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The treatment strategy for non-functioning pituitary adenomas (NFPA) includes surgery, radiotherapy, medical treatment, or follow-up. Prior series of patients with NFPAs followed without intervention include small numbers of patients with macroadenomas. This study investigated the natural history of patients with macroadenomas followed without treatment.Retrospective cohort study included patients18 years, with a diagnosis of NFPA≥10 mm who were naïve to surgery or medical treatment and followed more than 12 months after diagnosis. Patients with chiasmal threat were excluded. Follow-up terminated if the patient underwent surgery, received cabergoline or was lost to follow-up.Data collected included evaluation of tumor characteristics and size by MRI, symptoms including visual disturbances, and hormonal levels. Tumor growth was defined as maximal diameter increase of2 mm.The cohort included 49 patients (30 males, mean age 68.0±12.0 years). At diagnosis, the average tumor size was 17.8±5.9 mm. Mean follow-up time was 4.9±4.9 years. Increase in tumor size occurred in 16 patients (33%), with an average growth of 5.1±4.4 mm. Reduction in tumor size occurred in 10 patients (20%), with a mean decrease of 3.5±1.3 mm. Twenty-three patients remained with stable tumors. Overall, 33 patients (67%) were observed without any intervention; 3 patients were operated and 13 were treated with cabergoline. None of the parameters including age, gender, baseline tumor size, invasiveness, visual disturbances, or hypopituitarism at diagnosis, predicted tumor growth.Observation of NFPAs without surgery or medical therapy is a reasonable approach in selected patients. In our study, no parameter predicted tumor growth. This article is protected by copyright. All rights reserved.

Objective The aim of the present study was to investigate the differences in quality of life (QOL) following complete or partial thyroidectomy and with regard to thyroid hormone replacement (LT4) therapy. Study Design Patients who underwent thyroidectomy were asked to complete the validated thyroid-specific ThyPRO QOL questionnaire at least 6 months following surgery. Setting Tertiary medical center. Methods Thyroid specific QOL questionnaire analysis. Results A total of 190 patients completed the ThyPRO questionnaire. Of them 89 patients had complete thyroidectomy and 101 patients had unilateral thyroid lobectomy. The total thyroidectomy group had significantly worse overall QOL self-assessment score than the lobectomy patients (p < 0.0001). Patients receiving LT4 therapy regardless of the extent of surgery, reported worse QOL compared to patients not receiving LT4. Conclusions Quality of life following thyroid surgery is significantly related to hypothyroidism and the requirement for LT4 therapy, rather to the extent of surgery. The best QOL was reported in patients treated with lobectomy who did not require LT4 therapy.

Background Lenvatinib is a multitargeted tyrosine kinase inhibitor approved for treating patients with locally recurrent or metastatic progressive radioiodine-refractory differentiated thyroid cancer (RR-DTC). In this review, we discuss recent developments in the optimization of RR-DTC treatment with lenvatinib. Summary Initiation of lenvatinib treatment before a worsening of Eastern Cooperative Oncology Group performance status and elevated neutrophil-to-lymphocyte ratio could benefit patients with progressive RR-DTC. The median duration of response with lenvatinib was inversely correlated with a smaller tumor burden, and prognosis was significantly worse in patients with a high tumor burden. An 18 mg/day starting dose of lenvatinib was not noninferior to 24 mg/day and had a comparable safety profile. Timely management of adverse events is crucial, as patients with shorter dose interruptions benefitted more from lenvatinib treatment. Caution should be exercised when initiating lenvatinib in patients who have tumor infiltration into the trachea or other organs, or certain histological subtypes of DTC, as these are risk factors for fistula formation or organ perforation. The Study of (E7080) LEnvatinib in Differentiated Cancer of the Thyroid (SELECT) eligibility criteria should be considered prior to initiating lenvatinib treatment. Conclusions Current evidence indicates that patients benefit most from lenvatinib treatment that is initiated earlier in advanced disease when the disease burden is low. A starting dose of lenvatinib 24 mg/day, with dose modifications as required, yields better outcomes as compared to 18 mg/day. Appropriate supportive care, including timely identification of adverse events, is essential to manage toxicities associated with lenvatinib, avoid longer dose interruptions, and maximize efficacy.

Contains fulltext : 287669.pdf (Publisher’s version ) (Open Access) The incidence of differentiated thyroid cancer (DTC) has been increasing worldwide, mostly, as an increase in the incidental detection of micro papillary thyroid carcinomas (microPTCs), many of which are potentially overtreated, as suggested by the unchanged mortality. Several international guidelines have suggested a less aggressive approach. More recently, it has been shown that active surveillance or minimally invasive treatments (MIT) are good alternatives for the management of these patients. In this context, patient participation in the decision-making process is paramount. The Endocrine Task Force of the European Organisation for Research and Treatment of Cancer (EORTC) has undertaken the task to establish consensus and define its position based on the scientific evidence concerning, 1) the current state of diagnostic and management options in microPTCs, including the current opinion of physicians about shared decision making (SDM), 2) the available evidence concerning patients' needs and the available decision instruments, and 3) to provide practical suggestions for implementation of SDM in this context. To improve SDM and patients' participation, knowledge gaps and research directions were highlighted.

The lymph node ratio (LNR), which represents the proportion of metastatic lymph nodes resected, has been found to be a prognostic variable in several cancers, but data for Medullary thyroid carcinoma (MTC) are sparse. The aim of this study was to determine the value of the LNR in predicting outcome in patients with MTC.A retrospective multicenter study design of 107 patients with MTC who underwent total thyroidectomy with neck dissection between 1984 and 2016. The association of LNR with patient and tumor characteristics and prognostic factors was evaluated.Study population consisted of 53.3% female, mean age at diagnosis was 50.3 ± 18.4 years; 16.8% had inherited MTC. LNR was positively correlated with tumor size (p = 0.018) and inversely correlated with age at diagnosis (p = 0.024). A higher LNR was associated with extrathyroidal extension (p 0.001), multifocality (p = 0.001), bilateral tumor (p = 0.002), distant metastases (p 0.001), and tumor recurrence (OR = 14.7, p 0.001). LNR was also correlated to postoperative calcitonin levels (p 0.001) and carcinoembryonic antigen (p = 0.011). LNR0.1 was associated with shorter disease-specific survival in patients at risk: tumor larger than 20 mm at diagnosis (p = 0.013), sporadic MTC (p = 0.01), and age above 40 years at diagnosis (p = 0.004). Cox multivariate survival analysis revealed LNR as the only significant independent factor for disease free survival (p = 0.005).This study showed that LNR correlates well with patient and tumor characteristics and prognostic variables. We suggest that LNR should be considered an important parameter for predicting outcome in MTC.

Objective: Outcomes of patients with cytologically indeterminate thyroid nodules not referred for thyroidectomy have hardly been investigated. We previously reported outcomes of 322 patients with thyroid nodules classified according to the Bethesda System of Reporting Thyroid Cytology (BSRTC) as indeterminate (B3/B4), of whom 123 (38.2%) underwent thyroidectomy. In the present extension study, we investigated adherence and outcomes in the remaining unoperated 199 patients. Methods: We conducted a file review of 189/199 patients with thyroid nodules cytologically diagnosed as B3 (n = 174) or B4 (n = 15) in 2011–2012 who were conservatively followed at our institution until 2019. Results: Among 174 patients with B3 nodules, 140 (80.4%) underwent repeated ultrasound. Nodular growth was detected in 23 (16.4%), and findings remained stable in 105 (75%). Fine-needle aspiration was repeated in 88/174 patients (50.6%), with B2 results in 62 (70.4%) and B3/B4/B5 in 20 (22.7%). Thyroidectomy was performed in 14/174 patients (8%) in the B3 and 5/15 patients (33%) in the B4 group at a median of 5 years’ follow-up; thyroid cancer was diagnosed in 4/14 patients (28.5%) and 3/5 patients (60%), respectively. For B3 patients who remained unoperated, none had evidence of thyroid cancer at last follow-up. A reason for avoiding surgery was documented in 6/10 unoperated B4 patients (1 thyroid lymphoma, 3 died of unrelated causes, 2 were considered inoperable due to advanced age). Conclusions: Most patients with initially unoperated B3/B4 nodules adhere, at least partially, to active surveillance. For B3 nodules, subsequent thyroidectomy and thyroid cancer detection are rare events, and patients may be safely managed without using molecular markers. Thyroid cancer is diagnosed in most B4 patients who undergo thyroidectomy in our institution.

With the current aging of the world's population, primary hyperparathyroidism (PHPT) is increasingly detected in the elderly. Yet data on the presentation and outcome of PHPT in this group are scarce. The objective was to describe a cohort of patients aged 75 years or more with PHPT observed in our endocrine clinic.A retrospective analysis of medical records in an endocrine clinic at a tertiary hospital. We evaluated 182 patients with PHPT, aged 75 years or more at their last follow-up, all diagnosed at age 65 or more. Laboratory data were compared at diagnosis and last follow-up.Mean age at diagnosis was 73 ± 4 years, last follow-up was at 83 ± 4 years, and mean follow-up was 11.3 ± 5.5 years. Osteoporosis, fractures, and nephrolithiasis were diagnosed in 114(63 %), 84(46 %), and 43(24 %) patients, respectively. Overall, 150 patients had an indication for surgery; of them, the 29 who underwent parathyroidectomy were younger than the non-operated patients and had higher rates of hypercalciuria. During the follow-up of the 141 patients who did not undergo operation, serum and urinary calcium levels significantly had decreased, and vitamin D level had increased at last visit (10.4 ± 0.5 mg/dl, 161 ± 70 mg/24 h, 69 ± 17 nmol/l, p0.01 respectively) compared with levels at diagnosis (10.6 ± 0.2 mg/dl, 223 ± 95 mg/24 h, 53 ± 15 nmol/l, respectively, p = 0.001). Overall, 38 of the 182 patients (20 %) died during follow-up; these patients were significantly older at diagnosis (76 ± 5 vs. 72 ± 4 years) but there were no differences in laboratory variables.While most patients had a formal indication for surgery, few underwent parathyroidectomy. Serum and urinary calcium significantly decreased during follow-up in patients who did not undergo surgery. Our data are reassuring and support at least the consideration of conservative treatment for these patients.

Background The use of thyroglobulin (Tg) and thyroglobulin antibodies (TgAb) for detecting disease recurrence is well validated following total thyroidectomy and radioiodine ablation. However, limited data are available for patients treated with thyroid lobectomy. Methods Patients who had lobectomy for papillary thyroid cancer followed for >1 year, with sufficient data on Tg and TgAb, including subgroup analysis for Hashimoto’s thyroiditis and contralateral nodules. Results One-hundred sixty-seven patients met the inclusion criteria. Average tumor size was 9.5 ± 6 mm. Following lobectomy, Tg was 12.1 ± 14.8 ng/mL. Of 52 patients with Hashimoto’s thyroiditis, 38% had positive TgAb with titers of 438 ± 528 IU/mL, and in patients without TgAb the mean Tg level was 14.7 ± 19.0 ng/mL. In 34 patients with contralateral nodules ≥1 cm, Tg was 15.3 ± 17 ng/mL. During the first 2 years of follow-up, Tg declined ≥1 ng/mL in 42% of patients (by 5.1 ± 3.7 ng/mL), remained stable in 22%, and increased in 36% (by 4.9 ± 5.7 ng/mL). During a mean follow-up of 6.5 years (78 ± 43.5 months), 18 patients had completion thyroidectomy and 12 were diagnosed with contralateral cancer (n = 8) or lymph node metastases (n = 4). In patients with recurrence followed for >2 years, there was a rise in Tg in 3 cases, Tg was stable in 2 cases, and in 1 TgAb decreased from 1534 to 276 IU/mL despite metastatic lymph nodes. Basal Tg and Tg dynamics did not predict disease recurrence. Conclusions Serum thyroglobulin used independently is of limited value for predicting or detecting disease recurrence following thyroid lobectomy. Other potential roles of Tg, such as detecting distant metastases following lobectomy, should be further studied.

Background While the popularity of lobectomy for differentiated thyroid cancer (DTC) has increased since the 2015 ATA guidelines, recent studies reported that adverse histological features (minimal extra-thyroidal extension (mETE), multifocality, vascular invasion and lymph node (LN) metastases) may be found in 30-60% of lobectomy specimens, questioning the validity of this approach. Aim To assess the prevalence adverse histological features in occult DTC detected in autopsy studies. Methods Meta-analysis of autopsy studies of the thyroid in subjects without known history of thyroid cancer. Results Twenty nine studies including 8,750 subjects fulfilled the inclusion criteria, with incidentally discovered DTC in 740 autopsies (8.5%). Age was reported in 17 studies, with a median age of 61 years (range 41-68 years). Multifocality was reported in 27 studies with a calculated event rate of 28.2% (95%CI 23.1% to 33.8%; I2=46.3%), with bilateral involvement in 18% (95%CI 12.6%-25.1%). Minimal ETE was reported in five studies, with an event rate of 24.5% (95%CI 9.3% to 50.7%, I2=88.5%), and the presence of LN metastases were reported in 13 studies with an event rate of 11% (95%CI 6.1% to 19.1%, I2=69.5%). Vascular invasion was reported in seven studies with an event rate of 16% (95%CI 4% to 47%, I2=86.8%). Of 25 studies with whole body autopsies (722 subjects), three cases of distant metastases were reported, of which two had fatal metastatic disease (where thyroid origin was not diagnosed before death), and one had occult disease. Conclusions Adverse histological features including mETE, LN metastases, multifocality, and vascular invasion are common in occult DTC. When minimal in size, these adverse histological features do not seem to be markers of aggressive disease and may not be an indication for completion thyroidectomy or radioiodine therapy.

To characterize a cohort of elderly men with prolactinomas and their response to treatment. We have identified 28 elderly men diagnosed after the age of 65 with prolactinomas at seven different endocrine clinics in Israel. A retrospective electronic chart review identified a control group of 76 younger men with macroprolactinomas treated in one of the centers. Mean age at diagnosis was 71.3 ± 5.6 (range 65–86) years, and current age 76.6 ± 7.5 years. Initial complaints leading to diagnosis included sexual dysfunction in 17 males (61%), headaches in two patients (7%), and visual abnormalities in two (7%). Three men presented with osteoporosis. Ten patients (36%) were diagnosed incidentally following brain imaging for unrelated reasons. Seventeen patients (61%) had macroadenoma, while eleven (39%) presented with a microadenoma or no visible adenoma. Mean prolactin (PRL) at presentation was 1594 (median 382; range 50–18,329) ng/ml. Testosterone was low in 21 men. Patients were treated with cabergoline (max dose, 1.1 ± 0.5 mg/week), except for one given bromocriptine; none required pituitary surgery or radiotherapy. Treatment normalized PRL in 24 patients, and in three men PRL suppressed to

Background Papillary thyroid cancer (PTC) usually metastasizes via lymphatic channels in a sequential fashion, first to the central compartment, followed by the lateral neck. PTC patients diagnosed with lateral neck disease (N1b) without proof for central involvement traditionally undergo prophylactic central neck dissection (pCND). However, substantial evidence on outcomes to support this approach is lacking. Materials and methods We conducted a dual center retrospective study to compare the rate of central neck recurrence between N1b PTC patients undergoing pCND and those spared pCND. All patients diagnosed with N1b PTC who underwent total thyroidectomy and lateral neck dissections with or without pCND between January 1998 and December 2015 were included in this study. The rates of central neck recurrences were compared between the groups. Results The 111 patients who met the inclusion criteria were 44 females (39.6%) and 67 males (60.4%), with a mean age of 50.2 ± 17.7 years, and a mean follow-up of 10.2 ± 5.3 years. Sixty patients (54.1%) underwent a pCND and 51 patients (45.9%) did not (non-pCND). During follow-up, 18 patients (16.2%) had level VI recurrences, 13 in the pCND group and 5 in the non-pCND group. Cox-regression models with propensity scoring did not reveal any inclination or an advantage for performing pCND. Conclusion The present study demonstrated no advantage in performing pCND to prevent central neck recurrence among PTC patients with lateral neck involvement only. These findings question the need for pCND in patients without clinical evidence of central neck disease.

Introduction: The 2015 American Thyroid Association (ATA) guidelines recommend response to therapy (RTT) assessment 1–2 years after initial treatment in differentiated thyroid cancer (DTC) patients...

Background Familial non-medullary thyroid carcinoma (FNMTC), mainly of papillary histotype (FPTC), is defined by the presence of the disease in two or more first-degree relatives in the absence of other known familial syndromes. With the increasing incidence of PTC in the recent years, the familial form of the disease has also become more common than previously reported and constitutes nearly 10% of all thyroid cancers. Many aspects of FNMTC are debated, concerning both clinical and genetic aspects. Several studies reported that, in comparison with sporadic PTCs, FPTCs are more aggressive at disease presentation, while other authors reported no differences in the clinical behavior of sporadic and familial PTCs. For this reason, recent guidelines do not recommend screening of family members of patients with diagnosis of differentiated thyroid cancer (DTC). FNMTC is described as a polygenic disorder associated with multiple low- to moderate-penetrance susceptibility genes and incomplete penetrance. At the moment, the genetic factors contributing to the development of FNMTC remain poorly understood, though many putative genes have been proposed in the recent years. Purpose Based on current literature and our experience with FNMTC, in this review, we critically discussed the most relevant controversies, including its definition, the genetic background and some clinical aspects as screening and treatment.

The widespread use of neck sonography in recent years has led to a dramatic increase in the detection of thyroid cancer, accompanied by changes in the clinicopathologic features of the disease. However, small papillary carcinomas account for the bulk of this increase, while little is known about temporal changes in medullary thyroid carcinoma (MTC). The aim of this study was to evaluate trends in the presentation, treatment, and outcome of MTC.Patients treated for MTC at four medical centers in Israel were divided into three groups by year of diagnosis: 19811995 (period A), 1996-2005 (period B), and 2006-2016 (period C). Clinicopathologic and survival data were collected retrospectively from the medical files and compared between the groups.The cohort included 182 patients (54.9% female) with a mean age of 49.2 ± 18.7 years: 43 (23.6%) diagnosed in period A, 54 (29.7%) in period B, and 85 (46.7%) in period C. No significant differences were found between the groups in primary tumor size (25.7 ± 18.9 mm, 26.6 ± 18 mm, and 23.7 ± 17.6 mm, respectively), proportion of micro-MTC (30.8%, 20.0%, and 25.3%, respectively), or TNM staging. Age at diagnosis significantly increased over time (38.7 ± 17.2 years, 51.7 ± 18.4 years, and 53.7 ± 17.7 years, respectively; p 0.001), and the rate of familial MTC significantly decreased (41.9%, 14.8%, and 8.2%, respectively; p = 0.002). Although the implementation of cervical lymph node dissection increased (62.1%, 78.4%, and 85%, respectively; p = 0.01), detection of metastatic lymph nodes decreased from 88.9% in period A to 65.0% in periods B and C (p = 0.06). There was no difference between the groups in disease-specific survival or disease-free state at one year from diagnosis (37.5%, 43.1%, and 50%, respectively) and last follow-up (27%, 41.2%, and 48%, respectively). Similar findings on MTC presentation and outcomes were obtained when only patients with non-familial MTC were analyzed.Unlike differentiated thyroid cancer, most of the presenting features of MTC have not changed over time. The most significant temporal change is a decreased rate of familial MTC. Despite more extensive surgery and the use of new treatment modalities in recent years, significant improvement in disease-related outcomes were not found.

Objectives Radioactive iodine (RAI) treatment is often indicated after total thyroidectomy in differentiated thyroid cancer (DTC). However, its role in biochemical or locoregional persistent DTC is unclear. We aimed to investigate the effect of a second RAI treatment in patients with incomplete response to initial treatment and no evidence of distant metastases. Methods Patients who underwent at least two RAI treatments over a 20-year period at a tertiary hospital were identified. Thyroglobulin levels and neck imaging were compared before and 1 to 2 years after RAI retreatment and evaluated at the last visit. Results The cohort included 164 patients (103 female; mean age, 46.6 ± 17 years). Of 114 patients retreated without prior reoperation, 53 had structural disease. At 1 to 2 years after RAI retreatment, 10 of the 41 patients with sufficient data had structural progression, 5 resolution/shrinkage, and 26 stable disease. Stimulated thyroglobulin (stTg) measured 93.7.1 ± 108 ng/mL before and 102.2 ± 124 ng/mL after retreatment (P = NS). The other 61 patients had biochemical-only persistence. Their stTg levels decreased from 41.9 ± 56 to 24.6 ± 54 ng/mL (P = 0.003). The 50 patients who underwent neck reoperation before RAI retreatment showed no substantial change in stTg; 21 (42%) still had imaging findings 1 to 2 years later. At final follow-up, despite additional treatment in 63/164 patients (38.4%), only 56/164 (34.1%) had no evidence of disease. Conclusions This comprehensive study showed limited benefit of second RAI treatment in DTC patients with biochemical or locoregional structural persistent disease. Prospective studies are needed to distinguish patients for whom repeated RAI may be indicated to avoid unnecessary exposure.

Background: While the popularity of lobectomy for differentiated thyroid cancer (DTC) has increased since the 2015 American Thyroid Association guidelines, several recent studies reported that “high risk” histological features may be found in up to half of lobectomy specimens, questioning the validity of this approach. In turn, the actual risk associated with some “high risk” features (multifocality, minimal extra-thyroidal extension (ETE), and small lymph node (LN) metastases) has been questioned in recent years. Aim: To assess the prevalence of “high risk” pathological features in occult DTC detected in autopsy studies. Methods: Meta-analysis of autopsy studies of the thyroid gland in subjects without history of thyroid cancer. Studies with DTC lesions and details on histological features were included. Results: Twenty nine studies including 8,750 subjects fulfilled the inclusion criteria, with incidentally discovered DTC in 740 autopsies (prevalence of 8.5%). Age was reported in 17 studies, with a median age of 61 years (range 41-68 years). Multifocality was reported in 27 studies with a calculated event rate of 28.2% (95%CI 23.1% to 33.8%, random effect), with bilateral involvement in 18% (95%CI 12.6%-25/1%). Minimal ETE was reported in five studies, with an event rate of 24.5% (95%CI 9.3% to 50.7%, random effect), and the presence of LN metastases was reported in 13 studies with an event rate of 11% (95%CI 6.1% to 19.1%, random effect). Vascular invasion was reported in seven studies with an event rate of 16% (95%CI 4% to 47%, random effect). Conclusions: “High risk” histological features are common in occult DTC found in autopsy studies, and do not seem to be markers of aggressive disease. These data support a less aggressive therapeutic approach in patients with microscopic “high risk” features which were not detected on pre-operative ultrasound.

Distant metastatic spread is the most frequent cause of thyroid cancer-related death. The objective of this study was to evaluate overall and disease-related survival of patients with differentiated thyroid cancer (DTC) and distant metastases (DM) attending a single medical center and to investigate variables predictive of better long-term outcomes.The Rabin Medical Center Thyroid Cancer Registry was searched for patients with DM from DTC.The cohort included 138 patients (58.7% female) diagnosed at age 54.7 ± 19.5 years. Mean primary tumor size was 33.9 ± 26 mm. Most patients (57.7%) were stage T3/T4; 48.7% had extrathyroidal extension; 53.5% had lymph node metastases. Histopathology yielded papillary and follicular thyroid carcinoma in 66.7% and 13.8%, respectively, and intermediate/poorly differentiated carcinoma in 19.6%. All but 2 patients underwent total thyroidectomy, and 133/138 (96.4%) received radioactive iodine (RAI) therapy. DM were synchronous in 55.1%. The mean follow-up was 8.2 years from detection of metastases. The common sites of metastases were the lungs (85.6% of patients), bones (39.9%), brain (5.8%) and liver (3.6%). At last follow-up, resolution was documented in 24.6% of patients, improvement/stable disease in 31.6%, and structurally progressive disease in 43.4%. By the end of the study, 40.6% of patients died, 23.2% of DTC. Improved overall survival and disease progression were associated with younger age, lung-only DM, and metastatic RAI avidity.Patients with DTC and DM treated by standard-of-care approaches frequently achieve favorable long-term outcomes. Novel therapies might be necessary in only a minority of these patients, and the reported prognostic factors can aid in their identification.CR = complete response; DM = distant metastases; DTC = differentiated thyroid cancer; ETE = extra-thyroidal extension; M0 = detected during follow-up; M1 = detected at diagnosis; MSKCC = Memorial Sloan Kettering Cancer Center; NED = no evidence of disease; OS = overall survival; PFS = progression free survival; PTC = papillary thyroid cancer; RAI = radioactive iodine; Tg = thyroglobulin.

The current trend of less aggressive treatment of low-risk differentiated thyroid cancer (DTC) patients was recently challenged by a study reporting10% disease-related mortality (DRM) in low-risk patients ablated with radioiodine activities below 54 mCi. However, this study and others were limited by incomplete data on disease severity at presentation. Whether patients presenting with low-risk disease are at risk for disease-related mortality is crucial for planning current treatment strategies.Patients with documented DRM from DTC were included from the Rabin thyroid cancer registry and the Davidoff Head and Neck cancer service databases. Disease characteristics at presentation, treatments, disease course, and cause of death were analyzed.Of 1374 patients whose charts were reviewed, 56 were confirmed to have died of DTC, and 53 had sufficient data for analysis. Median time from diagnosis to death was 9 years (range 1-36). Cause of death was related to distant metastases in 46 patients and aggressive neck disease in 7 patients. The median age at diagnosis was 62 years (range 22-83, 83% older than 45), and were initially categorized as American Thyroid Association high risk in 89% of cases (in 4 cases due to high thyroglobulin levels), intermediate risk in 6% (3 older patients with N1b disease), misclassification as benign in one case, and none was low risk. Most patients had an advanced disease stage (stage IV, 88%; III, 2%; II, 2%; I, 8%). All patients with stage I disease were45 years, with aggressive features (1 poorly differentiated, 3 gross extrathyroidal extension). One patient with stage II disease was45 years and had distant metastases. Detection of distant metastases occurred within the first year in 25 patients and during subsequent follow-up in 25 patients. Overall, aside from one patient who was misdiagnosed as having a benign follicular adenoma at presentation, all patients had aggressive disease features at presentation.None of the patients with DRM had low-risk features at presentation, supporting the current paradigm of less aggressive approach in the low-risk group. Studies analyzing mortality from thyroid cancer should stratify patients into the various risk categories based on full baseline data, including postoperative thyroglobulin levels.

Objective: This institutional study sought to retrospectively evaluate disease progression and survival of patients with differentiated thyroid cancer (DTC) and bone metastases (BM) and to investigate variables predictive of better long-term outcomes. Methods: The Rabin Medical Center Thyroid Cancer Registry was searched for patients with bone-metastatic DTC. Variables including a patient's gender and age, pathology of the thyroid tumor, and characteristics of BM were retrieved and analyzed in association with disease progression and mortality. Results: The cohort included 64 patients (48.4% female). Mean age at diagnosis was 62.1 ± 14.3 years; mean primary tumor size was 41 ± 30 mm. Overall, 60.4% had stage T3/T4 disease; 46.3% had extrathyroidal extension; 40% had lymph-node metastases. Histopathology yielded papillary and follicular DTC in 40.6% and 32.8% of patients, respectively, and poorly/intermediately differentiated carcinoma in 26.6%. BM were synchronous in 50%. Mean follow-up was 11 ± 9.6 years from DTC detection. The common first sites of BM detection were spine (46.9% of patients), pelvis (37.5%) and ribs (21.9%). Nineteen patients (29.7%) presented with multiple-site BM, of whom 15 (78.9%) had spinal metastases. After initial treatment, 62/64 patients had structural persistence, and at last follow-up, 57.8% had progressive disease. Overall, 54.7% of patients died, 71.4% of DTC. Improved long-term outcomes were associated with younger age, lower tumor stage, no extrathyroidal extension, bone-only metastases, and non-spinal BM. Younger age and non-spinal BM were the only independent predictors for improved survival. Conclusions: Selected patients with bone-metastatic DTC may achieve fair long-term outcomes. Spinal metastases are associated with disseminated skeletal spread and increased mortality. Abbreviations: BM = bone metastases; COX = multivariate analyses; DM = distant metastases; DSM = disease-specific mortality; DSS = disease-specific survival; DTC = differentiated thyroid carcinoma; ETE = extrathyroidal extension; LNM = lymph node metastases; OM = overall mortality; OS = overall survival; PTCFV = papillary thyroid carcinoma; RAI = radioactive iodine; SM = spinal metastases; SRE = skeletal-related event; txWBS = whole-body scan after RAI therapy.

Objective: Male gender is considered an adverse prognostic factor for remission of Graves disease treatment with antithyroid drugs (ATDs), although published data are conflicting. This often results in early consideration of radioiodine treatment and surgery for men. Our objective was to compare disease presentation and outcome in men versus women treated with ATDs. Methods: Retrospective study of 235 patients (64 men, 171 women) with Graves disease who were evaluated for features at presentation and outcome at the end of follow-up between 2010 and 2015. Results: Disease presentation was similar in men and women for age at diagnosis (41.4 ± 14 years vs. 40 ± 15 years), duration of follow-up (6.6 ± 7 years vs. 7.7 ± 6 years), rates of comorbid autoimmune diseases, and rate of Graves ophthalmopathy. Smoking was more prevalent in males (31% vs. 15%; P = .009). Free thyroxine and triiodothyronine levels were comparable. ATDs were first-line treatment in all males and in 168 of 171 females, for a median duration of 24 and 20 months, respectively (P = .55). Remission rates were 47% in men and 58% in women (P = .14). Males had fewer adverse events (9% vs. 18%) and treatment discontinuation (5% vs. 16%). Disease recurrence was comparable (14% vs. 20%; P = .32), as was requirement for second-line treatment, either radioiodine therapy or thyroidectomy. Conclusion: Graves disease presentation is similar in men and women. Men treated with ATDs have high remission rates and similar recurrence rates compared to women, with fewer adverse events and less discontinuation of treatment. ATDs are an attractive first-line treatment for both genders. Abbreviations: ATA = American Thyroid Association; ATD = antithyroid drug; GO = Graves ophthalmopathy; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone

The occurrence of nonthyroidal primary malignancy (NTPM) and the potential association of with radioiodine (RAI) treatment are important concerns in patients with differentiated thyroid cancer (DTC), but incidence data are conflicting. The aims of the present study were to investigate the incidence of NTPM and its association with RAI treatment in a cohort of DTC patients treated at a single tertiary medical center.The data of 1943 patients with DTC recorded in the Rabin Medical Center Thyroid Cancer Registry were cross-matched with data from the Israeli National Cancer Registry to identify those diagnosed with an NTPM. Patient medical files were reviewed. Second primary malignancy (SPM) was defined as new malignancy diagnosed at least two years after DTC diagnosis.For 1434 of the 1943 patients (73.8%), the American Joint Committee on Cancer TNM stage was 1-2. The mean follow-up was 9.3 years. Of the 1943 patients, 1574 (81%) were treated with RAI, and 1467 were followed for at least 2 years, and of these, 1145 patients (78%) received a cumulative dose of ≤200 mCi. A total of 409 NTPMs were diagnosed in 368/1943 patients with DTC (18.9%; 265 female, mean age 53.9 ± 15 years), including 173 SPMs (42.3%) in 166/368 patients. The most common NTPM and SPM was breast cancer followed by hematologic malignancies. In patients followed for ≥2 years, SPMs were diagnosed in 9% of RAI-treated patients and 10.5% of non-RAI-treated patients. SPM rates were 10.2% and 7.8% for a cumulative RAI dose of ≤100 mCi and100 mCi respectively. Hazard ratios for SPM in patients that received/did not receive RAI treatment was 1.27 (95% confidence interval 0.88-1.82; p = 0.1). There was no correlation between first or cumulative RAI dose and diagnosis of SPM.NTPMs are not uncommon in patients with DTC and usually antecede the DTC. In a population of mostly low-risk DTC patients, in whom limited activities of RAI are usually administered, this treatment is apparently not associated with an overall increased risk of SPMs compared with subjects not receiving RAI treatment.

Objective Clinically nonfunctioning pituitary adenoma (NFPA) remains the only pituitary tumor subtype for which no effective medical therapy is available or recommended. We evaluated dopamine agonist (DA) therapy for preventing growth of postsurgical pituitary tumor remnants. Design The study design included historical cohort analysis of clinical results at two pituitary referral centers with different standard practices for postoperative NFPA management: DA therapy or conservative follow-up. Methods Seventy-nine patients followed for 8.8±6.5 years were treated with DA, initiated upon residual tumor detection on postoperative MRI (preventive treatment (PT) group, n=55), or when tumor growth was subsequently detected during follow-up (remedial treatment (RT) group, n=24). The control group (n=60) received no medication. Tumoral dopamine and estrogen receptor expression assessed by quantitative RT-PCR and immunostaining were correlated with response to treatment. Results Tumor mass decreased, remained stable, or enlarged, respectively, in 38, 49, and 13% of patients in the PT group, and in 0, 53, and 47% of control subjects; shrinkage or stabilization was achieved in 58% of enlarging tumors in the RT group, P < 0.0001. Fifteen-year progression-free survival rate was 0.805, 0.24, and 0.04, respectively, for PT, RT, and control groups (PP=0.002). Outcome measures were not related to NFPA D2R abundance. Conclusions Dopamine agonist therapy in patients with NFPA is associated with decreased prevalence of residual tumor enlargement after transsphenoidal surgical resection.

Bone disease is a major cause for morbidity in multiple myeloma (MM), with the main focus concerning the manifestation as osteolytic lesions. Bone mineral loss is another reflection of myeloma bone involvement. Recently, osteoporosis has been omitted as a defining criterion for symptomatic disease in MM. We conducted a retrospective study to evaluate the use of bone mineral density (BMD) exams by dual-energy X-ray absorptiometry (DXA) among MM patients in a tertiary medical care centre. One-hundred seventy three patients were included. The T-scores of lumbar spine (LS), left femur neck (FN) and left total hip (TH) were obtained and analysed. The extent of osteolytic disease was categorized based on six bony areas. There was a strong correlation between spine and femur's T-scores (r = 0.56-0.61, p

To evaluate the utility of Insulin-like growth factor I (IGF-I) standard deviation score (SDS) as a surrogate marker of severity of hypopituitarism in adults with pituitary pathology. We performed a retrospective data analysis, including 269 consecutive patients with pituitary disease attending a tertiary endocrine clinic in 1990–2015. The medical files were reviewed for the complete pituitary hormone profile, including IGF-I, and clinical data. Age-adjusted assay reference ranges of IGF-I were used to calculate IGF-I SDS for each patient. The main outcome measures were positive and negative predictive values of low and high IGF-I SDS, respectively, for the various pituitary hormone deficiencies. IGF-I SDS correlated negatively with the number of altered pituitary axes (p

To describe the various patterns of presentation, including assisting analyses, associated with the timing of diagnosis of females with hypopituitarism and suspected clinical diagnosis of lymphocytic hypophysitis.A retrospective study of 9 consecutive females with pituitary dysfunction developed during or after pregnancy. All subjects were treated in our clinics between 2008 and 2014. Data were collected on clinical characteristics, pituitary hormone levels, and imaging findings.The study group included 9 patients with a mean age 33.7 ± 7.8 years at delivery. The probable cause of disease was lymphocytic hypophysitis. Headache or specific symptoms/signs of hypopituitarism appeared within 1 year of delivery. Five patients had headache, and 8 had difficulty breastfeeding or amenorrhea. Laboratory findings included central hypocortisolism (8/9 patients), hypogonadotropic hypogonadism (8/9), and central hypothyroidism (6/7). Insulin-like growth factor-1 (IGF-1) levels were low in 8/8 patients. Prolactin levels were low in 3/9 patients, and 1 patient had diabetes insipidus. Seven patients were diagnosed less than 1 year from symptom onset; 4 (57%) complained of headaches, and 5 (71%) had panhypopituitarism. Two patients were diagnosed later. Both had difficulty breastfeeding and amenorrhea, and one also had headaches. Both had panhypopituitarism and reduced pituitary volume. None of the patients fully recovered pituitary function. Normalization of the thyrotroph axis occurred in 3 patients, gonadotroph function in 3, the corticotroph axis in 2, and IGF-1 normalized in 1 subject.Hypopituitarism attributed to lymphocytic hypophysitis may present during pregnancy or early postpartum period with a clear clinical picture, or later, with indolent and nonspecific symptoms and signs.

The prevalence of adrenal incidentalomas (AIs) in asymptomatic individuals is unknown. This study evaluated the prevalence of AIs in healthy kidney donors in whom pre-operative computed tomography (CT) is performed routinely.All potential kidney donors evaluated at the Rabin Medical Center who had routine abdominal CT were identified and their medical records were retrospectively reviewed. Subjects who had normal CT scans were compared with those with a finding of an AI, evaluating demographic (age, body mass index, systolic and diastolic blood pressure) and laboratory variables (glucose, sodium, potassium, calcium, phosphorus, albumin and creatinine). In addition, prevalence of hypertension, rate of donation and surgical mortality were compared between the two groups.CT was performed in 673 potential kidney donors. Of these, 645 had a normal CT and 28 (4.2%) had evidence of an AI. Those with AIs had a similar prevalence of hypertension, kidney donation and surgical mortality as those with a normal CT. Those with AIs were older (50.93 ± 11.1 versus 43.76 ± 11.1 years) but other demographic variables were similar; laboratory variables were also similar except for slightly lower albumin and creatinine in those with AIs.The prevalence of AIs is high even in healthy asymptomatic individuals.

Euvolemic hyponatremia results from either the syndrome of inappropriate antidiuretic hormone secretion (SIADH), hypothyroidism, or adrenal insufficiency. Furthermore, the criteria for diagnosis of SIADH entail the exclusion of hypothyroidism and hypoadrenalism. We aim to assess the yield of euvolemic hyponatremia workup focusing on underlying endocrinopathies in a real-world setting. A single-center retrospective study includes all patients diagnosed with euvolemic hyponatremia in a tertiary hospital between 1.1.2007 and 1.1.2013. Demographic, clinical, and laboratory data were collected from medical charts. Euvolemic hyponatremia was detected in 564 patients. Thyroid function was tested in 69% (391/564) and adrenal function was assessed in 29% (164/564) of cases. Endocrinopathy-induced euvolemic hyponatremia was diagnosed in nine (1.6%) patients: three patients were diagnosed with hypothyroidism-induced hyponatremia, three with adrenal insufficiency as an underlying cause, and three with central hypothyroidism and central hypoadrenalism. All nine had medical history and symptoms suggestive of endocrine deficiencies other than the hyponatremia, which resolved within 1–3 days after administration of hormone replacement therapy. Yield of performed workup for hypothyroidism and hypoadrenalism in euvolemic hyponatremia was low. However, in this real-world study, only a limited number of patients underwent a full ascertainment of hypoadrenalism and hypothyroidism, which was diagnosed only in patients with additional findings supportive of these endocrinopathies; a higher rate of undiagnosed endocrinopathies cannot be ruled out. As both hypoadrenalism and hypothyroidism are easily treatable, potentially life-threatening conditions, there are insufficient data to change current recommendation for their universal evaluation in patients with euvolemic hyponatremia.

Background Minimal extrathyroid extension (mETE) in patients with differentiated thyroid cancer (DTC) was defined as an intermediate risk feature in the 2015 American Thyroid Association guidelines. However, controversy persists as several studies suggested mETE has little effect on disease outcome. Objective To assess the impact of mETE on DTC patients' outcome. Methods Meta-analysis of controlled trials comparing patients with DTC with and without mETE. Data Extraction and Synthesis Thirteen retrospective studies including 23,816 patients were included, with a median follow-up of 86 months. mETE in patients without lymph node involvement (N0 disease) was associated with increased risk of recurrence [seven studies: odds ratio (OR), 1.73; 95% confidence interval (CI), 1.03 to 2.92]. The absolute risk of recurrence was 2.2% in patients without extension and 3.5% in patients with mETE (P = 0.04). In studies including patients with and without lymph node involvement (N1/N0 disease), mETE resulted in a significantly higher risk of recurrence (eight studies: OR, 1.82; 95% CI, 1.14 to 2.91). The absolute risk of recurrence was 6.2% in patients without extension and 7% in patients with mETE (P = 0.01). In patients with micropapillary carcinoma ( Conclusion mETE increases risk of recurrence in patients with DTC; however, the absolute increase in risk is small, and in patients with N0 disease the risk is within the low-risk of recurrence category at 3.5%. mETE has no impact on disease-related mortality and should not change tumor stage.

Brain metastases from non-medullary thyroid carcinoma (NMTC) are rare, with a reported frequency of ~1%, and patient survival time is 2 years, supporting an aggressive treatment approach.

Background Bilateral thyroid nodularity is considered an indication for total thyroidectomy in papillary thyroid carcinoma (PTC). However, the natural history and outcome of contralateral nodules have never been studied. Objective To investigate the natural history of nonsuspicious contralateral nodules after lobectomy for PTC. Methods We included patients who had one or more solid nodules (≥3 mm) in the contralateral lobe with benign cytology before surgery or small nonsuspicious nodules per ultrasonography. Results One hundred and twelve patients were included. Median age was 57 years, and median size of the PTC (initial lobectomy) was 8 mm (range, 0.5 to 28 mm). On the contralateral side, the median size of nodules was 7 mm (range, 3 to 30 mm). Thirty-three nodules (29%) had fine-needle aspiration (FNA) before surgery, and all were benign. After a median follow-up of 6 years, median growth was zero (range, −20 to 19 mm). Twenty-six nodules (23%) increased ≥3 mm in size (median, 6 mm; range, 4 to 19 mm). Twenty patients (18%) developed new nodules. Twelve patients (11%) underwent completion thyroidectomy for growth (three), suspicious FNA (seven; Bethesda III to V), malignancy (one), or unknown reason (one). Overall, according to the completion thyroidectomy specimen, six patients (5%) were diagnosed with contralateral PTC (five micro-PTCs, one 20 mm), and all were without evidence of disease at the end of follow-up. There were no surgical difficulties or local complications during completion surgery. Conclusions Lobectomy for low-risk patients with a small PTC and nonsuspicious contralateral thyroid nodule(s) is a reliable and safe initial treatment option. In the few patients who required completion thyroidectomy, treatment with surgery and radioiodine was effective.

Limited data is available regarding the association between pre-admission thyroid function and prognosis of hospitalized patients treated for hypothyroidism. Evaluate an association between thyroid stimulating hormone (TSH) levels and mortality in hospitalized levothyroxine-treated patients. Observational data of patients admitted to medical wards between 2011 and 2013. TSH levels obtained up to 180 days prior to admission were stratified as follows: low (≤0.5 mIU/L), normal (0.5–5 mIU/L), high (>5 mIU/L). Patients aged 60–80 years with available thyroid function tests were matched with controls without hypothyroidism. All-cause mortality up to 66-months following discharge. One thousand and fifty seven patients (73% females, mean (SD) age 71 ± 6 years) were matched with controls without hypothyroidism. Mean hospital stay and in-hospital mortality were not different between groups. Mortality risk at the end-of-follow-up was 41% (438/1057) and 37% (392/1057) for patients with and without hypothyroidism (p

Evaluation of surgical specimens suggests that patients with Hashimoto thyroiditis (HT) have a higher prevalence of differentiated thyroid cancer. Although patients with HT are reported to present with earlier stage disease, there is controversy as to whether these patients have better prognosis when adjusted for histology and stage at presentation.To investigate differences between patients with differentiated thyroid cancer patients and without HT for aggressiveness of disease and clinical outcome, and the decline rate of antithyroglobulin antibodies titers over time.A retrospective study using the Rabin Medical Center Thyroid Cancer Registry. Seven hundred fifty-three patients were included and divided into 2 groups of patients with and without HT at diagnosis. Disease severity at presentation was evaluated using the entire cohort, whereas a control group matched for age, gender, histology, and stage was used to evaluate disease course and outcome.HT was present in 14.2% (n = 107) of included patients and was associated with smaller primary tumor (17.9 vs 21.2 mm, P = .01) and less lymph node involvement (23% vs 34%, P = .02) at presentation. When matched groups were compared, patients with HT received less additional radioactive iodine (RAI) treatments (1.24 vs 1.45, P = .03) and showed lower rates of persistence at 1 year (13% vs 26%, P = .04) and higher rates of disease remission at the end of follow-up (90% vs 79%, P = .05). On multivariate analysis HT was predictive of a lower rate of lymph nodes involvement (odds ratio 0.34, 95% confidence interval 0.17-0.66) and persistent disease at the end of follow-up (odds ratio 0.48, 95% confidence interval 0.24-0.93). Antithyroglobulin antibodies slowly disappeared in most patients with no evidence of disease.Our study demonstrates that HT is associated with a less aggressive form of differentiated thyroid cancer and a better long-term outcome.

Objectives: To compare the incidence of cardiac and cerebrovascular events following non-arteritic anterior ischemic optic neuropathy (NAION) compared to published control data using the Framingham, United Kingdom Prospective Diabetes Study (UKPDS) and the National Vascular Disease Prevention Alliance (NVDPA) data. Methods: A retrospective study of all consecutive cases of NAION between 1990 and 2005. Patients were stratified into those with or without prior ischemic events and into diabetics and non-diabetics. Outcome measures included cardiovascular morbidity, cerebrovascular events and the Framingham, UKPDS and NVDPA scores for each patient. Results: According to the NVDPA, the average absolute 5-year risk for cardiovascular disease (CVD) was 8.98, compared to 9 CVD events in our study. In the diabetic patients, 5 (17%) had a cardiac event and 2 (8%) had a cerebral vascular accident (CVA). Based on the UKPDS risk calculator, the average 10-year risk for cardiac events is 21.6%, CVA –6.8%. In the non-diabetics, there were 3 cases (7.5%) of myocardial infarction, compared to the average 10-year Framingham risk for myocardial infarction or coronary death of 11% (±8 SD). Conclusions: Following NAION, the incidence of cardiovascular or cerebrovascular events in patients taking aspirin is not in major excess from that expected in risk-factor age-matched controls.

While involvement of macrometastatic lymph nodes is a recognized independent predictor of an adverse course in papillary thyroid cancer (PTC) patients, the clinicopathological variables associated with disease persistence/recurrence in clinically node-negative (cN0) disease are not well defined. The indications for prophylactic central neck dissection (pCND) in this patient group remain unclear as well. We aim to investigate the risk factors associated with short- and long-term persistence/recurrence of PTC in patients with cN0 disease at presentation compared to patients with PTC and cervical lymph node involvement (N1) and the response to initial treatment in these subgroups of patients. Data were collected retrospectively for 392 consecutive patients with PTC, 223 with cN0 disease and 169 with N1 disease, who were treated and followed at a single tertiary medical center in which pCND is not routinely performed for PTC. Compared to patients with N1 disease, patients with cN0 disease had significantly smaller tumors, lower rates of multifocality, and less extrathyroidal extension. Persistency rates at 1 year were 6.7 % in the cN0 group and 47 % in the N1 group, and at last follow-up, 3.6 and 33.5 %, respectively (p = 0.001 for both time points). Within the cN0 group, those with persistent disease at 1 year (n = 15) had significantly larger tumors and higher stimulated thyroglobulin. Only six had structural residual disease, four of them lymph node metastases. All patients with persistent disease were initially treated with total thyroidectomy and radioiodine. Recurrence occurred in only three patients. After 8.3 ± 3.8 years of follow-up, eight patients with cN0 had persistent disease, three of them biochemical. Higher American Joint Committee of Cancer stage and extrathyroidal extension were the only factors that predicted disease persistence at the last follow-up in this group. Patients with cN0 PTC and no distant metastases are usually disease free after thyroidectomy with/without radioactive iodine and do not need further interventions. The initial staging in these patients is a valid prognostic factor for disease outcomes.

Radiation exposure is a well-known risk factor for well-differentiated thyroid cancer (WDTC). However, disease characteristics, optimal treatment, time from exposure to disease appearance, and the effect of age at initial exposure on the outcome have yet to be determined.To identify the characteristics of radiation-induced thyroid carcinoma.We retrieved the charts of all patients previously exposed to radiation who were diagnosed with WDTC between the years 1985 and 2013 in a tertiary referral center.Forty-four patients were reviewed. Median time from radiation exposure to diagnosis was 23 years. These patients had higher rates of aerodigestive symptoms and distant metastases on presentation than seen in non-radiated patients. Patients who were exposed to radiation before age 15 years tended to develop the disease at a younger age but had a longer latency period (34.7 ± 15.3 vs. 16.3 ± 10 years, P0.001) and none had significantly higher rates of vocal cord palsy, hoarseness on presentation, or aggressive variants on histology compared to patients exposed to radiation at an older age. Disease-specific survival (DSS) was the same for both groups and were similar to that seen in the general population (95% 20 year DSS).Radiation-induced thyroid cancer has a more aggressive presentation and the age at exposure affects the presentation of disease. Nonetheless, appropriate treatment leads to a favorable prognosis.

Context: The risk of loco-regional recurrence in papillary thyroid cancer (PTC) patients ranges from 15–30%. However, the clinical significance of small-volume loco-regional recurrence detected by highly sensitive ultrasonography is unclear. Objective: Our objective was to describe the natural history of abnormal cervical lymph nodes (LN) diagnosed after initial treatment. Design: We conducted a retrospective cohort study. Patients: 166 PTC with patients who had at least one abnormal LN outside the thyroid be on ultrasound and selected for active surveillance were included. Main Outcome Measure: LN growth during a period of active surveillance was the primary outcome. Results: Most patients had classical PTC (85%) and an intermediate risk of recurrence (77%). The median LN size at the start of the observation period was 1.3 cm (range, 0.5–2.7 cm) in largest diameter, with all nodes having at least one abnormal sonographic characteristic (70% of patients had LN with at least two abnormal features). In almost all patients, the LN were in the lateral neck, primarily in levels 3 (43%) and 4 (58%). After a median follow-up of 3.5 yr, only 20% (33 of 166) grew at least 3 mm, 9% (15 of 166) grew at least 5 mm, and 14% (23 of 166) resolved. None of the clinical or sonographic features were predictive of LN growth (positive predictive value range = 0.21–0.57). There were no local complications (nerve damage or local invasion) related to the abnormal nodes and no disease-related mortality. Conclusions: Suspicious cervical LN in the lateral neck usually remain stable for long periods of time in properly selected PTC patients and can be safely followed with serial ultrasounds

Quantifying the benefit of early antibiotic treatment is crucial for decision making and can be assessed only in observational studies. We performed a systematic review of prospective studies reporting the effect of appropriate empirical antibiotic treatment on all-cause mortality among adult inpatients with sepsis. Two reviewers independently extracted data. Risk of bias was assessed using the Newcastle-Ottawa score. We calculated unadjusted odds ratios (ORs) with 95% confidence intervals for each study and extracted adjusted ORs, with variance, methods, and covariates being used for adjustment. ORs were pooled using random-effects meta-analysis. We examined the effects of methodological and clinical confounders on results through subgroup analysis or mixed-effect meta-regression. Seventy studies were included, of which 48 provided an adjusted OR for inappropriate empirical antibiotic treatment. Inappropriate empirical antibiotic treatment was associated with significantly higher mortality in the unadjusted and adjusted comparisons, with considerable heterogeneity occurring in both analyses ( I 2 > 70%). Study design, time of mortality assessment, the reporting methods of the multivariable models, and the covariates used for adjustment were significantly associated with effect size. Septic shock was the only clinical variable significantly affecting results (it was associated with higher ORs). Studies adjusting for background conditions and sepsis severity reported a pooled adjusted OR of 1.60 (95% confidence interval = 1.37 to 1.86; 26 studies; number needed to treat to prevent one fatal outcome, 10 patients [95% confidence interval = 8 to 15]; I 2 = 46.3%) given 34% mortality with inappropriate empirical treatment. Appropriate empirical antibiotic treatment is associated with a significant reduction in all-cause mortality. However, the methods used in the observational studies significantly affect the effect size reported. Methods of observational studies assessing the effects of antibiotic treatment should be improved and standardized.

Graves' ophthalmopathy (GO) is a common cause of morbidity in patients with Graves' disease. Optimal treatment of GO remains unclear, and an evidence-based approach may improve patients' outcome.A systematic review and metaanalysis of randomized, controlled trials comparing treatment modalities for GO vs. placebo, no intervention, or other treatments. Primary outcome was the clinical activity score (CAS).Thirty-three trials evaluating 1367 patients fulfilled inclusion criteria. In patients with moderate to severe GO, iv pulse corticosteroids were significantly better than oral corticosteroids in reducing CAS [standardized mean difference -0.64, 95% confidence interval (CI) -1.11 to -0.17, chi(2) 7.91, I(2) 62%, random effect], with lower rate of adverse events. Somatostatin analogs showed a minor but statistically significant advantage over placebo (mean difference -0.63, 95% CI -0.98 to -0.28). There was no advantage of orbital radiotherapy over sham radiation in CAS, but radiotherapy was superior for response rates of diplopia (odds ratio 4.88, 95% CI 1.93-12.34, two trials). Treatment with combination of orbital radiotherapy and corticosteroids was significantly better than with either treatment alone (standardized mean difference -1.05, 95% CI -1.62 to -0.48).Current evidence demonstrates the efficacy of iv corticosteroids in decreasing CAS in patients with moderate to severe GO. Intravenous pulse corticosteroids therapy has a small but statistically significant advantage oral therapy and causes significantly fewer adverse events. Somatostatin analogs have marginal clinical efficacy. The efficacy of orbital radiotherapy as single therapy remains unclear, whereas the combination of radiotherapy with corticosteroids has better efficacy than either radiotherapy or oral corticosteroids alone.

Objectives To assess the evidence for the current standard of practice of using empirical antifungal treatment in febrile neutropenic cancer patients. Methods Systematic review and meta-analysis of randomised controlled trials comparing empirical or preemptive antifungal treatment with placebo, no intervention, or another antifungal. The primary outcomes were all-cause mortality and invasive fungal infections (IFI) (documented or probable). Relative risks (RR) with 95% confidence intervals (CI) were pooled. Results Six trials assessed the efficacy of empirical treatment compared to no treatment and one compared empirical to preemptive therapy. Empirical treatment did not decrease mortality significantly (RR 0.82, 95% CI 0.50–1.34), but significantly decreased IFIs (RR 0.25, 0.12–0.54). Twenty-three trials assessed the efficiency of different antifungals. All-cause mortality was lower with azoles compared to amphotericin B (AB) (RR 0.81, 0.65–1.01); IFI rates were not different while adverse events were less frequent with azoles (RR 0.40; 0.34–0.66). Liposomal AB was associated with lower mortality and IFIs than other AB formulations (RR 1.57, 1.10–2.23 and 1.48, 0.98–2.25, respectively). Caspofungin was associated with fewer adverse events, but otherwise comparable to liposomal AB. All trials included patients with haematological malignancies. Major limitations included per-protocol analysis, non-blinded design and inconsistent definitions of IFIs. Conclusions Empirical antifungal treatment is associated with a lower rate of IFIs but no significant difference in overall mortality. The assessment of IFIs in these trials may have been biased, offering only weak support to standard practice. Azoles, liposomal amphotericin B or caspofungin should be preferred. Pre-emptive antifungal therapy should be considered and further investigated.

Purpose To evaluate the effect of antifungal prophylaxis on all-cause mortality as primary outcome, invasive fungal infections (IFIs), and adverse events. Many studies have evaluated the role of antifungal prophylaxis in cancer patients, with inconsistent conclusions. Methods We performed a systematic review and meta-analysis of randomized, controlled trials comparing systemic antifungals with placebo, no intervention, or other antifungal agents for prophylaxis in cancer patients after chemotherapy. The Cochrane Library, MEDLINE, conference proceedings, and references were searched. Two reviewers independently appraised the quality of trials and extracted data. Results Sixty-four trials met inclusion criteria. Antifungal prophylaxis decreased all-cause mortality significantly at end of follow-up compared with placebo, no treatment, or nonsystemic antifungals (relative risk [RR], 0.84; 95% CI, 0.74 to 0.95). In allogeneic hematopoietic stem-cell transplantation (HSCT) recipients, prophylaxis reduced all-cause mortality (RR, 0.62; 95% CI, 0.45 to 0.85), fungal-related mortality, and documented IFI. In acute leukemia patients, there was a significant reduction in fungal-related mortality and documented IFI, whereas the difference in mortality was only borderline significant (RR, 0.88; 95% CI, 0.74 to 1.06). Prophylaxis with itraconazole suspension reduced documented IFI when compared with fluconazole, with no difference in survival, and at the cost of more adverse events. On the basis of two studies, posaconazole prophylaxis reduced all-cause mortality (RR, 0.74; 95% CI, 0.56 to 0.98), fungal-related mortality, and IFI when compared with fluconazole. Conclusion Antifungal prophylaxis decreases all-cause mortality significantly in patients after chemotherapy. Antifungal prophylaxis should be administered to patients undergoing allogeneic HSCT, and should probably be administered to high-risk acute leukemia patients.

Bone disease is a major cause for morbidity in multiple myeloma (MM), with the main focus concerning the manifestation as osteolytic lesions. Bone mineral loss is another reflection of myeloma bone involvement. Recently, osteoporosis has been omitted as a defining criterion for symptomatic disease in MM. We conducted a retrospective study to evaluate the use of bone mineral density (BMD) exams by dual-energy X-ray absorptiometry (DXA) among MM patients in a tertiary medical care centre. One-hundred seventy three patients were included. The T-scores of lumbar spine (LS), left femur neck (FN) and left total hip (TH) were obtained and analysed. The extent of osteolytic disease was categorized based on six bony areas. There was a strong correlation between spine and femur's T-scores (r = 0.56-0.61, p 0.0001), although different sets of variables were correlated with LS and femur's T-scores. There was no correlation between BMD measurements and osteolytic disease extent. Patients with vertebral fracture(s) had significant lower T-scores of the spine in comparison to patients without vertebral fractures. Sixty-three patients (36.4% of the cohort) had follow-up DXA exam. In general, there was an increase in the LS T-scores, while femoral values decreased. However, in patients who achieved complete response (CR) and in those who retained CR during follow-up, femoral BMD increased as well. Because correlation between BMD and the extent of osteolytic lesions was not seen, our data support the recent exclusion of BMD assessment from the definition of symptomatic myeloma. Still, its use should be considered for evaluation of age- or therapy-related osteoporosis. Copyright © 2016 John WileySons, Ltd.

The Bethesda system for reporting thyroid cytopathology (TBSRTC) was developed in 2009 to standardize the terminology for interpreting fine-needle aspiration (FNA) specimens. A historical prospective case series design was employed. The study group included patients with a thyroid nodule classified as TBSRTC AUS/FLUS (B3) or FN/SFN (B4) in 2011–2012 in a tertiary university-affiliated medical center. Rates of surgery and malignancy detection were compared to our pre-TBSRTC (1999–2000) study. Of 3927 nodules aspirated, 575 (14.6 %) were categorized as B3/B4. Complete data were available for 322. Thyroidectomy was performed in 123 (38.2 %) cases: 66/250 (26.4 %) B3 and 57/72 (79.2 %) B4. Differentiated thyroid cancer was found in 66 (53.7 %) patients: 30/66 (45.5 %) B3 and 36/57 (63.2 %) B4 (p = 0.075). Operated patients were younger than the non-operated (B3: 52.4 ± 16 vs. 59.7 ± 13 years, p = 0.009; B4: 51.7 ± 15 vs. 60.5 ± 14 years, p = 0.042), and operated B3 nodules were larger than the non-operated (27.2 vs. 22.2 mm, p = 0.014). Additional FNA was done in 160 patients (49.7 %): 137/250 (54.8 %) B3 and 23/72 (31.9 %) B4 (p = 0.002). The additional B3 nodules aspirations yielded a diagnosis of B2 in 84 patients (61.3 %), B3 in 48 (35 %), and B4 in 5 (3.6 %). Of the 23 repeated B4 aspirations, B2 was reported in 5 (21.7 %), B3 in 12 (52.2 %), B4 in 4 (17.4 %), and B6 in 2 (8.7 %). The number of aspirated nodules was twice that reported in 1999–2000. The rate of indeterminate nodules increased from 6 to 14.6 %, the surgery rate decreased from 52.3 to 38.2 %, and the accuracy of malignancy diagnosis increased from 25.9 to 53.7 %. The application of TBSRTC significantly improves diagnostic accuracy for indeterminate thyroid nodules, leading to higher rates of malignancy detection despite lower rates of thyroidectomies.