Laura Marino

Very low expression of PD-L1 in medullary thyroid carcinoma

Immunotherapy inhibiting the signaling interaction between programmed death 1 (PD1) and its ligand programmed death-ligand 1 (PD-L1) is rapidly expanding as an established or experimental oncological treatment for several types of solid tumors, especially melanoma and non-small cell lung carcinoma (NSCLC) (Gandini et al. 2016) as well as for various hematopoietic malignancies, notably Hodgkin’s lymphomas (HL). PD1 is one of the immune response-regulating checkpoints: interaction between PD1 on T-cells and PD-L1 on cancer cells provides a mechanism for cancer cells to evade proper recognition as foreign and thus escape attack by the immune system. Currently, several monoclonal anti-PD1 or anti-PD-L1 antibodies that inhibit this interaction ‘–checkpoint inhibitors’ – are approved by the FDA for clinical use; the first was pembrolizumab, an anti-PD1 agent, initially approved for the treatment of advanced melanoma and currently also for advanced NSCLC and for recurrent or metastatic head and neck squamous cell carcinoma (http://www.accessdata.fda.gov/scripts/cder/ daf/index.cfm?event=overview.process&applno=125514; accessed 17.03.2017). The second anti-PD1 agent approved was nivolumab, initially approved for the treatment of advanced melanoma and currently also for several other tumors such as advanced NSCLC; metastatic renal cell carcinoma; HL; recurrent or metastatic head and neck squamous cell carcinoma; and previously-treated locally advanced or metastatic urothelial carcinoma (http://www.accessdata.fda.gov/scripts/cder/daf/index. cfm?event=overview.process&ApplNo=125554; accessed 17.03.2017). Atezolizumab is currently the only approved anti-PD-L1 agent; it is in use for urothelial carcinoma and for metastatic NSCLC (https://www.fda.gov/drugs/ informationondrugs/approveddrugs/ucm525780.htm; accessed 17.03.2017). In several cancer types where these checkpoint inhibitors are used, clinical responses rates as high as 30% to 50% have been demonstrated (Gandini et al. 2016). When considering such molecular-targeted therapies for an individual patient, identification of predictive biomarkers may be useful for patient selection to improve treatment efficacy while avoiding unjustified secondary effects and also making rational use of healthcare resources. Thus, several studies have investigated the immunohistochemical expression of PD1 and PD-L1 in both tumor cells and tumor-infiltrating immune cells, showing that malignant cells are PD-L1-positive in a variable proportion of HL, melanoma, glioblastoma, NSCLC and head and neck, breast, ovarian, renal, pancreatic and esophageal carcinoma (Chowdhury et al. 2016). Regarding thyroid tumors, a few papers have reported on PD-L1 expression in thyroid (Cunha et al. 2013, Angell et al. 2014, Wu et al. 2015, Bastman et al. 2016, Chowdhury et al. 2016, Ahn et al. 2017, Shi et al. 2017). With the exception of two studies on anaplastic (undifferentiated) thyroid carcinoma (ATC) (Wu et al. 2015, Ahn et al. 2017), these studies were focused primarily on follicular cell-derived tumors (differentiated thyroid carcinoma, DTC), including papillary thyroid carcinoma (PTC), follicular thyroid carcinoma (FTC) and poorly differentiated thyroid carcinoma (PDTC) (Cunha et al. 2013, Angell et al. 2014, Bastman et al. 2016, Chowdhury et al. 2016, Ahn et al. 2017, Shi et al. 2017). For these tumors (i.e., DTC), immunotherapy could be considered in the small minority of cases that are classed as refractory to radioiodine treatment. The latest study by Ahn and coworkers recently published in Endocrine-Related Cancer used tissue microarrays to investigate 407 primary thyroid cancers for PD-L1 expression using the monoclonal antibody SP142 (Ahn et al. 2017). PD-L1 was found to be expressed in cancer cells in 6.1% of PTC, 7.6% of FTC and 22.2% of ATC; regarding immune cells, they were positive for PD-L1 in 28.5% of PTC, 9.1% of FTC and 11.1% of ATC. In general, the more aggressive the tumor, the higher the expression of PD-L1, yet no significant

Congenital hypogonadotropic hypogonadism and constitutional delay of growth and puberty have distinct genetic architectures

Objective Congenital hypogonadotropic hypogonadism (CHH) and constitutional delay of growth and puberty (CDGP) represent rare and common forms of GnRH deficiency, respectively. Both CDGP and CHH present with delayed puberty, and the distinction between these two entities during early adolescence is challenging. More than 30 genes have been implicated in CHH, while the genetic basis of CDGP is poorly understood. Design We characterized and compared the genetic architectures of CHH and CDGP, to test the hypothesis of a shared genetic basis between these disorders. Methods Exome sequencing data were used to identify rare variants in known genes in CHH (n = 116), CDGP (n = 72) and control cohorts (n = 36 874 ExAC and n = 405 CoLaus). Results Mutations in at least one CHH gene were found in 51% of CHH probands, which is significantly higher than in CDGP (7%, P = 7.6 × 10−11) or controls (18%, P = 5.5 × 10−12). Similarly, oligogenicity (defined as mutations in more than one gene) was common in CHH patients (15%) relative to CDGP (1.4%, P = 0.002) and controls (2%, P = 6.4 × 10−7). Conclusions Our data suggest that CDGP and CHH have distinct genetic profiles, and this finding may facilitate the differential diagnosis in patients presenting with delayed puberty.

DCC/NTN1 complex mutations in patients with congenital hypogonadotropic hypogonadism impair GnRH neuron development

Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic disease characterized by absent puberty and infertility due to GnRH deficiency, and is often associated with anosmia [Kallmann syndrome (KS)]. The genetic etiology of CHH is heterogeneous, and more than 30 genes have been implicated in approximately 50% of patients with CHH. We hypothesized that genes encoding axon-guidance proteins containing fibronectin type-III (FN3) domains (similar to ANOS1, the first gene associated with KS), are mutated in CHH. We performed whole-exome sequencing in a cohort of 133 CHH probands to test this hypothesis, and identified rare sequence variants (RSVs) in genes encoding for the FN3-domain encoding protein deleted in colorectal cancer (DCC) and its ligand Netrin-1 (NTN1). In vitro studies of these RSVs revealed altered intracellular signaling associated with defects in cell morphology, and confirmed five heterozygous DCC mutations in 6 probands-5 of which presented as KS. Two KS probands carry heterozygous mutations in both DCC and NTN1 consistent with oligogenic inheritance. Further, we show that Netrin-1 promotes migration in immortalized GnRH neurons (GN11 cells). This study implicates DCC and NTN1 mutations in the pathophysiology of CHH consistent with the role of these two genes in the ontogeny of GnRH neurons in mice.

Subclinical hypothyroidism: new trials, old caveats

The indications for levothyroxine replacement therapy for subclinical hypothyroidism (SH) remain a subject of debate, especially when prescribed for older adults. The results of the recent TRUST trial indicate that levothyroxine does not improve clinical symptom scores among elderly patients with SH. While there is much concern regarding the dilemma of introducing or withholding levothyroxine, less attention may be paid to the differential diagnosis of an elevated TSH level, which is the prerequisite for diagnosing SH. Herein, we review these issues facing endocrinologists and internists/generalists either in practice or in training. When a patient presents abnormal thyroid test results compatible with SH, a series of issues need to be addressed before the implementation of replacement therapy is considered: first, an isolated TSH elevation not linked to a primary thyroid pathology should be excluded; second, the persistent nature of the patient’s TSH elevation and SH profile should be verified; third, SH symptoms and potential complications relevant for the specific patient should be documented; fourth, expectations from levothyroxine substitution therapy for SH in the specific patient should be clarified. Only then can the decision be made whether levothyroxine substitution should be introduced or not.

Evaluating CHARGE syndrome in congenital hypogonadotropic hypogonadism patients harboring CHD7 variants.

PurposeCongenital hypogonadotropic hypogonadism (CHH), a rare genetic disease caused by gonadotropin-releasing hormone deficiency, can also be part of complex syndromes (e.g., CHARGE syndrome). CHD7 mutations were reported in 60% of patients with CHARGE syndrome, and in 6% of CHH patients. However, the definition of CHD7 mutations was variable, and the associated CHARGE signs in CHH were not systematically examined.MethodsRare sequencing variants (RSVs) in CHD7 were identified through exome sequencing in 116 CHH probands, and were interpreted according to American College of Medical Genetics and Genomics guidelines. Detailed phenotyping was performed in CHH probands who were positive for CHD7 RSVs, and genotype–phenotype correlations were evaluated.ResultsOf the CHH probands, 16% (18/116) were found to harbor heterozygous CHD7 RSVs, and detailed phenotyping was performed in 17 of them. Of CHH patients with pathogenic or likely pathogenic CHD7 variants, 80% (4/5) were found to exhibit multiple CHARGE features, and 3 of these patients were reclassified as having CHARGE syndrome. In contrast, only 8% (1/12) of CHH patients with nonpathogenic CHD7 variants exhibited multiple CHARGE features (P = 0.01).ConclusionPathogenic or likely pathogenic CHD7 variants rarely cause isolated CHH. Therefore a detailed clinical investigation is indicated to clarify the diagnosis (CHH versus CHARGE) and to optimize clinical management.