodules: A review. Peer Review reports. Biological diversity in metastatic neoplasms: origins and implications. Oncologists increasingly use molecular characterization of a sample of primary or metastatic tumour to guide their selection of treatments for an individual patient.

Zafon, Ask if your condition can be treated in other ways. J Clin Endocrinol Metab 83 : — Thyroid hormones T3 and T4 : dual effect on human cancer cell proliferation.


For this study, we recorded tumour heterogeneity in the clinic hypothyroidism results by retrospectively reviewing the cytological reports. In addition, there are some data suggesting that other factors, such as surgeon age, should be considered LT4 therapy was inhomogeneous in the patients included in this study, the purpose of LT4 treatment being to reduce TSH levels to the lower values of normal range in patients with nodular goiter and to correct hypothyroidism, bringing serum TSH within the range of normal values in more than half of patients with nodules in HT.

Tumpur effects were reproduced by T4-agarose and blocked by tetrac, suggesting a membrane receptor involvement 50 — Hyperthyroidism induced by T4 administration significantly increased growth of tumors inoculated by subcutaneous injections of 3LL cells in mice. Q1—4: OR 0. Pan-cancer analysis of the extent and consequences of intratumor heterogeneity. If US detects cervical lymph nodes that are sonographically suspicious for thyroid cancer Table 7FNA of the suspicious lymph node should be performed for cytology and washout for Tg measurement if indicated. Patients with multiple thyroid nodules have the same risk of malignancy as those with solitary nodules 32 ,

Hypothyoidism, K. In previous years, many high throughput methodologies have raised for the study of heterogeneity at different levels i. Funding Funders who supported this work. The N-of-1 clinical-trial design framework has been pursued for non-oncology diseases, most frequently in neuropsychiatric, pulmonary and musculoskeletal conditions 80 Kinde, I. In: Diagnostic Ultrasound. September 15,

What are thyroid nodules?

Because of interobserver variation, Brauer et al. J Mol Endocrinol. None of these studies reported any degree of blinding.

Policlinico G. Walker, B. Journal information About the Journal Awards Hypothyrokdism policies. Overview Thyroid gland Open pop-up dialog box Close. Interestingly, RAS mutations have a higher prevalence in FA of persons living in area of iodine deficiency [ 56 ]. BMC Endocr Disord 20, 83 The increasing prevalence of chronic lymphocytic thyroiditis in papillary microcarcinoma.

Hyperthyroidism and thyroid cancer risk: a population-based cohort study. Efficacy of thyroid hormone suppression for benign thyroid nodules: meta-analysis of randomized trials. Thyroid hormones T3 and T4 : dual effect on human cancer cell proliferation. New issue alert.

The genetic evolution of melanoma from precursor lesions. Both the longitudinal cohort strategy and the histology-based design to evaluate multiple aberrations would be reasonable frameworks to consider for metastatic potential of localized cancer. Download citation. Constraints in cancer evolution. Hansen1, 2 Mark J. Tsimberidou, A.

Materials and Methods

Bedard P, et al. Everolimus in postmenopausal hormone-receptor—positive advanced breast cancer. Hochhaus et al recently examined treatment-emergent mutations in patients randomly assigned to treatment with either imatinib or nilotinib for BCR-ABL —mutant chronic myelogenous leukemia CML. Autoimmunity and hypothyroidism in patients with uveal melanoma. Cancer 14—

Histology-based design Histology-agnostic basket the clinic hypothyroidism. Garnett MJ, et al. Hypoechoic heterogeneous thyroid nodule. The availability of molecular profiling technologies such as next-generation sequencing coupled with advances in bioinformatics has enabled these previously elusive phenomena to be assayed in the clinical setting. PLoS Med. The rapidity of this effect supported the idea that selection of pre-existing mutant clones rather than induction of new mutations was occurring in these patients.

More hypothyfoidism, two additional studies have analyzed the SEER database, and both have failed to demonstrate a significant difference in survival when comparing total thyroidectomy with thyroid lobectomy The direct effects of T4 on lung cancer cells are probably heterogneeity result of non-genomic actions. In conclusion, the in vivo studies in animal models indicate that TH have broad effects on cancer development and progression. In addition, some patients with malignancy may require completion thyroidectomy to provide complete resection of multicentric disease and to allow for efficient RAI therapy. Furthermore, it has been shown that thyroid diseases that affect the function of the gland, influencing pituitary secretion of TSH, are associated with a different risk of PTC—the likelihood of thyroid malignancy being reduced when TSH is lower, as in thyroid autonomy, and increased when TSH is higher, as in thyroid autoimmunity Supplemental Fig. Lymphocytic infiltrates were more prevalent in patients with papillary carcinoma than in those with adenomatous goiter or follicular adenoma in Japanese females Thyroid ultrasonography as a tool for detecting thyroid autoimmune diseases and predicting thyroid dysfunction in apparently healthy subjects.

Current models for diagnosis and treatment

Diaz LA, Jr, et al. During the course of disease, cancers generally become more heterogeneous. A five-gene signature is a prognostic biomarker in pan-cancer and related with immunologically associated extracellular matrix.

Thyroid nodules Open pop-up dialog box Close. Tumor cells can follow distinct evolutionary paths to become resistant to epidermal growth factor receptor inhibition. Vall d'Hebron Institute of Oncology. Comparison and validation of genomic predictors for anticancer drug sensitivity. Artale S, et al. Table 3 Prospective and retrospective programmes that evaluate tumour heterogeneity by institution or consortium. Furthermore, since fine needle aspiration cytology FNAC has been considered the commonly utilized morphological test, the molecular profiling may improve the diagnostic accuracy mainly in indeterminate or gray zone, furtherly supporting a personalized treatment for DTCs [ ].

Compared to euthyroid reference group, increased cancer risk HR 1. To verify this hypothesis, Fiore et al. Observation without FNA is also a reasonable option. In contrast, coexistent hyperthyroidism may be an indication for total thyroidectomy depending upon the etiology. These studies indicate that the use of suspicious US characteristics rather than nodule growth should be the indication for repeat FNA despite an initial benign cytology diagnosis. Factors related to inflammation of the ovarian epithelium and risk of ovarian cancer.

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Skip to main content Thank you for visiting nature. Noninvasive identification and monitoring of cancer mutations by targeted deep sequencing of plasma DNA. Abstract Cancer is a dynamic disease. Detection and clinical significance of intratumoral EGFR mutational heterogeneity in Chinese patients with advanced non-small cell lung cancer. Le, D.

The use, distribution or reproduction in the clinic forums is permitted, provided the original author s and the copyright owner s are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. Rates of vocal cord paralysis after thyroid surgery can only be assessed by laryngeal exam postoperatively. The clinicopathologic differences in papillary thyroid carcinoma with or without co-existing chronic lymphocytic thyroiditis. Graves' disease and toxic nodular goiter are both associated with increased mortality but differ with respect to the cause of death: a Danish population-based register study. The demonstration that the PTC tumor mass frequently consists of a mixture of few cells bearing mutant BRAF and more abundant tumor cells bearing wild-type BRAF was further confirmed after normalization for the percentage of tumor cells, and by the analysis of single cells obtained by laser capture [ 57 ]. NTIS, or sick euthyroid syndrome, is characterized by alterations in circulating thyroid hormone levels in euthyroid patients with acute or chronic systemic illnesses.

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Chen P. Leary, R. Jang, M. Current Cancer Epidemiology. PD on 1 SOC treatment.

Observation without FNA is also a reasonable option. Kim KW, Clin Res Hepatol Gastroenterol. It is worth noting that even high-volume surgeons have a higher overall postoperative complication rate when performing total thyroidectomy compared with lobectomy In Pinter et al.

  • Studies of the BRAF VE mutation have suggested an association between presence of the mutation and the risk of nodal disease —although results across all patients with papillary thyroid carcinoma are mixed — Histopathology results from surgery or US-FNA cytology were considered the standard reference of thyroid nodules.

  • Buy or subscribe. Maheswaran, S.

  • Therefore, a selection bias may exist. In both patients, although L-T3 produced early resistance to treatment, a direct tumor growth inhibition effect was also observed.

  • Patient-derived models of acquired resistance can identify effective drug combinations for cancer. Genomic Characterization of Differentiated Thyroid Carcinoma.

  • Repplinger, Nodules with larger cystic portion have a higher chance to yield nondiagnostic samples on the initial and repeated FNA.

Frequency of thyroid malignancy increases with serum TSH 2. Annually hetergoeneity 0. If the diagnostic US confirms the presence of a predominantly solid nodule corresponding to what is palpated, the FNA may be performed using palpation or US guidance. Finkel A. The hierarchical or cancer stem cell CSC model proposes that TC arises from the remnants of undifferentiated fetal thyroid cells, especially thyroid stem cells. However, risk of breast cancer mortality after 60 years of age was increased in patients with self-reported hyperthyroidism HR 2.

Cited by: 31 articles PMID: Author information Copyright and License information Disclaimer. Arch Geschwulstforsch. Weller, M. Table 4 Quality assessment of case-control studies using the Newcastle —Ottawa quality assessment scale Full size table. DhadiD.

Key Points

In chronic inflammation, there are reactive alterations of stroma brought on by injury from chemokines, tumour heterogeneity in the clinic hypothyroidism, and growth factors that cause damage to stromal cells. However, a meta-analysis from including six studies evaluating the relationship between thyroid hormone supplementation and risk of breast cancer found no statistical correlation between the two Thyroid lobectomy hemithyroidectomy provides definitive histological diagnosis and complete tumor removal for cytologically indeterminate nodules with a lower risk of complications compared to total thyroidectomy and may be sufficient for smaller, solitary intrathyroidal nodules that ultimately prove malignant. Table 1 summarizes studies of FNAC and thyroidectomy specimens. The association between NTIS and malignancies is later detailed in this review in a designated section.

  • Kim et al.

  • The accessibility to approved or experimental agents in such scenarios may be limited. Cell—

  • The effects of T3 in pancreatic tumor cells depend on tumor type. The value for an individual patient depends upon the utility of the staging information to the treatment team in specific patient circumstances ,

  • Evaluation of DNA from the papanicolaou test to detect ovarian and endometrial cancers. Support Center Support Center.

  • Tseng et al.

Diagn Cytopathol. AMA Arch Surg 70 : — Advanced Search. Bradly et al hypothyroidlsm examined partial and total thyroidectomy specimens from patients undergoing surgery for benign thyroid disease. In colon cancer cells T3 increases the expression of P-gp MDR1one of the key mediators of xenobiotic efflux 67 When there is concern, a urinary iodine to creatinine ratio can be measured.

Ehrlich tumor as model to study artificial hyperthyroidism influence on breast cancer. Citing articles via Web of Science There is no standardization of FNA-Tg procedures or assays to date, the clinic makes this additional diagnostic tool sometimes difficult to interpret Cheng Y. Based on the retrospective nature of the survival data, unresolved issues of assay performance, lack of availability of pentagastrin in North America, and potential biases in the cost-effective analysis, the task force cannot recommend for or against the routine measurement of serum calcitonin as a screening test in patients with thyroid nodules, although there was not uniform agreement on this recommendation. Medically induced euthyroid hypothyroxinemia may extend survival in compassionate need cancer patients: an observational study.


This lesion maybe associated with chronic thyroiditis, nodular goiter or PTC [ 444546 ] Figure 3 C. Mark J. Reprod Biol Endocrinol. Janjigian YY, et al. Nature Rev.

Recent therapeutic advances in oncology have been driven tumour heterogeneity in the clinic hypothyroidism the identification of tumour genotype variations between tumoru, called interpatient heterogeneity, that predict the response of patients to targeted treatments. Misale S, et al. Mok, T. Recent therapeutic advances in oncology have been driven by the identification of tumour genotype variations between patients, called interpatient heterogeneity, that predict the response of patients to targeted treatments. Kim S.

Surg Gynecol Obstet. Triiodothyronine mimics the effects of estrogen in breast cancer cell lines. Case-control and population-based studies provide conflicting results regarding the association between thyroid hormones and cancer. Search ADS. Trans Med Chir Soc Edinb.

Hetergoeneity et al recently examined treatment-emergent mutations in patients randomly assigned to treatment with either imatinib or nilotinib for BCR-ABL —mutant chronic myelogenous leukemia CML. Cancer genome scanning in plasma: detection of tumor-associated copy number aberrations, single-nucleotide variants, and tumoral heterogeneity by massively parallel sequencing. Garnett MJ, et al. Breast Cancer Res Treat. The implications of clonal genome evolution for cancer medicine. Levothyroxine treatment of subclinical hypothyroidism, fatal and nonfatal cardiovascular events, and mortality.