BRAF((V600E)) mutation is the most frequent genetic alteration in papillary thyroid carcinomas (PTCs) that are 80-90% of all thyroid cancers. We evaluated the relationship between BRAF((V600E)) and tumor, host, and environmental factors in PTCs from all geographical areas of Sicily. By PCR, BRAF((V600E)) was investigated in a series of 323 PTCs diagnosed in 2002-2005. The correlation between clinicopathological tumor, host, and environmental characteristics and the presence of BRAF((V600E)) were evaluated by both univariate and multivariate analyses. BRAF((V600E)) was found in 38.6% PTCs, with a 52% frequency in the classical PTCs and 26.4% in the tall cell variant. Univariate analysis indicated that BRAF((V600E)) was associated with greater tumor size (P=0.0048), extra-thyroid invasion (P<0.0001), and cervical lymph nodal metastases (P=0.0001). Multivariate logistic regression analysis confirmed that BRAF((V600E)) was an independent predictor of extra-thyroid invasion (P=0.0001) and cervical lymph nodal metastasis (P=0.0005). The association between BRAF((V600E)) and extra-thyroid invasion was also found in micro-PTCs (P=0.006). In 60 classical PTCs, BRAF((V600E)) was positively correlated with matrix metalloproteinase-9 expression (P=0.0047), suggesting a possible mechanism for BRAF((V600E)) effect on PTC invasiveness. No association was found between BRAF((V600E)) and patient age, gender, or iodine intake. In contrast, a strong association was found with residency in Eastern Sicily (P<0.0001 compared with Western Sicily). These results indicate that BRAF((V600E)) mutation is a marker of aggressive disease in both micro- and macro-PTCs. Moreover, for the first time, a possible link between BRAF((V600E)) mutation and environmental carcinogens is suggested.

BACKGROUND It has been suggested recently that 1,1‐dichlorodiphenildichloroethane (o,p′DDD) elicits a dose effect relation in the treatment of patients with adrenocortical carcinoma (ACC). The authors performed a single‐center, prospective study with two major objectives: 1) to confirm the interest of plasma o,p′DDD level measurement as a prognostic factor of response to o,p′DDD therapy; and 2) to look for parameters associated with a therapeutic plasma o,p′DDD level, especially the daily o,p′DDD dose. METHODS Since 1995, patients with ACC who were referred to the Gustave‐Roussy Institute have been enrolled prospectively in the study. Therapy with o,p′DDD was given as first‐line therapy in 13 patients with metastatic disease or as adjuvant therapy in 11 patients. Oral o,p′DDD was given in three separate doses up to at least 6–12 g per day together with substitutive adrenal therapy. Plasma o,p′DDD levels were measured using high‐performance liquid chromatography every 2 months. The o,p′DDD therapy was monitored to achieve plasma o,p′DDD levels within 14–20 mg/L. World Health Organization criteria were used to evaluate tumor response and toxicity. RESULTS Twenty‐four patients with ACC were studied, and a plasma o,p′DDD level > 14 mg/L was achieved in 14 patients (58%). An objective tumor response was observed in four patients with metastatic lesions (31%): One was response was complete, and three were objective hormonal responses. These tumor responses were observed among the six patients who achieved therapeutic plasma o,p′DDD levels. In contrast, no response was observed among the seven patients with plasma o,p′DDD levels that remained consistently low. Eight of 11 patients who received o,p′DDD as adjuvant therapy had disease recurrence, although the plasma o,p′DDD level was > 14 mg/L in 6 patients. Grade 3 or 4 neurologic toxicity was observed in three patients (12%), all with an o,p′DDD level > 20 mg/L. The daily o,p′DDD dose was the only parameter associated with the highest plasma o,p′DDD trough levels: It explained 35% of the variability in the plasma o,p′DDD level. A median interval of 3.7 months was found necessary to achieve the highest o,p′DDD trough levels. CONCLUSIONS The results confirm the prognostic impact of the plasma o,p′DDD level in patients with metastatic ACC and its interest in avoiding toxicity. Cancer 2001;92:1385–92. © 2001 American Cancer Society.

The steadily increasing incidence of thyroid cancer has been attributed mostly to more sensitive thyroid nodule screening. However, various environmental factors, such as those associated with volcanic areas, cannot be excluded as risk factors. We evaluated thyroid cancer incidence in Sicily, which has a homogenous population and a province (Catania) that includes the Mt Etna volcanic area. In a register-based epidemiological survey, we collected all incident thyroid cancers in Sicily from January 1, 2002, through December 31, 2004. The age-standardized incidence rate for the world population (ASR _w ) was calculated and expressed as the number of thyroid cancer diagnoses per 100 000 residents per year. The association of thyroid cancer incidence rate with sex, age, tumor histotype, and various environmental factors was evaluated by modeling the variation of the ASR _w . All statistical tests were two-sided. In 2002–2004, 1950 incident thyroid cancers were identified in Sicily (among women, ASR _w = 17.8, 95% confidence interval [CI] = 16.9 to 18.7; and among men, ASR _w = 3.7, 95% CI = 3.3 to 4.1). Although the percentage of thyroid cancers that were microcarcinomas (ie, ≤10 mm) and ratio of men to women with thyroid cancer were similar in all nine Sicilian provinces, thyroid cancer incidence was statistically significantly higher in the province of Catania (among women, ASR _w = 31.7, 95% CI = 29.1 to 34.3; and among men, ASR _w = 6.4, 95% CI = 5.2 to 7.5) than in the rest of Sicily (among women, ASR _w = 14.1, 95% CI = 13.2 to 15.0; and among men, ASR _w = 3.0, 95% CI = 2.6 to 3.4) (all P values < .001). Incidence of papillary, but not follicular or medullary, cancers was statistically significantly increased in Catania province, and papillary tumors from patients in Catania more frequently carried the BRAF V600E gene mutation (55 [52%] of 106 tumors) than tumors from patients elsewhere in Sicily (68 [33%] of 205 tumors) (relative risk = 1.7, 95% CI = 1.0 to 2.8, P = .02). Cancer incidence was statistically significantly lower in rural areas than in urban areas of Sicily ( P = .003). No association with mild iodine deficiency or industrial installations was found. Levels of many elements (including boron, iron, manganese, and vanadium) in the drinking water of Catania province often exceeded maximum admissible concentrations, in contrast to water in the rest of Sicily. Residents of Catania province with its volcanic region appear to have a higher incidence of papillary thyroid cancer than elsewhere in Sicily.