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Open access

Yiqiang Huang, Lin-ang Wang, Qiubo Xie, Jian Pang, Luofu Wang, Yuting Yi, Jun Zhang, Yao Zhang, Rongrong Chen, Weihua Lan, Dianzheng Zhang and Jun Jiang

Pheochromocytoma and paragangliomas (PCC/PGL) are neuroendocrine tumors that arise from chromaffin cells of the adrenal medulla and sympathetic/parasympathetic ganglia, respectively. Of clinical relevance regarding diagnosis is the highly variable presentation of symptoms in PCC/PGL patients. To date, the clear-cut correlations between the genotypes and phenotypes of PCC/PGL have not been entirely established. In this study, we reviewed the medical records of PCC/PGL patients with pertinent clinical, laboratory and genetic information. Next-generation sequencing (NGS) performed on patient samples revealed specific germline mutations in the SDHB (succinate dehydrogenase complex iron-sulfur subunit B) and SDHD (succinate dehydrogenase complex subunit D) genes and these mutations were validated by Sanger sequencing. Of the 119 patients, two were identified with SDHB mutation and one with SDHD mutation. Immunohistochemical (IHC) staining was used to analyze the expression of these mutated genes. The germline mutations identified in the SDH genes were c343C>T and c.541-542A>G in the SDHB gene and c.334-337delACTG in the SDHD gene. IHC staining of tumors from the c.343C>T and c.541-2A>G carriers showed positive expression of SDHB. Tumors from the c.334-337delACTG carrier showed no expression of SDHD and a weak diffused staining pattern for SDHB. We strongly recommend genetic testing for suspected PCC/PGL patients with a positive family history, early onset of age, erratic hypertension, recurrence or multiple tumor sites and loss of SDHB and/or SDHD expression. Tailored personal management should be conducted once a patient is confirmed as an SDHB and/or SDHD mutation carrier or diagnosed with PCC/PGL.

Open access

Tao Mei, Jianhe Zhang, Liangfeng Wei, Xingfeng Qi, Yiming Ma, Xianhua Liu, Shaohua Chen, Songyuan Li, Jianwu Wu and Shousen Wang

Tumor cells require large amounts of energy to sustain growth. Through the mediated transport of glucose transporters, the uptake and utilization of glucose by tumor cells are significantly enhanced in the hypoxic microenvironment. Pituitary adenomas are benign tumors with high-energy metabolisms. We aimed to investigate the role of expression of glucose transporter 3 (GLUT3) and glucose transporter 1 (GLUT1) in pituitary adenomas, including effects on size, cystic change and hormone type. Pituitary adenomas from 203 patients were collected from January 2013 to April 2017, and immunohistochemical analysis was used to detect the expression of GLUT3 and GLUT1 in tumor specimens. GLUT3-positive expression in the cystic change group was higher than that in the non-cystic change group (P = 0.018). Proportions of GLUT3-positive staining of microadenomas, macroadenomas, and giant adenomas were 22.7 (5/22), 50.4 (66/131) and 54.0% (27/50), respectively (P = 0.022). In cases of prolactin adenoma, GLUT3-positive staining was predominant in cell membranes (P = 0.000006), while in cases of follicle-stimulating hormone or luteotropic hormone adenoma, we found mainly paranuclear dot-like GLUT3 staining (P = 0.025). In other hormonal adenomas, GLUT3 was only partially expressed, and the intensity of cell membrane or paranuclear punctate staining was weak. In contrast to GLUT3, GLUT1 expression was not associated with pituitary adenomas. Thus, our results indicate that the expression of GLUT3 in pituitary adenomas is closely related to cystic change and hormonal type. This study is the first to report a unique paranuclear dot-like GLUT3 staining pattern in pituitary adenomas.

Open access

Erika Urbano Lima, Ileana G S Rubio, Joaquim Custodio Da Silva, Ana Luiza Galrão, Danielle Pêssoa, Taise Cerqueira Oliveira, Fabiane Carrijo, Igor Silva Campos, Luciano Fonseca Espinheira, Luiz Jose Sampaio, Claudio Rogerio Lima, Janete Maria Cerutti and Helton Estrela Ramos

Background

The inactivation of the tumor-suppressor homeodomain-only protein X (HOPX) usually involves promoter methylation in several cancer types. This study aimed to investigate the HOPX-β mRNA expression and promoter methylation and their clinical relevance in differentiated thyroid cancer (DTC).

Patients and methods

Clinicopathological data and paraffin-embedded thyroid tumor tissues from 21 patients with DTC and 6 with benign tumors (T) and their non-tumor parenchyma (NT) were investigated. Tumor cell lines (FTC238, FTC236 and WRO) were treated with demethylating agent. HOPX-β mRNA expression was assessed by qRT-PCR and methylation status by Q-MSP. Thyroid cancer data from Cancer Genome Atlas (TCGA) was also collected.

Results

HOPX-β mRNA re-expression in two cell lines treated with demethylating agent was observed concomitantly with reduced promoter methylation. Reduced mRNA expression in T group compared to their NT was observed, and reduced protein expression in T compared to NT was observed in three cases. Low mRNA expression with high methylation status was detected in 6/14 DTC samples. High methylation status was associated with older age at diagnosis, recurrent or progressive disease and with the presence of new neoplasm event post initial therapy while hyper-methylation correlated with worse overall survival, worse disease-free status and older age.

Conclusion

A moderate coupling of downregulation of HOPX-β mRNA expression in DTC followed by high HOPX-β promoter methylation was observed however; high HOPX promoter methylation status was associated with the worse prognosis of DTC patients.

Open access

Elena Galazzi, Paolo Duminuco, Mirella Moro, Fabiana Guizzardi, Nicoletta Marazzi, Alessandro Sartorio, Sabrina Avignone, Marco Bonomi, Luca Persani and Maria Teresa Bonati

Ulnar-mammary syndrome (UMS) is characterized by ulnar defects, and nipple or apocrine gland hypoplasia, caused by TBX3 haploinsufficiency. Signs of hypogonadism were repeatedly reported, but the mechanisms remain elusive. We aim to assess the origin of hypogonadism in two families with UMS. UMS was suspected in two unrelated probands referred to an academic center with delayed puberty because of the evident ulnar ray and breast defects in their parents. Clinical, biochemical and genetic investigations proved the existence of congenital normosmic IHH (nIHH) associated with pituitary hypoplasia in the two probands who were heterozygous for novel TBX3 pathogenic variants. The mutations co-segregated with delayed puberty, midline defects (nose, teeth and tongue anomalies) and other variable features of UMS in the two families (absent axillary hairs and nipple hypoplasia, asymmetrical features including unilateral ulnar or renal abnormalities). The combined analysis of these findings and of the previous UMS reports showed delayed puberty and other signs of hypogonadism in 79 and 37% of UMS males, respectively. Proband 1 was followed up to adulthood with persistence of nIHH. In conclusion, UMS should be suspected in patients with delayed puberty and midline defects, including pituitary hypoplasia, in the presence of mild cues for TBX3 mutation, even in the absence of limb malformations. In addition, TBX3 should be included among candidate genes for congenital nIHH.

Open access

Deborah Cosentini, Salvatore Grisanti, Alberto Dalla Volta, Marta Laganà, Chiara Fiorentini, Paola Perotti, Sandra Sigala and Alfredo Berruti

Immunotherapy is widely used in the treatment of different cancer types, including metastatic melanoma, non-small cell lung cancer, renal cell carcinoma and urothelial cancer. The results of the phase I JAVELIN study failed to demonstrate a substantial activity of the PDL-1 inhibitor Avelumab in advanced adrenocortical carcinoma (ACC). This editorial focus on the possible mechanisms of ACC immunoevasion and suggests strategies to overcome the intrinsic immunotherapy resistance of this disease.

Open access

Zofia Kolesinska, James Acierno Jr, S Faisal Ahmed, Cheng Xu, Karina Kapczuk, Anna Skorczyk-Werner, Hanna Mikos, Aleksandra Rojek, Andreas Massouras, Maciej R Krawczynski, Nelly Pitteloud and Marek Niedziela

46,XY differences and/or disorders of sex development (DSD) are clinically and genetically heterogeneous conditions. Although complete androgen insensitivity syndrome has a strong genotype–phenotype correlation, the other types of 46,XY DSD are less well defined, and thus, the precise diagnosis is challenging. This study focused on comparing the relationship between clinical assessment and genetic findings in a cohort of well-phenotyped patients with 46,XY DSD. The study was an analysis of clinical investigations followed by genetic testing performed on 35 patients presenting to a single center. The clinical assessment included external masculinization score (EMS), endocrine profiling and radiological evaluation. Array-comparative genomic hybridization (array-CGH) and sequencing of DSD-related genes were performed. Using an integrated approach, reaching the definitive diagnosis was possible in 12 children. The correlation between clinical and genetic findings was higher in patients with a more severe phenotype (median EMS 2.5 vs 6; P = 0.04). However, in 13 children, at least one variant of uncertain significance was identified, and most times this variant did not correspond to the original clinical diagnosis. In three patients, the genetic studies guided further clinical assessment which resulted in a reclassification of initial clinical diagnosis. Furthermore, we identified eight patients harboring variants in more than one DSD genes, which was not seen in controls (2.5%; P = 0.0003). In summary, taking into account potential challenges in reaching the definitive diagnosis in 46,XY DSD, only integrated approach seems to be the best routine practice.

Open access

Yongli Fu, Yaowu Sun, Jiankun Zhang and Yu Cheng

This meta-analysis aims to update the evidence for the effects of intensive glucose control (IGC) on the outcomes among critically ill patients. We performed a systematic literature review from inception through December, 2017 by two independent authors by searching PubMed, EMBASE and Cochrane Library. Randomized clinical trials of the effects of IGC compared with conventional glucose control were selected. Random-effect models were applied to calculate summary relative risks (RRs) for the related outcomes. Of 4247 records identified, we abstracted data from 27 relevant trials for meta-analysis. Compared with patients receiving conventional glucose control (controls), patients with IGC did not have significantly decreased risk of short-term mortality (in-hospital mortality or intensive care unit (ICU) mortality) (RR 0.99, 95% CI 0.92–1.06) or 3- to 6-month mortality (RR 1.02, 95% CI 0.97–1.08). These results remained constant among different study settings including surgical ICUs, medical ICUs or mixed ICUs. Similarly, we also found that patients with IGC did not have significantly lower risk of sepsis (RR 1.00, 95% CI 0.89–1.11) or new need for dialysis (RR 0.97, 95% CI 0.84–1.11). However, patients with IGC had almost 4-fold increase in risk of hypoglycemia (RR 4.86, 95% CI 3.16–7.46). In conclusion, in this updated meta-analysis of published trials, critically ill patients receiving IGC were found to be at neutral risk for short-term or 3- 6-month mortality, risk of sepsis or new need for dialysis, but at higher risk of hypoglycemia.

Open access

Myrtille Fouché, Yves Bouffard, Mary-Charlotte Le Goff, Johanne Prothet, François Malavieille, Pierre Sagnard, Françoise Christin, Davy Hayi-Slayman, Arnaud Pasquer, Gilles Poncet, Thomas Walter and Thomas Rimmelé

Only few descriptions of intraoperative carcinoid syndrome (ioCS) have been reported. The primary objective of this study was to describe ioCS. A second aim was to identify risk factors of ioCS. We retrospectively analysed patients operated for small-bowel neuroendocrine tumour in our institution between 2007 and 2015, and receiving our preventive local regimen of octreotide continuous administration. ioCS was defined as highly probable in case of rapid (<5 min) arterial blood pressure changes ≥40%, not explained by surgical/anaesthetic management and regressive ≥20% after octreotide bolus injection. Probable cases were ioCS which did not meet all criteria of highly-probable ioCS. Suspected ioCS were detected on the anaesthesia record by an injection of octreotide due to a manifestation which did not meet the criteria for highly-probable or probable ioCS. A total of 81 patients (liver metastases: 59, prior carcinoid syndrome: 49, carcinoid heart disease: 7) were included; 139 ioCS occurred in 45 patients: 45 highly probable, 67 probable and 27 suspected. ioCs was hypertensive (91%) and/or hypotensive (29%). There was no factor, including the use of vasopressors, significantly associated with the occurrence of an ioCS. All surgeries were completed and one patient died from cardiac failure 4 days after surgery. After preoperative octreotide continuous infusion, ioCS were mainly hypertensive. No ioCS risk factors, including vasopressor use, were identified. No intraoperative carcinoid crisis occurred, suggesting the clinical relevance of a standardized octreotide prophylaxis protocol.

Open access

Peng Fan, Chao-Xia Lu, Di Zhang, Kun-Qi Yang, Pei-Pei Lu, Ying Zhang, Xu Meng, Su-Fang Hao, Fang Luo, Ya-Xin Liu, Hui-Min Zhang, Lei Song, Jun Cai, Xue Zhang and Xian-Liang Zhou

Liddle syndrome (LS), a monogenetic autosomal dominant disorder, is mainly characterized by early-onset hypertension and hypokalemia. Clinically, misdiagnosis or missing diagnosis is common, since clinical phenotypes of LS are variable and nonspecific. We report a family with misdiagnosis of primary aldosteronism (PA), but identify as LS with a pathogenic frameshift mutation of the epithelial sodium channel (ENaC) β subunit. DNA samples were collected from a 32-year-old proband and 31 other relatives in the same family. A designed panel including 41 genes associated with monogenic hypertension was screened using next-generation sequencing. The best candidate disease-causing variants were verified by Sanger sequencing. Genetic analysis of the proband revealed a novel frameshift mutation c.1838delC (p.Pro613Glnfs*675) in exon 13 of SCNN1B. This heterozygous mutation involved the deletion of a cytosine from a string of three consecutive cytosines located at codons 612 to 613 and resulted in deletion of the crucial PY motif and elongation of the β-ENaC protein. The identical mutation was also found in 12 affected family members. Amiloride was effective in alleviating LS for patients. There were no SCNN1A or SCNN1G mutations in this family. Our study emphasizes the importance of considering LS in the differential diagnosis of early-onset hypertension. The identification of a novel frameshift mutation of SCNN1B enriches the genetic spectrum of LS and has allowed treatment of this affected family to prevent severe complications.

Open access

Lauren E Henke, John D Pfeifer, Thomas J Baranski, Todd DeWees and Perry W Grigsby

The majority of papillary thyroid carcinoma (PTC) cases comprise classic papillary (C-PTC) and follicular variant (FV-PTC) histologic sub-types. Historically, clinical equivalency was assumed, but recent data suggest C-PTC may have poorer outcomes. However, large single-institution series with long-term outcomes of C-PTC and FV-PTC, using modern pathologic criteria for FV-PTC, are needed. Our objective was to compare prevalence and impact of clinicopathologic factors, including BRAF mutation status, on long-term outcomes of C-PTC and FV-PTC. We hypothesized that patients with C-PTC would have higher risk disease features and worse survival outcomes. This retrospective study included 1293 patients treated at a single, US academic institution between 1943 and 2009 with mean follow-up of 8.6 years. All patients underwent either partial or total thyroidectomy and had invasive C-PTC or FV-PTC per modern pathology criteria. Primary study measurements included differences in recurrence-free survival (RFS), disease-specific survival (DSS) and associations with clinicopathologic factors including the BRAF mutation. Compared to FV-PTC, C-PTC was associated with multiple features of high-risk disease (P < 0.05) and significantly reduced RFS and DSS. Survival differences were consistent across univariate, multivariate and Kaplan–Meier analyses. BRAF mutations were more common in C-PTC (P = 0.002). However, on Kaplan–Meier analysis, mutational status did not significantly impact RFS or DSS for patients with either histologic sub-type. C-PTC therefore indicates higher-risk disease and predicts for significantly poorer long-term outcomes when compared to FV-PTC. The nature of this difference in outcome is not explained by traditional histopathologic findings or by the BRAF mutation.