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conclusive diagnosis of unilateral PA by the "four corners" criteria:

1. Biochemical evidence of PA
2. Lateralization of aldosterone secretion at adrenal venous sampling.
3. Correction of biochemical values and fall of blood pressure after adrenalectomy.
4. Immunohistochemical demonstration of CYP11B2 positive nodule(s)

Presumed diagnosis of bilateral PA, defined as above but without evidence of lateralized aldosterone excess.

Primary (essential) Hypertension (PH): conclusively ascertained high blood pressure and exclusion of secondary hypertension

comprising patients submitted to surgery but free of hypertension

Skin biopsies were obtained in all recruited patients.

Skin Biopsy

Video-laparoscopic adrenalectomy in those with unilateral PA. (PA group 1)

Video-laparoscopic adrenalectomy

Gian Paolo Rossi, Prof.

WHYSKI is a prospective within-patient observational clinical study designed to test the hypothesis that alterations of Na+, K+, water, and the lympho-angiogenetic transcription factor Tonicity Enhancing Binding Protein (TonEBP) mRNA take place in the interstitium of the skin compartment of patients with arterial hypertension due to primary aldosteronism in whom hypertension can be surgically cured.

Background. Given the key role of Na+ in the pathophysiology of HT, this study will test the hypothesis that in PA, which is the paradigm of salt-dependent hypertension, the skin, Na+, K+ and water content is altered and these alterations are corrected by surgical cure of PA with video-laparoscopic adrenalectomy. The investigators will use skin biopsies to directly examine the content of Na+, K+, water, and the lympho-angiogenetic transcription factor Tonicity Enhancing Binding Protein (TonEBP) mRNA in the skin, an important reservoir of body Na+, in primary aldosteronism (PA), the prototype of salt-dependent hypertension.

Methods. The investigators will measure Na+, K+, and water content (by chemical-physical methods) and TonEBP mRNA copy number (by droplet digital PCR) in skin biopsies from a sex-mixed cohort of consecutive consenting patients with unilateral PA treated with a mineralocorticoid receptor antagonist (MRA), before surgery, at doses that correct hypokalemia and HT in order to refer them for surgery with normokalemia and controlled high blood pressure, as per protocol at our institution. The participants will be reassessed in an identical way again after surgical cure.

The investigators expect the dry weight (DW) of the skin specimen obtained at surgery to be significantly higher than at follow-up and to correlate positively with skin Na+, K+, and water content. Hence, if these predictions will be verified, the skin cations and water content will need to be DW-adjusted in order to provide meaningful comparisons across specimen obtained at different time points. The investigators expect the TonEBP mRNA copy number to be markedly overexpressed compared to healthy subjects.

The WHYSKI study will provide solid knowledge of the skin Na+, K+ and water content in patients with arterial salt-dependent hypertension due to PA, PH, and on the effect of cure of the hyperaldosteronism on these variables. The investigators also expect to gather novel knowledge on the molecular and cellular mechanisms involved in the regulation of the content on Na+, K+ and water in a compartment as the skin interstitium that has been largely neglected thus far.

Water and Electrolytes Content in HYpertension (WHYSKI) in the SKIn

The Water and Electrolytes Content in Salt-dependent Human HYpertension (WHYSKI) in the SKIn Before and After Surgical Cure of Primary Aldosteronism

IPD available on reasonable request but if consistent with the ongoing privacy legislation.

With validated chemical physical methods, we will measure the Na+, K+ and water content in the skin of patients with primary aldosteronism (PA, PA Group), primary (essential) hypertension HT patients (PH Group) and in normotensive patients (Control Group). The skin biopsy will be performed during adrenalectomy in consecutive patients with confirmed unilateral PA (PA Group) and in parallel in the same anatomical region in the PH group and in the Control Group, during surgery for benign diseases.

To verify if the cure of PA improves Na+, K+ and water skin clearance in the PA Group the skin biopsy obtained during adrenalectomy will be within-patient compared to that obtained one month after adrenalectomy (PA Group 1). In PA patients found not to have unilateral PA (PA Group 2), the biopsy will be obtained after one month of target medical treatment with canrenone, a mineralocorticoid receptor antagonist.

While the measurement of skin Na+, K+ and water is the main study outcome, an additional important goal will be to determine the molecular mechanisms driven by "skin sodium storage" that underlie the crosstalk between skin cells, macrophages and lymphatic vessels in the interstitium of the patient with PA (PA group 1) and essential hypertensive patients (EH Group) compared with the normotensive patient (Control Group). To this end we will explore the mRNA content of Tonicity-Enhancing Binding Protein TonEBP (also known as NFAT5), a transcription factor known to activate neo-lymphoangiogenesis, using molecular biology techniques.

University Hospital Padova

Full Professor of Internal Medicine, MD, FAHA, FACC

Pheochromocytoma

Paraganglioma

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms, Nerve Tissue

Paragangliomas 1

Neuroendocrine Tumor

Neuroepithelioma

Patients with pheochromocytoma / paraganglioma are being followed as recommended according to international standards. No intervention is expected except regular measurement of plasma CgA (as usual) and EM66 (research purpose) levels.

Patients with essential hypertension will be selected as controls. EM66 and CgA plasma levels will be assessed in these patients after having excluded the presence of a pheochromocytoma / paraganglioma with normal urinary metanephrines / normetanephrines excretion levels.

After inclusion checking to eliminate the presence of pheochromocytoma / paraganglioma, a blood sample will be drawn to assess plasma EM66 and CgA levels.

plasma EM66 & CgA levels assessment

Patients with pheochromocytoma / paraganglioma will be followed-up as the international standards recommend.

Regularly, blood samples will be drawn for the usual assessment of CgA levels and also EM66 (research purpose) levels.

usual follow up with regular EM66 & Cga levels assessment

Anne F Cailleux, MD

Pheochromocytoma or paraganglioma are tumors generating hypertension as a symptom. Different biological tests are currently available to diagnose these tumors. However, they all lack specificity since they do not distinguish cases of hypertension without pheochromocytoma or paraganglioma. To improve the diagnostic specificity of these tumors, the investigators are testing a new marker called EM66.

Neuroendocrine tumors (NT) correspond to neoplasms that develop from endocrine and neuroendocrine cells scattered throughout the body. They are characterized by the occurrence, in their cytoplasm, of dense-core secretory vesicles containing hormones, neuropeptides and acidic proteins such as granins. The diversity of NT (from hypophysis, pancreas, adrenal, gastrointestinal tract) makes very difficult the identification and evaluation of the different types of tumors by the diagnostic and prognostic tools currently available. We have thus established a research program aimed at identifying new biological markers for the detection, the prognosis and the follow-up of NT by seeking in tumor and plasma samples of patients, granin-derived peptides. Our program was initiated on one type of NT : pheochromocytoma. These neoplasms correspond to tumoral chromaffin cells mainly originating from the adrenal medulla. It is considered that 10 % of pheochromocytoma patients will develop metastases and, currently, except in the presence of metastases, there are no means to predict malignancy of the tumor. We setup a radioimmunoassay of EM66 (a secretogranin II-derived peptide) that allowed us to demonstrate that (i) plasma concentrations of the peptide are significantly elevated in pheochromocytoma patients, (ii) combined with other biological tests EM66 measurement increase the diagnostic sensitivity for these neoplasms, (iii) after surgical removal of the tumor, plasma EM66 concentrations rapidly return to basal level and, (iv) intra-tumoral EM66 concentrations are higher in benign than in malignant pheochromocytomas (Yon et al., 2003, Guillemot et al., 2006). These results reveal that EM66 constitutes a novel tool for the diagnosis, prognosis and follow-up of pheochromocytoma. In the frame of a clinical use of an EM66 measurement test, it is necessary to evaluate the specificity of this marker. For instance, renal deficiency, hypergastrinemia, reduction of renal clearance, type A gastritis, Crohns disease, or proton-pump inhibitory treatment, lead to increase plasma chromogranin A (CgA) concentrations (false-positive cases). In addition, while hypertension account for one of the symptoms of pheochromocytoma patients, in essential hypertensive patients, CgA levels are higher than in normotensive individuals. The main objective of our clinical transfer research project consists to study the specificity of the measurement of EM66 as a diagnostic and prognostic marker of pheochromocytoma. This multicentric study will allow us to compare plasma EM66 levels in pheochromocytoma patients with a cohort of essential hypertensive patients. At the same time, in a long-range prospect, due to the lack of malignancy markers for these tumors, we will investigate if plasma or tumor EM66 levels are correlated to the differentiation status of pheochromocytomas, and if the expression level of a set of genes that we identified by a transcriptomic approach developed in the laboratory, is associated with the malignant status of the tumors. The stakes of this transfer research, involving our laboratory and the Center for Clinical Investigations (CIC) of Rouen and Lille, are to provide an easy and simple novel tool to practitioners and anatomo-pathologists for the screening, the evaluation and the follow-up of patients with neuroendocrine tumors.

5 ml blood sample on EDTA to collect 2,5 ml plasma, kept at -80°C, once a year.

Specificity of Elevated Plasma EM66 Levels in Pheochromocytoma

Clinical Application of New Pheochromocytoma Markers: INSERM Pilot Study of the Specificity of Elevated Plasma EM66 Concentrations in Patients With Pheochromocytoma or Paraganglioma Compared to Patients With Essential Hypertension

Institut National de la Santé Et de la Recherche Médicale, France

University Hospital, Rouen

Digestive System Diseases

Respiratory Tract (Lung and Bronchial) Diseases

Nervous System Diseases

Mouth and Tooth Diseases

Ear, Nose, and Throat Diseases

Kidney Diseases

Stomach Neoplasms

Lung Neoplasms

Pancreatic Neoplasms

Epilepsy

Acute Coronary Syndrome

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Liver Neoplasms

Dysbiosis

Nasopharyngeal Carcinoma

Hypothyroidism

Urologic Diseases

Nasopharyngeal Neoplasms

Carcinoma

Renal Insufficiency, Chronic

Renal Insufficiency

Disease Attributes

Coronary Artery Disease

Myocardial Ischemia

Ischemia

Heart Diseases

Thyroid Diseases

Pharyngeal Neoplasms

Otorhinolaryngologic Neoplasms

Head and Neck Neoplasms

Nasopharyngeal Diseases

Pharyngeal Diseases

Stomatognathic Diseases

Otorhinolaryngologic Diseases

Chronic Graft Versus Host Disease

Stomach Cancer

Pancreatic Cancer

Acute Graft Versus Host Disease

no intervention

Jiahui Zhang

Hui Xu

Wenming Wang

Xiaoli Zhang

Yingping Cao

Falin Chen

Yan Chen

Liqiong Yao

Gechong Yong

Tian Cai

Minmin Li

Zhaofan Luo

Kang Chen

Li Xie

Yulin Yuan

Minzhong Tang

Wei Wang

Hai Huang

Xiang Wu

Dejun Yun

Yingyu Jin

Haiyan Gao

Jinyu Yang

Wenxiu Liu

Zhanjun Zhang

Tao Jiang

Weibing Yin

Xiaoliang Zhou

Zhengjiang Cheng

Xuesheng Li

Zuiming Jiang

Guoli Liu

Hongyu Huang

Honghou Dai

Tianyu Zhong

Xiaozhong Wang

Jufen Ma

Kunping Guan

Yuanyuan Pan

Hongli Liu

Zhuo Li

Yuan Liu

Yuanjiu Xu

Yin Xiang

Kai Chen

Heng Zhang

Li Ren

Aimin Xu

Yong Duan

Fuxing Zhang

Yufeng Liao

Yan He

The human gut microbiome has been associated with many health factors but variability between studies limits the exploration of effects between them. This study aims to systematically characterize the gut microbiota of various critical chronic diseases, compare the similarities and differences of the microbiome signatures linked to different regions and diseases, and further investigate their impacts on microbiota-based diagnostic models.

Many studies demonstrate that microbial dysbiosis has been linked to many human pathologies. However, the current understanding of the identification of the disease-associated microbiome signatures remains limited, largely owing to the heterogeneity of microbial community structures which are shaped by the host. Undoubtedly, profiles of microbial biomarkers require validation in large, independent, population-based cohorts from different districts. Based on these, the investigator plan to organize a multicentric cross-sectional cohort, not only to systematically characterize the gut microbiota of various critical chronic diseases, such as liver cancer, gastric cancer, pancreatic cancer, lung cancer, nasopharyngeal cancer, hypertension, acute coronary syndrome, primary aldosteronism, epilepsy, chronic kidney disease, and subclinical hypothyroidism but also to compare the similarities and differences of the microbiome signatures linked to different regions and different diseases and to further investigate their impacts on microbiota-based diagnostic models. In this study, for each kind of disease, the investigators expect to recruit 500 patients with a confirmed diagnosis and 500 sex- and age-matched controls, to record their information related to demography, body measurement, lifestyle, diet, medication, diseases, and biochemistry, and to collect their feces, saliva, urine and blood samples.

Feces, saliva, urine, serum, plasma and buffy coat

A Multicentre Study on Features of the Gut Microbiota of Patients With Critical Chronic Diseases in China

The microbial composition of the stool and saliva samples was determined by 16S rRNA (ribosomal ribonucleic acid) gene sequencing analysis and metagenomics. Comparison of microbial abundance and diversity of healthy volunteers and patients with various diseases.

Comparison of serum markers of healthy volunteers and patients with various diseases.

Comparison of metabolites of healthy volunteers and patients with various diseases.

Comparison of peptides of healthy volunteers and patients with various diseases using mass spectrometry.

National Natural Science Foundation of China

Zhujiang Hospital

Professor

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Water and Electrolytes Content in HYpertension (WHYSKI) in the SKIn	NCT06090617	Hyperaldosteron... Hypertension Aldosterone-pro... Aldosteronism Aldosterone Dis... Essential Hyper... Bilateral Adren... Conn Adenoma	Skin Biopsy Video-laparosco...	18 Years - 75 Years	University Hospital Padova
Specificity of Elevated Plasma EM66 Levels in Pheochromocytoma	NCT01022515	Pheochromocytom... Paraganglioma Essential Hyper...	plasma EM66 & C... usual follow up...	18 Years - 90 Years	University Hospital, Rouen
A Multicentre Study on Features of the Gut Microbiota of Patients With Critical Chronic Diseases in China	NCT05638269	Essential Hyper... Liver Cancer Nasopharyngeal ... Pancreatic Canc... Lung Cancer Chronic Kidney ... Acute Coronary ... Epilepsy Gastric Cancer Primary Aldoste... Subclinical hyp...	no intervention	18 Years - 75 Years	Zhujiang Hospital
A Multicentre Study on Features of the Gut Microbiota of Patients With Critical Chronic Diseases in China	NCT05638269	Essential Hyper... Liver Cancer Nasopharyngeal ... Pancreatic Canc... Lung Cancer Chronic Kidney ... Acute Coronary ... Epilepsy Gastric Cancer Primary Aldoste... Subclinical hyp...	no intervention	18 Years - 75 Years	Zhujiang Hospital

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