Pulmonary carcinoid (PC) tumors are rare tumors that account for approximately 1% of all lung cancers. The primary treatment option is surgery, while there is no standard treatment for metastatic disease. As the number of PCs diagnosed yearly is increasing, there is a need to establish novel therapeutic options. This study aimed to investigate programmed death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) expression in PC tumors since blocking of the PD-1/PD-L1 pathway is a promising therapeutic option in various other malignancies. A total of 168 PC patients treated between 1990 and 2013 were collected from the Finnish biobanks. After re-evaluation of the tumors, 131 (78%) were classified as typical carcinoid (TC) and 37 (22%) as atypical carcinoid (AC) tumors. Primary tumor samples were immunohistochemically labeled for PD-1, PD-L1 and CD8. High PD-1 expression was detected in 16% of the tumors. PD-L1 expression was detected in 7% of TC tumors; all AC tumors were PD-L1 negative. PD-L1 expression was associated with mediastinal lymph-node metastasis at the time of diagnosis (P = 0.021) as well as overall metastatic potential of the tumor (P = 0.010). Neither PD-1 expression, PD-L1 expression nor CD8+ T cell density was associated with survival. In conclusion, PD-1 and PD-L1 were expressed in a small proportion of PC tumors and PD-L1 expression was associated with metastatic disease. Targeting of the PD-1/PD-L1 pathway with immune checkpoint inhibitors may thus offer a treatment option for a subset of PC patients.
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Tiina Vesterinen, Teijo Kuopio, Maarit Ahtiainen, Aija Knuuttila, Harri Mustonen, Kaisa Salmenkivi, Johanna Arola and Caj Haglund
Elham Barazeghi, Per Hellman, Gunnar Westin and Peter Stålberg
Small intestinal neuroendocrine tumors (SI-NETs) are small, slow growing neoplasms with loss of one copy of chromosome 18 as a common event. Frequently mutated genes on chromosome 18 or elsewhere have not been found so far. The aim of this study was to investigate a possible tumor suppressor role of the transmembrane receptor type tyrosine phosphatase PTPµ (PTPRM at 18p11) in SI-NETs. Immunohistochemistry, quantitative RT-PCR, colony formation assay and quantitative CpG methylation analysis by pyrosequencing were performed. Undetectable/very low levels of PTPRM or aberrant pattern of immunostaining, with both negative and positive areas, were detected in the majority of tumors (33/40), and a significantly reduced mRNA expression in metastases compared to primary tumors was observed. Both the DNA methylation inhibitor 5-aza-2′-deoxycytidine and the S-adenosylhomocysteine hydrolase inhibitor 3-deazaneplanocin A (DZNep) induced PTPRM expression in CNDT2.5 and KRJ-I SI-NET cells. CpG methylation of upstream regulatory regions, the promoter region and the exon 1/intron 1 boundary was detected by pyrosequencing analysis of the two cell lines and not in the analyzed SI-NETs. Overexpression of PTPRM in the SI-NET cell lines reduced cell growth and cell proliferation and induced apoptosis. The tyrosine phosphatase activity of PTPRM was not involved in cell growth inhibition. The results support a role for PTPRM as a dysregulated candidate tumor suppressor gene in SI-NETs and further analyses of the involved mechanisms are warranted.
Kristine Zøylner Swan, Steen Joop Bonnema, Marie Louise Jespersen and Viveque Egsgaard Nielsen
Thyroid nodular disease is common, but predicting the risk of malignancy can be difficult. In this prospective study, we aimed to assess the diagnostic accuracy of shear wave elastography (SWE) in predicting thyroid malignancy. Patients with thyroid nodules were enrolled from a surgical tertiary unit. Elasticity index (EI) measured by SWE was registered for seven EI outcomes assessing nodular stiffness and heterogeneity. The diagnosis was determined histologically. In total, 329 patients (mean age: 55 ± 13 years) with 413 thyroid nodules (mean size: 32 ± 13 mm, 88 malignant) were enrolled. Values of SWE region of interest (ROI) for malignant and benign nodules were highly overlapping (ranges for SWE-ROImean: malignant 3–100 kPa; benign 4–182 kPa), and no difference between malignant and benign nodules was found for any other EI outcome investigated (P = 0.13–0.96). There was no association between EI and the histological diagnosis by receiver operating characteristics analysis (area under the curve: 0.51–0.56). Consequently, defining a cut-off point of EI for the prediction of malignancy was not clinically meaningful. Testing our data on previously proposed cut-off points revealed a low accuracy of SWE (56–80%). By regression analysis, factors affecting EI included nodule size >30 mm, heterogeneous echogenicity, micro- or macrocalcifications and solitary nodule. In conclusion, EI, measured by SWE, showed huge overlap between malignant and benign nodules, and low diagnostic accuracy in the prediction of thyroid malignancy. Our study supports that firmness of thyroid nodules, as assessed by SWE, should not be a key feature in the evaluation of such lesions.
Sara Storvall, Helena Leijon, Eeva Ryhänen, Johanna Louhimo, Caj Haglund, Camilla Schalin-Jäntti and Johanna Arola
Parathyroid carcinoma represents a rare cause of primary hyperparathyroidism. Distinguishing carcinoma from the benign tumors underlying primary hyperparathyroidism remains challenging. The diagnostic criteria for parathyroid carcinoma are local and/or metastatic spreading. Atypical parathyroid adenomas share other histological features with carcinomas but lack invasive growth. Somatostatin receptors are commonly expressed in different neuroendocrine tumors, but whether this also holds for parathyroid tumors remains unknown.
Our aim is to examine the immunohistochemical expression of somatostatin receptor 1–5 in parathyroid typical adenomas, atypical adenomas and carcinomas.
We used a tissue microarray construct from a nationwide cohort of parathyroid carcinomas (n = 32), age- and gender-matched typical parathyroid adenomas (n = 72) and atypical parathyroid adenomas (n = 27) for immunohistochemistry of somatostatin receptor subtypes 1–5. We separately assessed cytoplasmic, membrane and nuclear expression and also investigated the associations with histological, biochemical and clinical characteristics.
All parathyroid tumor subgroups expressed somatostatin receptors, although membrane expression appeared negligible. Except for somatostatin receptor 1, expression patterns differed between the three tumor types. Adenomas exhibited the weakest and carcinomas the strongest expression of somatostatin receptor 2, 3, 4 and 5. We observed the largest difference for cytoplasmic somatostatin receptor 5 expression.
Parathyroid adenomas, atypical adenomas and carcinomas all express somatostatin receptor subtypes 1–5. Somatostatin receptor 5 may serve as a potential tumor marker for malignancy. Studies exploring the role of somatostatin receptor imaging and receptor-specific therapies in patients with parathyroid carcinomas are needed.
Boni Xiang, Ran Tao, Xinhua Liu, Xiaoming Zhu, Min He, Zengyi Ma, Yehong Yang, Zhaoyun Zhang, Yiming Li, Zhenwei Yao, Yongfei Wang and Hongying Ye
The aim of this study was to evaluate thyroid functions in Cushing’s syndrome (CS), the dynamic changes of thyroid hormones and antithyroid antibodies in Cushing’s disease (CD) pre- and postoperatively.
Design and methods
This is a retrospective study enrolling 118 patients with CS (102 CD, 10 adrenal CS and 6 ectopic adrenocorticotropic syndrome (EAS)). Thyroid functions (thyroid-stimulation hormone (TSH), T3, free T3 (FT3), T4 and free T4 (FT4)) were measured in all CS at the time of diagnosis and in all CD 3 months after transsphenoidal pituitary tumor resection. Postoperative hormone monitoring within 3 months was conducted in 9 CD patients completing remission. Twenty-eight remitted CD patients experienced hormone and antithyroid antibody evaluation preoperatively and on the 3rd, 6th and 12th month after surgery.
TSH, T3 and FT3 were below the reference range in 31%, 69% and 44% of the 118 CS patients. Remitted CD patients (81/102) had significantly higher TSH (P = 0.000), T3 (P = 0.000) and FT3 (P = 0.000) than those in the non-remission group (21/102). After remission of CD, TSH, T3 and FT3 showed a significant increase, with a few cases above the reference range. By 12 months, most CD patients’ thyroid functions returned to normal. Thyroid hormones (including TSH, T3 and FT3) were negatively associated with serum cortisol levels both before and after surgery. No significant changes of antithyroid autoantibodies were observed.
TSH, T3 and FT3 are suppressed in endogenous hypercortisolemia. After remission of CD, TSH, T3 and FT3 increased significantly, even above the reference range, but returned to normal 1 year after surgery in most cases. Antithyroid antibodies did not change significantly after remission of CD.
Jingya Zhou, Meng Zhang, Lin Lu, Xiaopeng Guo, Lu Gao, Weigang Yan, Haiyu Pang, Yi Wang and Bing Xing
To investigate the validity of discharge ICD-10 codes in detecting the etiology of endogenous Cushing’s syndrome (CS) in hospitalized patients.
We evaluated the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of CS etiology-related ICD-10 codes or code combinations by comparing hospital discharge administrative data (DAD) with established diagnoses from medical records.
Coding for patients with adrenocortical adenoma (ACA) and those with bilateral macronodular adrenal hyperplasia (BMAH) demonstrated disappointingly low sensitivity at 78.8% (95% CI: 70.1–85.6%) and 83.9% (95% CI: 65.5–93.9%), respectively. BMAH had the lowest PPV of 74.3% (95% CI: 56.4–86.9%). In confirmed ACA patients, the sensitivity for ACA code combinations was higher in patients initially admitted to the Department of Endocrinology before surgery than that in patients directly admitted to the Department of Urology (90.0 vs 73.1%, P = 0.033). The same phenomenon was observed in the PPV for the BMAH code (100.0 vs 60.9%, P = 0.012). Misinterpreted or confusing situations caused by coders (68.1%) and by the omission or denormalized documentation of symptomatic diagnosis by clinicians (26.1%) accounted for the main source of coding errors.
Hospital DAD is an effective data source for evaluating the etiology of CS but not ACA and BMAH. Improving surgeons’ documentation, especially in the delineation of symptomatic and locative diagnoses in discharge abstracts; department- or disease-specific training for coders and more multidisciplinary collaboration are ways to enhance the applicability of administrative data for CS etiologies.
Qi Che, Xirong Xiao, Jun Xu, Miao Liu, Yongning Lu, Suying Liu and Xi Dong
Accumulating evidence revealed that the leading risk factor of endometrial cancer is exposure to endogenous and exogenous estrogens, while the exact mechanism underlying estrogen contribution to endometrial cancer progression has not been elucidated clearly. Interleukin (IL)-6 has been verified to be critical for tumor progression in several human cancers. In this study, we provided evidence that 17β-estradiol (E2) could significantly promote endometrial cancer cells viability, migration and invasion through activation of IL-6 pathway, which involved in its downstream pathway and target genes (p-Stat3, Bcl-2, Mcl-1, cyclin D1 and MMP2). Meanwhile, utilization of IL-6-neutralizing antibody could partially attenuate the increased cancer growth and invasion abilities in Ishikawa and RL95-2 endometrial cancer cell lines and an orthotopic endometrial cancer model. We established a causative link between estrogen and IL-6 signaling activation in the development of endometrial cancer. The molecular mechanism defined in this study provided the evidence that E2 promotes endometrial carcinoma progression via activating the IL-6 pathway, indicating that interruption of IL-6 might be an essential therapeutic strategy in estrogen-dependent endometrial cancer.
Tatiana V Novoselova, Peter J King, Leonardo Guasti, Louise A Metherell, Adrian J L Clark and Li F Chan
The melanocortin-2-receptor (MC2R), also known as the ACTH receptor, is a critical component of the hypothalamic–pituitary–adrenal axis. The importance of MC2R in adrenal physiology is exemplified by the condition familial glucocorticoid deficiency (FGD), a potentially fatal disease characterised by isolated cortisol deficiency. MC2R mutations cause ~25% of cases. The discovery of a MC2R accessory protein MRAP, mutations of which account for ~20% of FGD, has provided insight into MC2R trafficking and signalling. MRAP is a single transmembrane domain accessory protein highly expressed in the adrenal gland and essential for MC2R expression and function. Mouse models helped elucidate the action of ACTH. The Mc2r-knockout (Mc2r − / −) mice was the first mouse model developed to have adrenal insufficiency with deficiencies in glucocorticoid, mineralocorticoid and catecholamines. We recently reported the generation of the Mrap − / − mice which better mimics the human FGD phenotype with isolated glucocorticoid deficiency alone. The adrenal glands of adult Mrap − / − mice were grossly dysmorphic with a thickened capsule, deranged zonation and deranged WNT4/beta-catenin and sonic hedgehog (SHH) pathway signalling. Collectively, these mouse models of FGD highlight the importance of ACTH and MRAP in adrenal progenitor cell regulation, cortex maintenance and zonation.
Masafumi Tetsuka and Misato Tanakadate
The bovine cumulus-oocyte complex (COC) is capable of converting cortisone, an inert glucocorticoid to active cortisol. This mechanism is mediated by 11β-hydroxysteroid oxidoreductase type 1 (HSD11B1), whose expression dramatically increases in the mature COC. In this study, we investigate the time course expression of HSD11B1 and the enzyme activity in the bovine COC undergoing maturation and fertilization in relation to key events taking place in the COC. Bovine COCs were subjected to in vitro maturation (IVM) and fertilization (IVF). The activities of HSD11B1 and HSD11B2, which mediates the opposite reaction, were measured using a radiometric conversion assay. In parallel studies, cumulus expansion, P4 production and the expression of genes associated with ovulation were measured. The reductive activity of HSD11B1 increased in the latter half of IVM and remained high during IVF, whereas the oxidative activity of HSD11B2 remained unchanged over both periods. Consequently, the net glucocorticoid metabolism in the bovine COC shifted from inactivation to activation around the time of ovulation and fertilization. The increase in HSD11B1 expression lagged behind that of P4 increase and cumulus expansion but ahead of the expressions of genes responsible for PGE2 synthesis. The reductive activity of HSD11B1 was well correlated with the cumulus expansion rate. This outcome indicates that the ability of the cumulus to activate glucocorticoids is related to its ability to synthesize hyaluronan. These results also indicate that the activation of HSD11B1 is an integral part of the sequential events taking place at the ovulation and fertilization in the bovine COC.
Mengxue Yang, Bowen Sun, Jianhui Li, Bo Yang, Jie Xu, Xue Zhou, Jie Yu, Xuan Zhang, Qun Zhang, Shan Zhou and Xiaohua Sun
The pathogenesis of Graves’ disease (GD) remains unclear. In terms of environmental factors, GD development may be associated with chronic inflammation caused by alteration of the intestinal flora. This study explored the association of intestinal flora alteration with the development of GD among the Han population in southwest China.
Design and methods
Fifteen GD patients at the Affiliated Hospital of Zunyi Medical College between March 2016 and March 2017 were randomly enrolled. Additionally, 15 sex- and age-matched healthy volunteers were selected as the control group during the same period. Fresh stool samples were collected, and bacterial 16S RNA was extracted and amplified for gene sequencing with the Illumina MiSeq platform. The sequencing results were subjected to operational taxonomic unit-based classification, classification verification, alpha diversity analysis, taxonomic composition analysis and partial least squares-discriminant analysis (PLS-DA).
The diversity indices for the GD group were lower than those for the control group. The GD group showed significantly higher abundances of Firmicutes, Proteobacteria and Actinobacillus and a higher Firmicutes/Bacteroidetes ratio than the control group. PLS-DA suggested the satisfactory classification of the flora between the GD group and the control group. The abundances of the genera Oribacterium, Mogibacterium, Lactobacillus, Aggregatibacter and Mogibacterium were significantly higher in the GD group than in the control group (P < 0.05).
The intestinal flora of GD patients was significantly different from that of the healthy population. Thus, alteration of intestinal flora may be associated with the development of GD.