The prevalence and prognostic value of BRAF mutation in thyroid cancer

OBJECTIVE: To examine the prevalence of BRAF mutation among thyroid cancer histologic subtypes and determine the association of BRAF mutation with indicators of poor prognosis for papillary thyroid cancer and patient outcome. SUMMARY BACKGROUND DATA: The appropriate extent of surgical treatment, adjuvant therapy and follow-up monitoring for thyroid cancer remains controversial. Advances in the molecular biology of thyroid cancer have helped to identify candidate markers of disease aggressiveness. A commonly found genetic alternation is a point mutation in the BRAF oncogene (BRAF V600E), which is primarily found in papillary thyroid cancer and is associated with more aggressive disease. METHODS: BRAF V600E mutation status was determined in 347 tumor samples from 314 patients with thyroid cancer (245 with conventional papillary thyroid cancer, 73 with follicular thyroid cancer, and 29 with the follicular variant of papillary thyroid cancer). Univariate and multivariate analyses were performed to determine the association of BRAF V600E with clinicopathologic factors and patient outcome. RESULTS:: The prevalence of BRAF V600E mutation was higher in conventional papillary thyroid cancer (51.0%) than in follicular variant of papillary thyroid cancer (24.1%) and follicular thyroid cancer (1.4%) (P < 0.0001). In patients with conventional papillary thyroid cancer, BRAF V600E mutation was associated with older age (P = 0.0381), lymph node metastasis (P = 0.0323), distant metastasis (P = 0.045), higher TNM stage (I and II vs. III and IV, P = 0.0389), and recurrent and persistent disease (P = 0.009) with a median follow-up time of 6.0 years. Multivariate analysis showed that BRAF V600E mutation [OR (95% CI) = 4.2 (1.2-14.6)] and lymph node metastasis [OR (95% CI) = 7.75 (2.1-28.5)] were independently associated with recurrent and persistent disease in patients with conventional papillary thyroid cancer. CONCLUSIONS: BRAF V600E mutation is primarily present in conventional papillary thyroid cancer. It is associated with an aggressive tumor phenotype and higher risk of recurrent and persistent disease in patients with conventional papillary thyroid cancer. Testing for this mutation may be useful for selecting initial therapy and for follow-up monitoring.     

Coexisting Chronic Lymphocytic Thyroiditis and Papillary Thyroid Cancer Revisited

The effect of chronic lymphocytic thyroiditis (CLT) on the behavior of papillary thyroid cancer (PTC) remains unclear. In recent studies the presence of CLT in patients with PTC was reported to be associated with a lower recurrence rate and an improved survival rate. Furthermore, patients with PTC and tumor infiltrating lymphocytes (TILs) have been reported to have lower recurrence rates and a lower frequency of distant metastases. Because of these and other observations, a tumor immune response in PTC has been suggested. The aim of our study was to determine: (1) the relative frequency of CLT in PTC; (2) the prognostic significance of CLT in patients with PTC; and (3) if TIL occurs independently or in association with CLT. A 10-year retrospective study of patients who underwent initial thyroidectomy for PTC from 1986 to 1996 was completed. The extent of thyroid lymphocytic infiltration was determined within the tumor, surrounding the tumor, and in the distant parenchyma by two independent observers blinded to the clinical data. Dense focal/diffuse lymphoid aggregates throughout the thyroid gland were diagnostic of CLT and when present within or surrounding the tumor were designated TILs. A total of 136 patients with PTC (typical and follicular variant of PTC histologic subtypes) were identified with a mean follow-up of 4.4 years and a 8% mortality rate at 10 years. Thirty percent of the patients with PTC had coexisting CLT, and 65% of these patients with CLT had positive anti-thyroglobulin antibodies. Patients with coexisting CLT and PTC were younger (p < 0.05), more likely to be female (p < 0.05), and more likely to have multicentric tumors (p < 0.001) compared to patients without CLT. Only 5% of patients had TILs without CLT, but 82.5% of patients with CLT had TILs identified (p < 0.0001). By univariate analysis CLT, age, gender, stage of PTC, tumor multicentricity, and tumor size were significant prognostic factors. Only age and TNM stage of PTC remained independent prognostic factors by multivariate analysis. We found a similar frequency (30%) of coexisting CLT and PTC as reported by others; but, more importantly, the presence of TILs primarily occurred in association with CLT. The presence of CLT in patients with PTC correlated with an improved prognosis. It was not an independent prognostic factor, however, and was not associated with a lower recurrence rate or a lower frequency of distant metastasis.     

Accuracy of preoperative localization studies and intraoperative parathyroid hormone assay in patients with primary hyperparathyroidism and double adenoma

BACKGROUND: The purpose of this retrospective investigation was to evaluate the results of preoperative localization studies and intraoperative parathyroid hormone (IOPTH) assay in patients with primary hyperparathyroidism and double adenomas. STUDY DESIGN: Twenty-one of 287 consecutive patients with primary hyperparathyroidism who had double adenomas identified during first-time parathyroid exploration between July 1999 and September 2002 were analyzed. Individual and combined accuracy of preoperative localization studies, and IOPTH assay and their influence on surgical strategy, were compared. RESULTS: Seven percent of these 287 patients had double adenomas. Fifteen of the patients were female and six were male with a mean age of 59 years (range 17 to 76 years). The accuracy of ultrasonography (US) and technetium 99m sestamibi ((99m)TC-sestamibi) was 40% and 30%, respectively, in this select group. Combined accuracy of both tests reached 60% and guided the surgeon to select a bilateral approach. After removal of the first gland, IOPTH failed to decrease by 50% relative to the highest baseline value in 43% of the cases, indicating other hyperfunctioning parathyroid glands. These results prompted the surgeon to explore further after an initially planned focused approach. When the combination of three tests was analyzed, at least one test accurately suggested a double adenoma in 80% of the patients; in 15% of the patients, no test was suggestive of a double adenoma and in 5% the sestamibi scan was false positive. CONCLUSIONS: This retrospective investigation documents that neither preoperative localization tests nor IOPTH assay accurately document double adenomas in patients with primary hyperparathyroidism. The combined accuracy of US, sestamibi, and IOPTH assay predicted a double adenoma in 80% of the patients.     

Temporal and Spatial Patterns and a Space–Time Cluster Analysis of Foot-and-Mouth Disease Outbreaks in Ethiopia from 2010 to 2019

Foot-and-mouth disease (FMD) is an endemic disease in Ethiopia, although space–time cluster and monthly variation studies have never been assessed at national level. The current study aimed to identify the spatial and temporal distribution of FMD outbreaks in Ethiopia from national outbreak reports over a period of ten years from 1 January 2010 to 31 December 2019. To this end, a total of 376,762 cases and 1302 outbreaks from 704 districts were obtained from the Minister of Agriculture for analyses. In general, the dry periods, i.e., October to March, of the year were recorded as the peak outbreak periods, with the highest prevalence in March 2012. The monthly average and the outbreak trends over ten years show a decrease of outbreaks from 2010 to 2019. Decomposing the FMD outbreak data time series showed that once an outbreak erupted, it continued for up to five years. Only 12% of the reported outbreaks were assigned to a specific serotype. Within these outbreaks, the serotypes O, A, SAT-2, and SAT-1 were identified in decreasing order of prevalence, respectively. When a window of 50% for the maximum temporal/space cluster size was set, a total of seven FMD clusters were identified in space and time. The primary cluster with a radius of 380.95 km was identified in the southern part of Ethiopia, with a likelihood ratio of 7.67 (observed/expected cases). The third cluster, with a radius of 144.14 km, was identified in the northeastern part of the country, and had a likelihood ratio of 5.66. Clusters 1 and 3 occurred from January 2017 to December 2019. The second cluster that occurred had a radius of 294.82 km, a likelihood ratio of 6.20, and was located in the central and western parts of Ethiopia. The sixth cluster, with a radius of 36.04 km and a likelihood ratio of 20.60, was set in southern Tigray, bordering Afar. Clusters 2 and 6 occurred in the same period, from January 2014 to December 2016. The fourth cluster in northern Tigray had a calculated radius of 95.50 km and a likelihood ratio of 1.17. The seventh cluster occurred in the north-central Amhara region, with a radius of 97 km and a likelihood ratio of 1.16. Clusters 4 and 7 occurred between January 2010 and December 2013. The spatiotemporal and cluster analysis of the FMD outbreaks identified in the context of the current study are crucial in implementing control, prevention, and a prophylactic vaccination schedule. This study pointed out October to March as well as the main time of the year during which FMD outbreaks occur. The area that extends from the south to north, following the central highlands, is the main FMD outbreak area in Ethiopia.     

Medullary thyroid cancer

Opinion statement Patients with clinically evident medullary thyroid cancer should have a total extracapsular thyroidectomy with bilateral central neck dissection and an ipsilateral prophylactic or therapeutic modified (functional) radical neck dissection when the primary tumor is greater than 1 cm and when the central neck nodes are positive. A prophylactic contralateral neck dissection should be done when the primary tumor is bilateral and when there is extensive lymphadenopathy on the side of the primary tumor. Patients who have gross, unresectable residual medullary thyroid cancer should receive postoperative external radiotherapy. Patients who are carriers of germ-line RET proto-oncogene point mutations or have an elevated (basal or stimulated) calcitonin levels on screening should have a prophylactic total thyroidectomy before age 6 years. In patients with an elevated basal or stimulated plasma calcitonin level and an intrathyroidal nodule on ultrasound, a total thyroidectomy and central neck lymph node dissection should be done. Patients with persistent or recurrent medullary thyroid cancer should have a complete thyroidectomy (if not done initially) and bilateral central and modified radical neck dissection, including upper mediastinal lymphadenectomy. Patients who are symptomatic from distant medullary thyroid cancer metastases (diarrhea, flushing, weight loss, or bone pain) should be treated with somatostatin analogs. Bone metastases should be resected if possible, and symptomatic lesions that are unresectable should be treated with external radiotherapy. Cytoreductive procedures such as radiofrequency ablation or cryoablation for liver metastases should be considered in symptomatic patients to reduce tumor burden. Localized pulmonary metastases should be resected. Chemotherapy or radioactive immunotherapy (iodine 131 labeled carcinoembryonic antigen monoclonal antibody) protocols should be considered in patients with nonoperative widely metastatic progressing medullary thyroid cancer.     

Evaluation of Community-Based Trichiasis Surgery in Northwest Ethiopia

Background

Surgery to correct trachomatous trichiasis (TT) is recommended to prevent blindness caused by trachoma. This study evaluated the outcomes of community-based trichiasis surgery with absorbable sutures, conductd in Amhara Regional State, Ethiopia.

Methods

A simple random sample of 431 patients was selected from surgical campaign records of which 363 (84.2%) were traced and enrolled into the study. Participants were interviewed and examined for trichiasis recurrence, complications of TT surgery and corneal opacity. Multilevel logistic regression models were used to explore the associations between trichiasis recurrence, corneal opacity and explanatory variables at the eye level.

Results

The prevalence of trichiasis recurrence was 9.4% (95% Confidence Interval [CI] 6.6–12.8) and corneal opacity was found in 14.3% (95% CI 10.9–18.3) of the study participants. The proportion of participants with complications of TT surgery was: granuloma 0.6% (95% CI 0.1–2.0); lid closure defects 5.5% (95% CI 3.4–8.4) and lid notching 16.8% (95% CI 13.1–21.1). No factors were identified for trichiasis recurrence. Corneal opacity was associated with increased age (Ptrend=0.001), more than 12 months post surgery (OR=2.7; 95%CI 1.3–5.6), trichiasis surgery complications (OR=2.9; 95%CI 1.4–5.9) and trichiasis recurrence (OR=2.5; 95%CI 1.0–6.3).

Conclusion

Prevalence of recurrent trichiasis and granuloma were lower than expected but higher for lid closure defects and lid notching. The majority of the participants reported satisfaction with the trichiasis surgery they had undergone. The findings suggest that recurrence of trichiasis impacts on the patients'' risk of developing corneal opacity but longitudinal studies are required to confirm this.     

An electrophysiological analysis of caudally-projecting neurones from the hypothalamic paraventricular nucleus in the rat

Using anaesthetized rats, experiments were performed to test whether neurones located in the hypothalamic paraventricular nuclei and sending axons caudally, could be identified electrophysiologically. Neurones projecting caudally were localized by antidromic invasion following electrical stimulation within the region of the dorsal motor nucleus of the vagus, the nucleus of the tractus solitarius and the hypoglossal nucleus. Stimulation of more ventral regions in the medulla oblongata was not effective. Caudally-projecting neurones were dispersed throughout the paraventricular nuclei and were often found close to magnocellular neurones antidromically invaded by stimulation of the pituitary stalk. About one-third of the caudally-projecting neurones were synaptically activated by pituitary stalk stimulation, but only at currents sufficient to antidromically invade the magnocellular neurones. This suggests a synaptic interaction between magnocellular and some caudally-projecting paraventricular neurones. The possible physiological significance of these findings is discussed.     

Selective Modified Radical Neck Dissection for Papillary Thyroid Cancer—Is Level I, II and V Dissection Always Necessary?

Background There is ongoing controversy as to the indications for and extent of lateral cervical lymphadenectomy for patients with papillary thyroid cancer (PTC). While most now agree that prophylactic lymph node dissections (LND) play no role, at the University of California, San Francisco (UCSF) we limit LND selectively on a level by level basis, and resect only the levels thought to harbor disease or to be at increased risk of metastases. This initial ‚selective LND’ usually includes levels III and IV (due to the well-documented increased likelihood of metastases to these levels) and levels I, II, and V are included when there is clinical or radiological evidence of disease or increased risk of it. Methods A retrospective review of the clinical charts and hospital records of 106 consecutive patients who had metastatic PTC and who underwent at least one lateral cervical LND at UCSF between January 1995 and December 2003 was carried out. Data were collected to assess which patients had levels I, II, and/or V included in their initial ipsilateral and/or contralateral LND and to determine the recurrence rates at these levels if they had previously been excised compared with if they had not. Chi-squared and Fisher exact tests were utilized for statistical comparison, where appropriate. Results A total of 140 initial lateral LND were performed: 104 ipsilateral and 36 contralateral. In these initial LND, 3.9%, 72.5%, and 18.6% of patients had levels I, II, and V resected on the ipsilateral side, and 2.9%, 60.0%, and 37.1% of patients had levels I, II, and V resected on the contralateral side. Recurrence at levels I and V was uncommon in all patient populations. Recurrence at level II was 19% ipsilaterally and 10% contralaterally when the level was previously resected and 21% ipsilaterally and 14% contralaterally when the level was not previously resected. There was no statistically significant difference in recurrence at level II when the level had previously been resected compared with when it had not. Conclusions If utilized in the appropriate patient population, a selective approach to lateral cervical LND for PTC can be a successful alternative to the routine modified radical LND. Levels I and V do not require resection unless there is clinical or radiological evidence of disease. Guidelines for which patients may be considered for this less aggressive approach to level II nodal metastases are suggested.     

Risk Assessment in 457 Adrenal Cortical Carcinomas: How Much Does Tumor Size Predict the Likelihood of Malignancy?

BACKGROUND: Laparoscopic adrenalectomy for tumors > 6 cm is controversial because of the risk of malignancy, but data to support this position are mostly from small series. The recent NIH consensus conference did not make a definitive recommendation about management of 4- to 6-cm nonfunctioning incidentalomas. STUDY DESIGN: Adrenocortical carcinomas (ACC) recorded in the Surveillance, Epidemiology, and End Results (SEER) database (1988 to 2000) were compared with benign functional or nonfunctional adrenal cortical adenomas (excluding aldosteronomas) operated on at our institution between January 1, 1993, and July 1, 2003. Data were compared using t-tests, chi-square tests, likelihood ratios, and receiver operating characteristic (ROC) curves. RESULTS: We identified 457 patients with ACC and 47 patients with adrenal cortical adenomas; 376 and 44 neoplasms, respectively, had tumor size data available. Tumor size was larger in ACC (12.0 +/- 5.6 versus 4.2 +/- 1.9 cm, mean +/- SD, p < 0.05). For ACC presenting with local disease, the sensitivity, specificity, and likelihood ratios of tumor size to predict malignancy were 96%, 52%, and 2.0, respectively, for tumors > or = 4 cm; 90%, 80%, and 4.4 for tumors > or = 6 cm; 77%, 95%, and 16.9 for tumors > or = 8 cm; and 55%, 98%, and 24.4 for tumors > or = 10 cm. Assuming a pretest probability of malignancy of 5%, the likelihood ratios derived from this study yield a posttest probability of 10%, 19%, and 47% for cancer in adrenal cortical tumors > or = 4 cm, > or = 6 cm, and > or = 8 cm, respectively. CONCLUSIONS: These data suggest that size is useful for predicting malignancy, and that at a size threshold of > or = 4 cm, the likelihood of malignancy doubles (to 10%) and it is more than ninefold higher for tumors > or = 8 cm (47%).     

Extent of Disease at Presentation and Outcome for Adrenocortical Carcinoma: Have We Made Progress?

Background Adrenocortical carcinoma (ACC), a rare and aggressive malignancy, accounts for up to14% of adrenal incidentalomas. The only chance of cure for ACC is diagnosis at an early stage; therefore, a main indication for adrenalectomy in patients with adrenal incidentaloma has been the potential risk of ACC. Recent studies suggest that this has led to earlier stage of ACC at diagnosis, more curative operations, and better survival. Methods We analyzed data on ACC from The National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database. Four equal time quartiles (1973–1979, 1980–1986, 1987–1993, and 1994–2000) were compared for changes in demographics, pathology, treatment, and cause-specific mortality. Results The average age was 51.2 years (range: 1–97), and 45.9% of patients were men. The average tumor size was 12 cm (range: 2–36 cm), and only 4.2% were ≤ 6 cm. Most (88%) patients had surgical resection of their tumor, and external beam radiotherapy was used in only 12% of patients. Between the time quartiles compared (as well as annually), there was no significant difference at presentation in age at diagnosis, sex, race/ethnicity, tumor size, tumor grade, the frequency of distant metastasis, and overall TNM stage. Low tumor grade, lower stage of ACC, later time quartile, and surgical resection were associated with a lower cause-specific mortality by univariate analysis (P ≤ 0.002) and by multivariate analysis (P ≤ 0.031). Conclusions Although adrenal incidentalomas have become a common indication for adrenalectomy, this has not resulted in patients with ACC being diagnosed earlier or treated at a lower stage of disease at the national level. The most important predictors of survival in these patients are tumor grade, tumor stage, and surgical resection.