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Background: Six to 20% of thyroid cancer (TC) patients develop distant metastases, and one-third become radioiodine refractory (RAIR). Available targeted therapies increase progression-free surviva...

Management of metastatic radioiodine refractory differentiated thyroid cancer (DTC) can be a therapeutic challenge. Generally, little is known about the paired molecular profile of the primary tumor and the metastases and whether they harbor the same genetic abnormalities. The present study compared the molecular profile of paired tumor specimens (primary tumor/metastatic sites) from patients with radioiodine refractory DTC in order to gain insight into a possible basis for resistance to radioiodine. Twelve patients with radioiodine refractory metastases were studied; median age at diagnosis of 61 years (range, 25–82). Nine patients had papillary TC (PTC), one had follicular TC (FTC), and two had Hürthle cell TC (HTC). Distant metastases were present in the lungs (n = 10), bones (n = 4), and liver (n = 1). The molecular profiling of paired tumors was performed with a panel of 592 genes for Next Generation Sequencing, RNA-sequencing, and immunohistochemistry. Digital microfluidic PCR was used to investigateTERTpromoter mutations. The genetic landscape of all paired sites comprisedBRAF,NRAS,HRAS,TP53,ATM,MUTYH,POLE, andNTRKgenes, includingBRAFandNTRKfusions.BRAFV600E was the most common point mutation in the paired specimens (5/12).TERTpromoter mutation C228T was detected in one case. PD-L1 expression at metastatic sites was highly positive (95%) for one patient with HTC. All specimens were stable for microsatellite instability testing, and the tumor mutation burden was low to intermediate. Therefore, the molecular profile of DTC primary and metastatic lesions can show heterogeneity, which may help explain some altered responses to therapeutic intervention.

Management of metastatic radioiodine refractory differentiated thyroid cancer (DTC) can be a therapeutic challenge. Generally, little is known about the paired molecular profile of the primary tumor and the metastases and whether they harbor the same genetic abnormalities. The present study compared the molecular profile of paired tumor specimens (primary tumor/metastatic sites) from patients with radioiodine refractory DTC in order to gain insight into a possible basis for resistance to radioiodine. Twelve patients with radioiodine refractory metastases were studied; median age at diagnosis of 61 years (range, 25–82). Nine patients had papillary TC (PTC), one had follicular TC (FTC), and two had Hürthle cell TC (HTC). Distant metastases were present in the lungs (n = 10), bones (n = 4), and liver (n = 1). The molecular profiling of paired tumors was performed with a panel of 592 genes for Next Generation Sequencing, RNA-sequencing, and immunohistochemistry. Digital microfluidic PCR was used to investigate TERT promoter mutations. The genetic landscape of all paired sites comprised BRAF, NRAS, HRAS, TP53, ATM, MUTYH, POLE, and NTRK genes, including BRAF and NTRK fusions. BRAF V600E was the most common point mutation in the paired specimens (5/12). TERT promoter mutation C228T was detected in one case. PD-L1 expression at metastatic sites was highly positive (95%) for one patient with HTC. All specimens were stable for microsatellite instability testing, and the tumor mutation burden was low to intermediate. Therefore, the molecular profile of DTC primary and metastatic lesions can show heterogeneity, which may help explain some altered responses to therapeutic intervention.

Background: Sex dimorphism strongly impacts tumor biology with most cancers having a male predominance. Uniquely, thyroid cancer is the only non-reproductive cancer that has a striking female predominance with 3-4 fold higher incidence among females, although males generally have more aggressive disease. Objective: To evaluate the sex-specific differences in clinicopathological characteristics of patients with differentiated thyroid cancer Method: We performed a retrospective study of 140 patients (≥ 18 years) with differentiated thyroid cancer (DTC) who had thyroidectomy at two tertiary care centers between 2010-2018. Females requiring hormone replacement therapy and patients undergoing gender transformation were excluded. Associations between sex and age controlling for race were explored using recursive partitioning, to find optimal thresholds for age at which tumor size is different. Linear regression was used to estimate the effect size difference between older and younger women. Results: Seventy males and 70 age-matched females were included in the study. Overall, average age was 59 years and majority of patients were of white (white 52%, black 24% and other race 29%). There was no association between race and gender. There were no significant differences in frequency of major histological types (follicular vs papillary) of thyroid cancer between male and female patients. Follicular thyroid cancers were diagnosed in 5/70 (7%) female and in 4/70 (6%) male patients. Papillary thyroid cancers (PTC) were found in 61/70 (87%) female and 64/70 (91%) male patients (p=0.623). However, analysis of histopathological subtypes of PTC revealed a sex-related difference. Classical variant of PTC was more frequently diagnosed in males (44/64 or 69%) compared to females (32//61 or 52%). In contrast, follicular variant PTC was more prevalent in females (29/61 or 48%) compared to males (20/64 or 31%). These differences were statistically significant (p=0.04). In addition, analysis of pathological features showed that average tumor size was significantly larger among males compared to females (2.7 vs 1.5 cm, p

Toxoplasma gondii is a globally distributed protozoan parasite. Prevalence of infection varies based on geography, and is estimated to be about 50%–85% in Europe and Central and South America [1]. Progression and severity of disease is variable, ranging from asymptomatic to causing lymphadenopathy, encephalitis, and infectious retinochoroiditis, which accounts for 30%–50% of all cases of posterior uveitis globally [2–5]. The risk of developing eye lesions among T. gondii–infected patients varies geographically. In the United States and Europe, approximately 2% of patients present with OT versus 18% in southern Brazil [6, 7]; permanent visual loss is observed in up to 25% of affected patients [8]. In Europe and North America, T. gondii possesses a simple population genetic structure; 3 clonal lineages (referred to as Type I, II, or III) dominate the majority of human infections. Animal infections have established Type I (but not Type II or III) strains as highly virulent in mice due primarily to their proliferative capacity and ability to inactivate host immune responses [9, 10]. Development of OT in people is multifactorial and variable in onset, recurrence rate, clinical presentation, and severity [2]. Disease is thought to be dependent on a variety of factors, including host genetics, immune status, parasite genotype, and when infection is acquired (ie, congenital or postnatally) [11]. Recently, Toxoplasma strain type was identified as a significant factor determining prematurity and severity of congenital toxoplasmosis in the United States [12], and a diversity of recombinant and atypical strains, including a recently described Type × (Haplogroup 12) strain commonly infecting US wildlife, have previously been found associated with severe disease in patients experiencing acquired immunodeficiency syndrome (AIDS) and OT in North, Central, and South America [13–20]. In Europe, however, Type II strains account for 70%–80% of human infections [1, 21], the majority of congenital cases (85%) among pregnant women [22, 23], and OT cases in France [24, 25]. To assess whether strain type is a contributing factor determining the severity and frequency of recurrence of OT, we utilized a previously established enzyme-linked immunosorbent assay (ELISA)–based serotyping assay that detects strain-specific antibodies circulating in human serum samples, to distinguish infection caused by Type II strains from non-Type II strains, both in prospectively as well as retrospectively collected samples [12, 23, 26, 27]. We applied this technique to serum samples obtained from a cohort of 114 consecutive OT and 56 T. gondii–seropositive control patients with (non T. gondii–related) uveitis in Germany. Parasite DNA amplified from aqueous humor specimens was used to validate some of the obtained serological results. We show that a novel Toxoplasma serotype is associated with recurrent OT, and our results have the potential to personalize disease management protocols to improve the treatment and control of OT.