A pooled analysis of overall survival in COMFORT-I and COMFORT-II, 2 randomized phase III trials of ruxolitinib for the treatment of myelofibrosis.

Ruxolitinib, a potent Janus kinase 1/2 inhibitor, resulted in rapid and durable improvements in splenomegaly and disease-related symptoms in the 2 phase III COMFORT studies. In addition, ruxolitinib was associated with prolonged survival compared with placebo (COMFORT-I) and best available therapy (COMFORT-II). We present a pooled analysis of overall survival in the COMFORT studies using an intent-to-treat analysis and an analysis correcting for crossover in the control arms. Overall, 301 patients received ruxolitinib (COMFORT-I, n=155; COMFORT-II, n=146) and 227 patients received placebo (n=154) or best available therapy (n=73). After a median three years of follow up, intent-to-treat analysis showed that patients who received ruxolitinib had prolonged survival compared with patients who received placebo or best available therapy [hazard ratio=0.65; 95% confidence interval (95%CI): 0.46-0.90; P=0.01]; the crossover-corrected hazard ratio was 0.29 (95%CI: 0.13-0.63). Both patients with intermediate-2- or high-risk disease showed prolonged survival, and patients with high-risk disease in the ruxolitinib group had survival similar to that of patients with intermediate-2-risk disease in the control group. The Kaplan-Meier estimate of overall survival at week 144 was 78% in the ruxolitinib arm, 61% in the intent-to-treat control arm, and 31% in the crossover-adjusted control arm. While larger spleen size at baseline was prognostic for shortened survival, reductions in spleen size with ruxolitinib treatment correlated with longer survival. These findings are consistent with previous reports and support that ruxolitinib offers a survival benefit for patients with myelofibrosis compared with conventional therapies. (clinicaltrials.gov identifiers: COMFORT-I, NCT00952289; COMFORT-II, NCT00934544).

Phase I Study of a Multivalent WT1 Peptide Vaccine (Galinpepimut-S) in Combination with Nivolumab in Patients with WT1-Expressing Ovarian Cancer in Second or Third Remission.

We examined the safety and immunogenicity of sequential administration of a tetravalent, non-HLA (human leukocyte antigen) restricted, heteroclitic Wilms' Tumor 1 (WT1) peptide vaccine (galinpepimut-S) with anti-PD-1 (programmed cell death protein 1) nivolumab. This open-label, non-randomized phase I study enrolled patients with WT1-expressing ovarian cancer in second or third remission from June 2016 to July 2017. Therapy included six (every two weeks) subcutaneous inoculations of galinpepimut-S vaccine adjuvanted with Montanide, low-dose subcutaneous sargramostim at the injection site, with intravenous nivolumab over 12 weeks, and up to six additional doses until disease progression or toxicity. One-year progression-free survival (PFS) was correlated to T-cell responses and WT1-specific immunoglobulin (Ig)G levels. Eleven patients were enrolled; seven experienced a grade 1 adverse event, and one experienced a grade ≥3 adverse event considered a dose-limiting toxicity. Ten (91%) of eleven patients had T-cell responses to WT1 peptides. Seven (88%) of eight evaluable patients had IgG against WT1 antigen and full-length protein. In evaluable patients who received >2 treatments of galinpepimut-S and nivolumab, the 1-year PFS rate was 70%. Coadministration of galinpepimut-S and nivolumab demonstrated a tolerable toxicity profile and induced immune responses, as indicated by immunophenotyping and WT1-specific IgG production. Exploratory analysis for efficacy yielded a promising 1-year PFS rate.

Novel biomarker panel predicts prognosis in human papillomavirus-negative oropharyngeal cancer: an analysis of the TAX 324 trial.

BACKGROUND: New treatment strategies for locally advanced head and neck squamous cell carcinoma combine induction chemotherapy and chemoradiation. Identifying the predictors of outcome in sequentially treated patients is critical for focusing therapeutic research. In this analysis, the authors evaluated human papillomavirus type 16 (HPV-16) status and the expression levels of a defined set of biomarkers to identify predictors of response to this treatment modality. METHODS: In total, 114 patients with oropharyngeal cancer (OPC) who were treated on the TAX 324 trial (cisplatin and fluorouracil with or without docetaxel in patients with locally advanced head and neck squamous cell carcinoma) had pretreatment biopsy specimens that were evaluable for HPV-16 DNA and immunohistochemical expression of the following biomarkers: beta-tubulin II (ßT-II), glutathione S-transferase (GST-π), p53, and B-cell lymphoma 2 (Bcl-2). Patients were categorized into risk groups based on their HPV status and biomarker expression levels. RESULTS: Patients with high-risk OPC were defined by HPV-negative status and either elevated expression of ßT-II or levels of at least 2 of the other 3 adverse markers (elevated GST-π, elevated p53, or low Bcl-2). All other HPV-negative patients were categorized as moderate risk. In total, 55 patients were HPV-positive, and 59 patients were HPV-negative, with 34 were categorized as high risk and 25 categorized as moderate risk. The median survival for HPV-positive patients was not reached. The median survival was 44.2 months for moderate-risk patients (95% confidence interval, 20.9 months to not reached) and 12.1 months for high-risk patients (95% confidence interval, 7.5-19.7 months). The 24-month survival rate was 89% for HPV-positive patients, 67% for moderate-risk patients, and 29% for high-risk patients (P < .0001). CONCLUSIONS: The molecular data set in this study readily differentiated between 2 distinct groups of patients with locally advanced, HPV-negative OPC. This risk-stratification strategy may serve as a guide for treatment selection.

Functional polymorphisms in the insulin-like binding protein-3 gene may modulate susceptibility to differentiated thyroid carcinoma in Caucasian Americans.

The insulin-like growth factor (IGF) pathway is believed to play a pivotal role in thyroid carcinogenesis. Polymorphisms of IGF-1 and IGF binding protein-3 (IGFBP-3) have been associated with modulation of risk for the emergence of assorted common malignancies, but studies of the influence of such polymorphisms on risk of differentiated thyroid carcinoma (DTC) are lacking. In a case-control study of 173 DTC patients, 101 patients with benign thyroid disease, and 401 controls, an unconditional logistical regression model adjusted for age and sex was applied to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between polymorphisms of IGF-1 and IGFBP-3 and DTC risk. IGFBP-3 rs2132572 GA/AA genotypes were associated with a decreased risk of DTC (adjusted OR = 0.6, 95% CI: 0.4-0.9), particularly multifocal DTC (adjusted OR = 0.3, 95% CI: 0.1-0.7). The association with DTC was more evident in subjects with a first-degree family history of cancer (adjusted OR = 0.4, 95% CI: 0.2-0.7, P(interaction) = 0.013) and non-drinkers (adjusted OR = 0.4, 95% CI: 0.2-0.7, P(interaction) = 0.028). A four single nucleotide polymorphism haplotype of IGFBP-3 was associated with a decreased risk of DTC (adjusted OR = 0.7, 95% CI: 0.5-1.0, P = 0.030). Our study suggests that polymorphic IGFBP-3 may be involved in susceptibility to DTC.

Four patients with cutaneous metastases from medullary thyroid cancer.

Cutaneous metastasis from thyroid cancer, especially medullary thyroid cancer (MTC) is rare. We report four patients with cutaneous metastases from sporadic MTC, three women and one man, aged 50 to 69 years. They presented different cutaneous lesions phenotypes. The first patient had a remote history of MTC and initial presentation of the recurrence was a rapidly progressing cutaneous lesion; on subsequent disease staging, widely metastatic disease was discovered. The other three patients developed cutaneous metastases in the presence of known distant metastases, indicating systemic spread of thyroid cancer. Definitive diagnosis of cutaneous metastases of MTC was made on biopsy of the lesions with cells that stained positive for neuroendocrine markers. Accurate diagnosis of cutaneous metastasis from MTC is important because it is a negative prognostic factor indicative of multisystemic disease. Thus, MTC metastases should be included in the differential diagnosis of erythematous maculopapular eruptions and nodular lesions of the skin, especially when these metastases occur in the upper part of the body and if the patient has a history of MTC. The appearing of cutaneous metastasis is a negative prognostic factor since all the patients here described died within one year from the diagnosis of cutaneous metastases.

Outcomes of patients with differentiated thyroid carcinoma following initial therapy.

This analysis was performed to determine the effect of initial therapy on the outcomes of thyroid cancer patients. The study setting was a prospectively followed multi-institutional registry. Patients were stratified as low risk (stages I and II) or high risk (stages III and IV). Treatments employed included near-total thyroidectomy, administration of radioactive iodine, and thyroid hormone suppression therapy. Outcome measures were overall survival, disease-specific survival, and disease-free survival. Near-total thyroidectomy, radioactive iodine, and aggressive thyroid hormone suppression therapy were each independently associated with longer overall survival in high-risk patients. Near-total thyroidectomy followed by radioactive iodine therapy, and moderate thyroid hormone suppression therapy, both predicted improved overall survival in stage II patients. No treatment modality, including lack of radioactive iodine, was associated with altered survival in stage I patients. Based on our overall survival data, we confirm that near-total thyroidectomy is indicated in high-risk patients. We also conclude that radioactive iodine therapy is beneficial for stage II, III, and IV patients. Importantly, we show for the first time that superior outcomes are associated with aggressive thyroid hormone suppression therapy in high-risk patients, but are achieved with modest suppression in stage II patients. We were unable to show any impact, positive or negative, of specific therapies in stage I patients.

Endothelial growth factor receptor inhibitors in recurrent metastatic cancer of the head and neck.

Targeted therapy has become an important new class of therapeutic agents used in squamous cell carcinoma of the head and neck (SCCHN). Among them epidermal growth factor receptor (EGFR) inhibitors have been studied the most. Today, two classes of EGFR inhibitors are routinely used in the clinic; anti-EGFR monoclonal antibodies and small-molecule inhibitors of the EGFR tyrosine kinase activity. These agents have been used clinically in the recurrent metastatic (R/M) settings but only cetuximab has reached a regulatory approval. Current research is focused on innovative compound design, predictive biomarker discovery, and combination strategies in order to overcome resistance. Efforts should also be focused on endpoints other than overall survival, which is the current gold standard, such as surrogate endpoints. This article summarizes the clinical evidence of the anticancer activity of EGFR inhibitors in patients with R/M SCCHN, and analyzes the current, controversial clinical issues with respect to their interpretation. © 2015 Wiley Periodicals, Inc. Head Neck 38: E2221-E2228, 2016.

Patterns of hydroxyurea use and clinical outcomes among patients with polycythemia vera in real-world clinical practice: a chart review.

BACKGROUND: Hydroxyurea (HU) is among the most commonly used cytoreductive treatments for polycythemia vera (PV), but previous research and clinical experience suggest that not all patients respond optimally, consistently, or durably to HU treatment. This study investigated patterns of HU use and impact on disease control among patients with PV in real-world clinical practice in the United States. METHODS: Oncologists and hematologists recruited between April and July 2014 reported data from patient charts. Treatment history and disease symptom comparisons between HU subgroups were performed using Chi square tests or one-way analyses of variance for categorical and continuous variables. Other analyses were performed using descriptive statistics. RESULTS: Overall, 329 physicians participated and provided data on 1309 patients with PV (62.3 % male; mean age = 62.5 years, mean time since diagnosis = 5.2 years). In the 229 (17.5 %) patients who had stopped HU, the most common reasons for HU discontinuation-as assessed by the treating clinician-were inadequate response (29.3 %), intolerance (27.5 %), and disease progression (12.7 %). Among patients currently on HU, a significant proportion had elevated blood cell counts: 34.4 % had hematocrit values ≥45 %, 59.4 % had platelet levels >400 × 10(9)/L, and 58.2 % had WBC counts > 10 × 10(9)/L. Two-thirds (66.3 %) of patients had ≥1 elevated count, 40.3 % had ≥2 elevated counts, and 19.8 % had all 3 counts elevated. The most common PV-related signs and symptoms among all patients were fatigue and splenomegaly. CONCLUSIONS: Although many patients with PV benefit from HU therapy, some continue to have suboptimal control of their disease, as evidenced by persistence of abnormally elevated blood cell counts and the continued experience of disease-related manifestations (signs and symptoms). These data further denote a significant medical need for some patients with PV currently or previously treated with HU.

Localization of medullary thyroid carcinoma metastasis in a multiple endocrine neoplasia type 2A patient by 6-[18F]-fluorodopamine positron emission tomography.

6-[(18)F]fluorodopamine, a substrate for the norepinephrine transporter, has been used as a tumor-seeking tracer in positron emission tomography (PET) to localize pheochromocytomas and other chromaffin tumors. Here, we report the case of a 42-yr-old woman with multiple endocrine neoplasia type 2A, in whom biopsy-proven recurrent medullary thyroid cancer (MTC) was detected by 6-[(18)F]fluorodopamine PET scanning. The patient had previously undergone bilateral adrenalectomy for pheochromocytoma, total thyroidectomy, and extirpation of a parapharyngeal MTC metastatic deposit. An increase in plasma calcitonin 5 yr after her initial presentation was further investigated, leading to the discovery of a mass in the left parapharyngeal space. Levels of serum and urine catecholamines and metanephrines were normal. To exclude a hormonally silent pheochromocytoma metastasis, 6-[(18)F]fluorodopamine PET was performed. The study showed a focus of radionuclide accumulation corresponding to the parapharyngeal mass. After resection of the latter, pathology confirmed metastatic MTC. To our knowledge, this is the first case of metastatic, histologically proven MTC, which was unequivocally detected by 6-[(18)F]fluorodopamine PET scanning. Because norepinephrine transporter systems have been previously found in MTC, it is conceivable that 6-[(18)F]fluorodopamine PET scanning can be used for the diagnostic localization of this tumor and its metastatic deposits because total and early resection is beneficial to the outcome of the patient.

Thyroid carcinoma in the McCune-Albright syndrome: contributory role of activating Gs alpha mutations.

McCune-Albright syndrome (MAS) is defined by the triad of café-au-lait skin pigmentation, polyostotic fibrous dysplasia, and hyperfunctioning endocrinopathies, such as precocious puberty, hyperthyroidism, GH excess, and Cushing's syndrome. This disorder is caused by sporadic, postzygotic activating mutations in the GNAS1 gene, which codes for the G(s)alpha protein in the cAMP signaling cascade. Nodular and diffuse goiters (with and without hyperthyroidism), as well as benign thyroid nodules, have been reported in association with MAS. Herein we report two cases of thyroid carcinoma in patients with MAS. The first is a case of papillary thyroid cancer detected incidentally during a hemithyroidectomy for hyperthyroidism in a 14-yr-old girl. The second is one of a 41-yr-old woman with long-standing MAS and an enlarging thyroid nodule, which was diagnosed as a clear cell thyroid carcinoma, a rare variant of thyroid cancer. Molecular analysis revealed that foci of malignancy and adjacent areas of hyperplasia and some areas of normal thyroid harbored activating mutations of Arg(201) in the GNAS1 gene. These findings suggest that the infrequent development of thyroid carcinoma in MAS patients involves additional mutational or epigenetic events.

Current controversies in the management of pediatric patients with well-differentiated nonmedullary thyroid cancer: a review.

Current treatment strategies for pediatric patients with nonmedullary, well-differentiated thyroid carcinoma (WDTC) are derived from single-institution clinical cohorts, reports of extensive personal experience, and extrapolation of several common therapeutic practices for this tumor in adults. Because pediatric WDTC is an uncommon malignancy, the issues of its optimal initial and subsequent long-term treatment and follow-up remain controversial. Pediatric patients with WDTC can be divided into two groups: children younger than 10 years of age and teenagers/adolescents between 10 and 18 years of age because these groups have different recurrence and mortality rates. We hereby present our views and interpret them in the light of the pertinent literature. Our recommendations on treatment strategies are more relevant for younger children. After midpuberty, optimal treatment is adequately addressed in the relevant literature on adults. For the majority of patients, total/near-total thyroidectomy is currently recommended as the standard initial therapy for WDTC. This is commonly followed by administration of radioiodine (RAI; (131)I) therapy to destroy residual normal thyroid tissue (remnant). Routine (131)I remnant ablation has been shown to: (1). decrease the risk of local recurrences, (2) increase the sensitivity of subsequent diagnostic RAI whole-body scanning (WBS), and (3) render serum thyroglobulin (Tg) a highly sensitive marker for recurrent/residual disease during long-term follow-up. We recognize that the above practices are not universally adhered to in children and adolescents, because the risk stratification and intensity of applied therapeutic measures are influenced by institutional traditions and personal experience. In our view, aggressive initial management, followed by evaluations at regular intervals after thyroidectomy and (131)I remnant ablation, in conjunction with long-term thyroid hormone suppressive therapy (THST), result in decreased recurrence rates in pediatric patients with WDTC. Follow-up examinations should include a diagnostic RAI ((131)I or (123)I) WBS and measurement of serum Tg, both performed under conditions of TSH stimulation, as well as neck ultrasonography (US). Our strategy is corroborated by data from retrospective clinical cohort studies. In this malignancy, no evidence of disease (NED) status can be defined as the combination of a negative diagnostic WBS and the presence of undetectable or low serum Tg levels, both tested under TSH stimulation. These findings should be accompanied by the absence of anatomically definable disease by standard imaging modalities, e.g., neck US or chest computed tomography (CT). Although the long-term survival rates are good overall in this disease, selected patients may require further surgery or (131)I therapy for the eradication or clinical control of metastases. Finally, and importantly, because the duration of follow-up is lifelong, the care of children with prior diagnosis of WDTC should be transferred to an adult endocrinologist after they reach adulthood, even if they have achieved NED status by that time.

Lack of effect of long-term octreotide therapy in severe thyroid-associated dermopathy.

Severe thyroid associated dermopathy (TAD), a rare complication of Graves' disease, currently lacks effective treatment. Mediators of growth and inflammation, including insulin-like growth factor-1 (IGF-1) and somatostatin (SST) have been implicated in its pathogenesis. Octreotide, a potent SST analogue, has been used in TAD with anecdotal success. Therefore, we evaluated the efficacy of long-term octreotide therapy in moderate to severe TAD. Three obese women with TAD were studied. Baseline treatment included levothyroxine, methimazole, fluocinonide ointment under occlusive dressing, and physiotherapy for lymphedema. After establishing baseline clinical status, octreotide was started (300 microg subcutaneously daily) for 10 to 28 months. Studies obtained at baseline and every 3 months included: leg circumference, skin examination, clinical photography, self-reported clinical status, body mass index (BMI), serum thyrotropin (TSH) and free thyroxine, titers of antithyroidal and anti-TSH receptor antibodies. Minimal changes in the edema, erythema, skin texture and size of nodules were observed. The minor changes seen followed significant decreases in the patients' BMI, and hence, cannot be specifically attributed to octreotide administration. No clinically significant benefit from long-term octreotide therapy was demonstrated in three patients with moderate to severe TAD. Weight loss and measures such as compression bandaging and topical corticosteroid application still remain the most cost effective treatment modalities for TAD.

Graves' disease after interleukin-2 therapy in a patient with human immunodeficiency virus infection.

Interleukin-2 (IL-2) is a cytokine that regulates the proliferation and differentiation of lymphocytes, and is currently used clinically in the treatment of assorted malignancies. Additionally, IL-2 is being actively investigated in clinical trials for treatment of human immunodeficiency virus (HIV) infection. Patients treated with IL-2 are susceptible to autoimmune thyroid disease (AITD), presenting as thyroiditis, which leads to either thyrotoxicosis or hypothyroidism, if not correctly and promptly identified and treated. IL-2-induced hypothyroidism can also sometimes follow a thyrotoxic phase. However, the development of Graves' disease (GD) in this clinical setting has not been reported to date. Here, we report the case of a 39-year-old HIV-infected man in whom GD developed after IL-2 therapy. We correlated the immunologic parameters pertinent to the patient's HIV infection status with clinical, hormonal, and serologic evidence of GD during its emergence. This revealed an association between peripheral blood cell numbers of specific lymphocyte subpopulations (CD4(+), CD3(+)CD25(+), and naïve T-cells) and serum levels of markers for AITD (free thyroxine [T(4)] and thyroid-stimulating immunoglobulin). Interestingly, no association was found between natural killer (NK) cell numbers and AITD markers. The immunopathogenesis of GD in this patient may be similar to that hypothesized for the GD that occurs in immune-reconstituted patients after combination antiretroviral therapy. From a practical standpoint, we propose that patients who have received or are receiving treatment with IL-2 who show signs of hyperthyroidism need to be carefully evaluated for GD.

Juxtathyroidal neck soft tissue angiosarcoma presenting as an undifferentiated thyroid carcinoma.

Angiosarcoma is a malignant growth of endothelial origin, uncommon in the head and neck. We present the case of a 38-year-old woman with long-standing goiter who presented with a rapidly growing 6.0-cm neck mass. Fine-needle aspiration biopsy of the tumor showed features of "undifferentiated thyroid carcinoma (ThyrCa)." Total thyroidectomy resulted in extirpation of all gross disease. Pathology revealed a high-grade angiosarcoma of the neck invading the thyroid gland, coexisting with papillary ThyrCa (follicular variant) in the contralateral lobe. Aggressive external electron beam radiotherapy was initiated for local control. Despite the absence of systemic dissemination initially, bulky neck recurrences, and pulmonary metastases developed rapidly, leading to the patient's demise on postoperative day 41. Autopsy showed metastatic disease involving most organs. This case illustrates that neck angiosarcomas need to be considered in the differential diagnosis of "poorly differentiated" thyroid malignancies. These soft tissue neck tumors may complicate postoperative management due to their bleeding tendency and aggressive infiltrative behavior, and carry a dismal prognosis because of the rapidity of development of local recurrence and distant metastases.

Successful outcome after surgical management in two cases of the "painful variant" of Hashimoto's thyroiditis.

OBJECTIVE: To describe two cases of the rare "painful variant" of Hashimoto's thyroiditis (HT) that were refractory to medical management and in which surgical intervention provided the definitive treatment. METHODS: We thoroughly review the clinical history as well as the laboratory, imaging, and surgical pathology data in these cases, and follow-up of the clinical response over time is provided. The relevant literature is also discussed. RESULTS: A 56-year-old woman, who had remotely undergone a left hemithyroidectomy and had been diagnosed with HT, sought further assessment because of neck pain and edema. Treatment with corticosteroids was partially successful but led to the development of Cushing's syndrome. A 32-year-old man had pain and swelling of the thyroid and was diagnosed with HT shortly thereafter. Levothyroxine treatment was unsuccessful. Both patients underwent thyroidectomy. Chronic lymphocytic thyroiditis (HT) with a variable degree of fibrosis was found on assessment of pathology specimens. The patients remained asymptomatic after the surgical procedure and did not require any further anti-inflammatory therapy. CONCLUSION: In selected cases, surgical treatment may become necessary for effective and permanent control of symptoms and local signs in painful HT. Access to experienced endocrine surgeons is important in order to avoid postoperative complications because the thyroid gland may be small or fibrosed in this rare variant of HT.

In-111 DTPA-octreotide scintigraphy for disease detection in metastatic thyroid cancer: comparison with F-18 FDG positron emission tomography and extensive conventional radiographic imaging.

PURPOSE: The utility of In-111 DTPA octreotide scintigraphy (SRS) for disease detection in patients with metastatic thyroid carcinoma (TCA) remains controversial. The authors compared the sensitivity of In-111-based SRS, F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET), and extensive conventional radiographic imaging (CRI) in this type of cancer. METHODS: SRS, FDG PET, and CRI were performed concurrently in 21 patients (age, 56.4 +/- 12.9 years) who had aggressive TCA. Concordance rates % of lesion positivity among pairs of different techniques (A and B) were calculated as the ratio of the number of lesions positive with both techniques divided by the sum of the total number of lesions positive with technique A + total number of lesions positive with technique B, which was then multiplied by 200. RESULTS: The combined use of CRI, FDG PET, and SRS resulted in the detection of 105 lesions, presumed to be due to metastatic deposits. Sensitivities for SRS and FDG-PET imaging were 49.5% and 67.6%, respectively. The lesion detection concordance rates were as follows: CRI versus FDG PET, 80.8%; CRI versus SRS, 74.2%; and FDG-PET versus SRS, 58.6%. Importantly, SRS detected five unexpected lesions, which were negative by both CRI and FDG-PET imaging. In two representative patients, a positive correlation (Spearman's rank = 0.71; = 0.0576) existed between the percentage of lesional In-111 DTPA octreotide uptake and the standard uptake value in eight concordant lesions. CONCLUSION: Although SRS has only moderate sensitivity for disease detection in metastatic TCA, sometimes it can reveal lesions that otherwise would be undetectable by either CRI or FDG-PET imaging.

Autoimmune and non-autoimmune hyperthyroidism in pediatric patients: a review and personal commentary on management.

Here we review the etiology, diagnosis, differential diagnosis, and clinical presentation of hyperthyroidism in neonates/infants, children, and adolescents and the standard and adjunct modalities used for its treatment. The most common cause of hyperthyroidism in pediatric patients is Graves' disease. The main options for its management include antithyroid drugs, surgery, and radioiodine therapy. Despite collective experience covering more than 4 decades in the management of hyperthyroidism in children, controversy still abounds regarding the choice of treatments. None of the current treatment options is ideal. Each has risks and selection should be tailored to individual patients, especially in view of the absence of large, prospective, randomized outcome studies. Finally, we discuss the diagnosis and management of less common causes of pediatric hyperthyroidism, including non-autoimmune causes in neonates, autonomously functioning thyroid adenomas, destructive thyroiditis, excessive or inappropriate thyroid-stimulating hormone production, excessive ingestion of thyroid hormone and exposure to large, stable iodine loads.

Unresolved issues, dilemmas and points of interest in thyroid cancer: a current perspective.

Thyroid cancer (TC) is the commonest endocrine malignancy. In the overwhelming majority of cases, thyroid carcinomas are well-differentiated malignancies that respond favorably to treatment; however, this outcome cannot be absolutely guaranteed. The absence of large prospective randomized clinical trials in TC-due to its low incidence and protracted clinical course in cases with persistent/recurrent metastatic disease-results in considerable debates regarding the optimal treatment and follow-up regimens in this malignancy. Some of these debates originated several decades ago, yet are still ongoing despite interim advancements in other domains of oncology. Here we discuss what we believe are the issues of major controversy in TC; these are mentioned in the following non-exhaustive list: (i) the optimal management of solitary and multiple thyroid nodules; (ii) the role of basal calcitonin measurements in the diagnostic investigation of nodular thyroid disease; (iii) the extent of the initial operation after establishment of the diagnosis of TC; (iv) the intensity and frequency of radioactive iodine (RAI; (131)I) therapies (especially in patients with persistent/recurrent metastatic disease); (v) the degree and duration of long-term thyroid hormone suppression therapy (THST) required for optimal outcomes in TC patients; (vi) the optimal management of patients with RAI-refractory disease or other "high-risk" clinicopathologic features; and, finally, (vii) the optimal algorithm for lifelong follow-up of TC patients after their initial treatment. We present elements of the above controversies as pertinent to the various types of TC. We have opted for breadth rather than depth of commentary, at the same time providing the reader with extended up-to-date bibliography.

Lack of association between Hashimoto thyroiditis and breast cancer: a quantitative research synthesis.

Several authors have suggested a positive association between Hashimoto thyroiditis (HT) and breast cancer (BrCa). Others have refuted these findings; hence, this subject remains controversial. We therefore reviewed the world literature on this subject accumulated over the last 50 years and performed a quantitative research synthesis, a meta-analysis variant. The incidence risk ratios and 95% confidence intervals (CI's) were calculated for each study and the combined relative risk (RR) was estimated. We found 37 relevant studies, of which only 13 were accessible to analysis. A significant association (RR=1.40; CI=1.29-1.53, P<0.022) was found for 6 of the 13 studies pertaining to 1,431 women. However, in the cumulative population of 14,226 women (from all 13 studies), we failed to demonstrate an association between the diagnoses of HT and BrCa (RR=1.07; CI=0.99-1.15; P=0.08). In conclusion, we believe that selection bias or institutional referral bias, in at least some of the "positive" studies, may have led to the spurious recognition of an association between HT and BrCa, especially as both of these conditions are highly prevalent in women between the 4th and 7th decade of life.