Natural history, treatment, and long-term follow up of patients with multiple endocrine neoplasia type 2B: an international, multicentre, retrospective study.

BACKGROUND: Multiple endocrine neoplasia type 2B is a rare syndrome caused mainly by Met918Thr germline RET mutation, and characterised by medullary thyroid carcinoma, phaeochromocytoma, and extra-endocrine features. Data are scarce on the natural history of multiple endocrine neoplasia type 2B. We aimed to advance understanding of the phenotype and natural history of multiple endocrine neoplasia type 2B, to increase awareness and improve detection. METHODS: This study was a retrospective, multicentre, international study in patients carrying the Met918Thr RET variant with no age restrictions. The study was done with registry data from 48 centres globally. Data from patients followed-up from 1970 to 2016 were retrieved from May 1, 2016, to May 31, 2018. Our primary objectives were to determine overall survival, and medullary thyroid carcinoma-specific survival based on whether the patient had undergone early thyroidectomy before the age of 1 year. We also assessed remission of medullary thyroid carcinoma, incidence and treatment of phaeochromocytoma, and the penetrance of extra-endocrine features. FINDINGS: 345 patients were included, of whom 338 (98%) had a thyroidectomy. 71 patients (21%) of the total cohort died at a median age of 25 years (range <1-59). Thyroidectomy was done before the age of 1 year in 20 patients, which led to long-term remission (ie, undetectable calcitonin level) in 15 (83%) of 18 individuals (2 patients died of causes unrelated to medullary thyroid carcinoma). Medullary thyroid carcinoma-specific survival curves did not show any significant difference between patients who had thyroidectomy before or after 1 year (comparison of survival curves by log-rank test: p=0·2; hazard ratio 0·35; 95% CI 0.07-1.74). However, there was a significant difference in remission status between patients who underwent thyroidectomy before and after the age of 1 year (p<0·0001). There was a significant difference in remission status between patients who underwent thyroidectomy before and after the age of 1 year (p<0·0001). In the other 318 patients who underwent thyroidectomy after 1 year of age, biochemical and structural remission was obtained in 47 (15%) of 318 individuals. Bilateral phaeochromocytoma was diagnosed in 156 (50%) of 313 patients by 28 years of age. Adrenal-sparing surgery was done in 31 patients: three (10%) of 31 patients had long-term recurrence, while normal adrenal function was obtained in 16 (62%) patients. All patients with available data (n=287) had at least one extra-endocrine feature, including 106 (56%) of 190 patients showing marfanoid body habitus, mucosal neuromas, and gastrointestinal signs. INTERPRETATION: Thyroidectomy done at no later than 1 year of age is associated with a high probability of cure. The reality is that the majority of children with the syndrome will be diagnosed after this recommended age. Adrenal-sparing surgery is feasible in multiple endocrine neoplasia type 2B and affords a good chance for normal adrenal function. To improve the prognosis of such patients, it is imperative that every health-care provider be aware of the extra-endocrine signs and the natural history of this rare syndrome. The implications of this research include increasing awareness of the extra-endocrine symptoms and also recommendations for thyroidectomy before the age of 1 year. FUNDING: None.

Quasispecies analysis and in vitro susceptibility of HBV strains isolated from HIV-HBV-coinfected patients with delayed response to tenofovir.

BACKGROUND: Among 141 HIV-HBV-coinfected patients treated with tenofovir in our centre, 87% were good-responders to therapy. Seven patients showed a delayed response to tenofovir. The present study was performed to evaluate the quasispecies variability and the in vitro drug susceptibility to approved antiviral drugs of HBV genomes directly isolated from patients' sera. METHODS: After purification of DNA from serum samples, full-length HBV DNA was amplified by PCR, cloned and sequenced. Drug sensitivity of HBV strains isolated from four delayed responders and five good-responders was assessed and compared to a wild-type HBV strain after transfection of the full genome into HepG2 cells. RESULTS: Delayed responders, compared with good responders, showed a higher incidence of lamivudine-resistant mutations (71% and 35%, respectively; P=0.021) and a higher proportion of HBV genotype G (57% versus 16%, respectively; P=0.026). Clonal analysis demonstrated a higher variability of HBV quasispecies in delayed reponders than in good responders. In vitro analysis showed a lower efficacy of adefovir and tenofovir in delayed reponders. Furthermore, HBV genotype G strains showed a mild to weak susceptibility to tenofovir. CONCLUSIONS: The reason for the slow decline in HBV DNA level observed during therapy in delayed responders is not clear. Delayed responders showed higher quasispecies variability, a higher proportion of HBV genotype G and a mild in vitro decreased susceptibility to tenofovir and adefovir. A combination of these factors in heavily treatment-experienced HIV-infected patients could explain the lower tenofovir activity. These patients must be closely monitored to prevent prospective emergence of resistance to approved antiviral drugs.