Effect of the COVID-19 pandemic on surgery for indeterminate thyroid nodules (THYCOVID): a retrospective, international, multicentre, cross-sectional study.

BACKGROUND: Since its outbreak in early 2020, the COVID-19 pandemic has diverted resources from non-urgent and elective procedures, leading to diagnosis and treatment delays, with an increased number of neoplasms at advanced stages worldwide. The aims of this study were to quantify the reduction in surgical activity for indeterminate thyroid nodules during the COVID-19 pandemic; and to evaluate whether delays in surgery led to an increased occurrence of aggressive tumours. METHODS: In this retrospective, international, cross-sectional study, centres were invited to participate in June 22, 2022; each centre joining the study was asked to provide data from medical records on all surgical thyroidectomies consecutively performed from Jan 1, 2019, to Dec 31, 2021. Patients with indeterminate thyroid nodules were divided into three groups according to when they underwent surgery: from Jan 1, 2019, to Feb 29, 2020 (global prepandemic phase), from March 1, 2020, to May 31, 2021 (pandemic escalation phase), and from June 1 to Dec 31, 2021 (pandemic decrease phase). The main outcomes were, for each phase, the number of surgeries for indeterminate thyroid nodules, and in patients with a postoperative diagnosis of thyroid cancers, the occurrence of tumours larger than 10 mm, extrathyroidal extension, lymph node metastases, vascular invasion, distant metastases, and tumours at high risk of structural disease recurrence. Univariate analysis was used to compare the probability of aggressive thyroid features between the first and third study phases. The study was registered on ClinicalTrials.gov, NCT05178186. FINDINGS: Data from 157 centres (n=49 countries) on 87 467 patients who underwent surgery for benign and malignant thyroid disease were collected, of whom 22 974 patients (18 052 [78·6%] female patients and 4922 [21·4%] male patients) received surgery for indeterminate thyroid nodules. We observed a significant reduction in surgery for indeterminate thyroid nodules during the pandemic escalation phase (median monthly surgeries per centre, 1·4 [IQR 0·6-3·4]) compared with the prepandemic phase (2·0 [0·9-3·7]; p<0·0001) and pandemic decrease phase (2·3 [1·0-5·0]; p<0·0001). Compared with the prepandemic phase, in the pandemic decrease phase we observed an increased occurrence of thyroid tumours larger than 10 mm (2554 [69·0%] of 3704 vs 1515 [71·5%] of 2119; OR 1·1 [95% CI 1·0-1·3]; p=0·042), lymph node metastases (343 [9·3%] vs 264 [12·5%]; OR 1·4 [1·2-1·7]; p=0·0001), and tumours at high risk of structural disease recurrence (203 [5·7%] of 3584 vs 155 [7·7%] of 2006; OR 1·4 [1·1-1·7]; p=0·0039). INTERPRETATION: Our study suggests that the reduction in surgical activity for indeterminate thyroid nodules during the COVID-19 pandemic period could have led to an increased occurrence of aggressive thyroid tumours. However, other compelling hypotheses, including increased selection of patients with aggressive malignancies during this period, should be considered. We suggest that surgery for indeterminate thyroid nodules should no longer be postponed even in future instances of pandemic escalation. FUNDING: None.

Prolonged culture of human pancreatic islets under glucotoxic conditions changes their acute beta cell calcium and insulin secretion glucose response curves from sigmoid to bell-shaped.

AIMS/HYPOTHESIS: The rapid remission of type 2 diabetes by a diet very low in energy correlates with a marked improvement in glucose-stimulated insulin secretion (GSIS), emphasising the role of beta cell dysfunction in the early stages of the disease. In search of novel mechanisms of beta cell dysfunction after long-term exposure to mild to severe glucotoxic conditions, we extensively characterised the alterations in insulin secretion and upstream coupling events in human islets cultured for 1-3 weeks at ~5, 8, 10 or 20 mmol/l glucose and subsequently stimulated by an acute stepwise increase in glucose concentration. METHODS: Human islets from 49 non-diabetic donors (ND-islets) and six type 2 diabetic donors (T2D-islets) were obtained from five isolation centres. After shipment, the islets were precultured for 3-7 days in RPMI medium containing ~5 mmol/l glucose and 10% (vol/vol) heat-inactivated FBS with selective islet picking at each medium renewal. Islets were then cultured for 1-3 weeks in RPMI containing ~5, 8, 10 or 20 mmol/l glucose before measurement of insulin secretion during culture, islet insulin and DNA content, beta cell apoptosis and cytosolic and mitochondrial glutathione redox state, and assessment of dynamic insulin secretion and upstream coupling events during acute stepwise stimulation with glucose [NAD(P)H autofluorescence, ATP/(ATP+ADP) ratio, electrical activity, cytosolic Ca2+ concentration ([Ca2+]c)]. RESULTS: Culture of ND-islets for 1-3 weeks at 8, 10 or 20 vs 5 mmol/l glucose did not significantly increase beta cell apoptosis or oxidative stress but decreased insulin content in a concentration-dependent manner and increased beta cell sensitivity to subsequent acute stimulation with glucose. Islet glucose responsiveness was higher after culture at 8 or 10 vs 5 mmol/l glucose and markedly reduced after culture at 20 vs 5 mmol/l glucose. In addition, the [Ca2+]c and insulin secretion responses to acute stepwise stimulation with glucose were no longer sigmoid but bell-shaped, with maximal stimulation at 5 or 10 mmol/l glucose and rapid sustained inhibition above that concentration. Such paradoxical inhibition was, however, no longer observed when islets were acutely depolarised by 30 mmol/l extracellular K+. The glucotoxic alterations of beta cell function were fully reversible after culture at 5 mmol/l glucose and were mimicked by pharmacological activation of glucokinase during culture at 5 mmol/l glucose. Similar results to those seen in ND-islets were obtained in T2D-islets, except that their rate of insulin secretion during culture at 8 and 20 mmol/l glucose was lower, their cytosolic glutathione oxidation increased after culture at 8 and 20 mmol/l glucose, and the alterations in GSIS and upstream coupling events were greater after culture at 8 mmol/l glucose. CONCLUSIONS/INTERPRETATION: Prolonged culture of human islets under moderate to severe glucotoxic conditions markedly increased their glucose sensitivity and revealed a bell-shaped acute glucose response curve for changes in [Ca2+]c and insulin secretion, with maximal stimulation at 5 or 10 mmol/l glucose and rapid inhibition above that concentration. This novel glucotoxic alteration may contribute to beta cell dysfunction in type 2 diabetes independently from a detectable increase in beta cell apoptosis.

Severe hypercalcaemia early after kidney transplantation in two patients with severe secondary hyperparathyroidism previously treated with etelcalcetide.

Cinacalcet and, more recently, etelcalcetide revolutionized the treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD). Kidney transplant (KT) usually improves CKD-MBD. However, a significant proportion of KT recipients have high serum calcium levels, not requiring any treatment. We report two patients previously treated with etelcalcetide who developed severe (>3.3 mmol/L) hypercalcaemia in the early post-KT course, requiring parathyroidectomy. Pathological studies showed parathyroid adenomas and hyperplasia. One patient had a graft biopsy showing numerous intratubular calcium phosphate crystals. These observations should prompt pharmacovigilance studies and careful follow-up of KT recipients previously treated with etelcalcetide.

Recurrence and Outcome of Anti-Glomerular Basement Membrane Glomerulonephritis After Kidney Transplantation.

INTRODUCTION: Recurrence of anti-glomerular basement membrane (anti-GBM) glomerulonephritis in the kidney graft is a rare event, described in limited reports. The aim of this study was to evaluate, in a large cohort of patients with long follow-up, the risk of recurrence of anti-GBM disease, the risk factors associated with clinical recurrence, and the long-term patient and graft survival. METHODS: This was a multicenter retrospective study. Inclusion criteria were patients with anti-GBM glomerulonephritis who underwent transplantation of a kidney between 1977 and 2015. Exclusion criteria were systemic vasculitis, lupus erythematosus, and cryoglobulinemia. Recurrence was defined as reappearance of clinical signs of glomerulonephritis along with histological signs of proliferative glomerulonephritis and linear IgG staining on kidney biopsy, with or without anti-GBM antibodies. RESULTS: A total of 53 patients were included. Recurrence of anti-GBM glomerulonephritis in a first kidney transplant occurred in only 1 patient 5 years after transplantation (a prevalence rate of 1.9%) in the context of cessation of immunosuppressive drugs, and resulted in graft loss due to recurrence. Linear IgG staining on kidney biopsy in the absence of histological signs of proliferative glomerulonephritis was observed in 4 patients, in the context of cellular rejection. Patient survival was 100%, 94%, and 89% at 5, 10, and 15 years, respectively. Death-censored first-graft survival rates were 88%, 83%, and 79% at 5, 10, and 15 years, respectively. CONCLUSION: The recurrence rate of anti-GBM glomerulonephritis after transplantation is very low but is associated with graft loss. The long-term patient and graft survival rates are excellent.

miR-199a Downregulation as a Driver of the NOX4/HIF-1α/VEGF-A Pathway in Thyroid and Orbital Adipose Tissues from Graves' Patients.

Graves' disease (GD) is an autoimmune thyroiditis often associated with Graves' orbitopathy (GO). GD thyroid and GO orbital fat share high oxidative stress (OS) and hypervascularization. We investigated the metabolic pathways leading to OS and angiogenesis, aiming to further decipher the link between local and systemic GD manifestations. Plasma and thyroid samples were obtained from patients operated on for multinodular goiters (controls) or GD. Orbital fats were from GO or control patients. The NADPH-oxidase-4 (NOX4)/HIF-1α/VEGF-A signaling pathway was investigated by Western blotting and immunostaining. miR-199a family expression was evaluated following quantitative real-time PCR and/or in situ hybridization. In GD thyroids and GO orbital fats, NOX4 was upregulated and correlated with HIF-1α stabilization and VEGF-A overexpression. The biotin assay identified NOX4, HIF-1α and VEGF-A as direct targets of miR-199a-5p in cultured thyrocytes. Interestingly, GD thyroids, GD plasmas and GO orbital fats showed a downregulation of miR-199a-3p/-5p. Our results also highlighted an activation of STAT-3 signaling in GD thyroids and GO orbital fats, a transcription factor known to negatively regulate miR-199a expression. We identified NOX4/HIF-1α/VEGF-A as critical actors in GD and GO. STAT-3-dependent regulation of miR-199a is proposed as a common driver leading to these events in GD thyroids and GO orbital fats.

Eliminating Hepatitis C Virus From a Prevalent Kidney Transplant Recipient Population: A Single-Center Study in Belgium in the Direct-Acting Antivirals Era.

BACKGROUND: Direct-acting antivirals (DAAs) have revolutionized the treatment of hepatitis C virus (HCV) infection. Although previous studies have reported positive results with DAAs after kidney transplantation (KT), their impact on the prevalence of HCV viremia (HCVv) in prevalent kidney transplant recipients (KTRs) remains ill defined. METHODS: We retrospectively reviewed the HCV status of all patients followed at Cliniques Universitaires Saint-Luc, Brussels, Belgium, outpatient KT clinic between January 2014 and December 2018. We collected the clinical features of KTRs treated with DAAs during this period and calculated the annual prevalence of HCVv over this period. RESULTS: Out of 1451 KTRs, 22 (1.52%) had HCVv in 2014 to 2018. From 2014 to 2018, the annual prevalence of HCVv dropped from 1.97% to 0.43%, (P < .001). Fourteen KTRs were treated with DAAs a median of 197 months (range: 5-374) after KT, mostly (79%) in 2017 after reimbursement restrictions of DAAs for KTRs in Belgium were removed. DAA treatment was safe with a sustained virological response rate at 12 weeks after treatment (SVR12) of 93%. Two patients died 14 months (lymphoma, despite SVR12) and 7 months (hepatocarcinoma, no SVR12) after DAAs initiation, respectively. Among HCVv KTRs not treated with DAAs (n = 8), 2 lost their graft, 5 died, and 1 is initiating therapy. The current prevalence of HCVv in the cohort is 0.08%, with a single patient currently on treatment. CONCLUSION: Treatment with DAAs led to a dramatic decrease of HCVv prevalence in this KTR cohort. DAA use was safe and effective. Elimination of HCV is possible at KT clinics.

Erythropoiesis and chronic kidney disease-related anemia: From physiology to new therapeutic advancements.

Erythropoiesis is triggered by hypoxia and is strictly regulated by hormones, growth factors, cytokines, and vitamins to ensure an adequate oxygen delivery to all body cells. Abnormalities in one or more of these factors may induce different kinds of anemia requiring different treatments. A key player in red blood cell production is erythropoietin. It is a glycoprotein hormone, mainly produced by the kidneys, that promotes erythroid progenitor cell survival and differentiation in the bone marrow and regulates iron metabolism. A deficit in erythropoietin synthesis is the main cause of the normochromic normocytic anemia frequently observed in patients with progressive chronic kidney disease. The present review summarizes the most recent findings about each step of the erythropoietic process, going from the renal oxygen sensing system to the cascade of events induced by erythropoietin through its own receptor in the bone marrow. The paper also describes the new class of drugs designed to stabilize the hypoxia-inducible factor by inhibiting prolyl hydroxylase, with a discussion about their metabolism, disposition, efficacy, and safety. According to many trials, these drugs seem able to simulate tissue hypoxia and then stimulate erythropoiesis in patients affected by renal impairment. In conclusion, the in-depth investigation of all events involved in erythropoiesis is crucial to understand anemia pathophysiology and to identify new therapeutic strategies, in an attempt to overcome the potential side effects of the commonly used erythropoiesis-stimulating agents.

Preperitoneal Surgical Approach to Treat Vesicoureteral Anastomotic Leakage, Distal Stenosis or Reflux After Kidney Transplantation.

BACKGROUND: If endourological approaches are not applicable to treat vesicoureteral anastomotic complications after kidney transplantation, the surgical gold standard in many transplant centers is pyeloureterostomy or ureteroureterostomy using the native ureter. We report an original preperitoneal technique that can be used for vesicoureteral reanastomosis in kidney transplant recipients not eligible for endourological treatment. METHODS: Between January 2011 and December 2015, 18 kidney transplant recipients underwent this new surgical procedure. Of this number, 15 subjects with at least 1 year of follow-up were included in the analysis. The indications were vesicoureteral reflux, anastomotic stenosis, and leakage in 8, 5, and 2 patients, respectively. Briefly, a double J stent was preoperatively inserted into the grafted ureter. Surgery was performed through a Pfannenstiel incision. The preperitoneal space surrounding the bladder was dissected and the distal part of the grafted ureter was identified and mobilized. The anastomotic area was resected and another vesicoureteral anastomosis was performed (Lich-Gregoir technique), keeping the JJ stent in place for three weeks. RESULTS: This procedure was performed 213 days (range 17-2608) after kidney transplantation. Median surgical duration was 179 minutes (range 112-314) and median hospital stay 8 days (range 4-14). The success rate was 86.7% (13/15), with a median follow-up of 1148 days (range 517-1808). In two patients, symptomatic recurrence of vesicoureteral reflux required a pyeloureterostomy using the native ureter. CONCLUSIONS: The authors describe a simple technique that avoids transperitoneal dissection, potentially yielding more esthetic results thanks to easy access, as well as excellent outcomes.

Unusual presentations of enlarged parathyroid cysts: two case reports.

INTRODUCTION: Parathyroid cysts are infrequently encountered and have a variable presentation pattern depending on their size, location and secreting character. PATIENTS AND METHODS: We report two cases of parathyroid cysts characterized by their uncommon clinical presentation. RESULTS: In the first case the patient presented with a large cervical cystic mass without hypercalcemia, while in the second case, the patient experienced a hypercalcemic crisis associated with acute renal failure. The variable pattern of clinical manifestations is discussed. CONCLUSION: Parathyroid cysts are a rare entity. Surgical resection is the key to therapy when hyperparathyroidism or local compression are identified.

Delayed graft function and chronic allograft nephropathy: diagnostic and prognostic role of neutrophil gelatinase-associated lipocalin.

CONTEXT: Available markers are not reliable parameters to early detect kidney injury in transplanted patients. OBJECTIVE: Examine neutrophil gelatinase associated lipocalin (NGAL) in early detection of delayed graft function (DGF) and as a long-term predictor of graft outcome. PATIENTS AND METHODS: NGAL was evaluated in 124 transplanted patients. RESULTS: Urinary NGAL levels were associated to a 10% (HR: 1.10; 95% CI: 1.04-1.25; p < 0.001) and 15% (HR: 1.15; 95% CI: 1.09-1.26; p < 0.001) increased risk of DGF and allograft nephropathy progression, respectively. CONCLUSION: NGAL reflects the entity of renal impairment in transplanted patients, representing a biomarker and an independent risk factor for DGF and chronic allograft nephropathy progression.

Phosphate binders for the treatment of chronic kidney disease: role of iron oxyhydroxide.

Chronic kidney disease-mineral bone disorder is frequent in patients with renal failure. It is characterized by abnormalities in mineral and bone metabolism with resulting hyperphosphatemia, low serum vitamin D, secondary hyperparathyroidism, altered bone morphology and strength, higher risk of bone fractures, and development of vascular or other soft tissue calcifications. Besides the recommendation to reduce phosphorus dietary intake, many drugs are currently available for the treatment of calcium/phosphate imbalance. Among them, phosphate binders represent a milestone. Calcium-based binders (calcium carbonate, calcium acetate) are effective in lowering serum phosphate, but their use has been associated with an increased risk of hypercalcemia and calcifications. Calcium-free binders (sevelamer hydrochloride, sevelamer carbonate, and lanthanum carbonate) are equally or slightly less effective than calcium-containing compounds. They would not induce an increase in calcium levels but may have relevant side effects, including gastrointestinal symptoms for sevelamer and risk of tissue accumulation for lanthanum. Accordingly, new phosphate binders are under investigation and some of them have already been approved. A promising option is sucroferric oxyhydroxide (Velphoro(®), PA21), an iron-based phosphate binder consisting of a mixture of polynuclear iron(III)-oxyhydroxide, sucrose, and starches. The present review is focused on pharmacology, mode of action, and pharmacokinetics of sucroferric oxyhydroxide, with a discussion on comparative efficacy, safety, and tolerability studies of this drug in chronic kidney disease and patient perspectives such as quality of life, satisfaction, and acceptability. Sucroferric oxyhydroxide has proven to be as effective as sevelamer in reducing phosphatemia with a similar safety profile and lower pill burden. Experimental and clinical studies have documented a minimal percentage of iron absorption without inducing toxicity. In conclusion, the overall benefit-risk balance of sucroferric oxyhydroxide is deemed to be positive, and this new drug may therefore represent a good alternative to traditional phosphate binders for the treatment of hyperphosphatemia in dialysis patients.

Surgical options for primary hyperparathyroidism.

Over the last two decades, surgery for primary hyperparathyroidism has evolved to offer a panel of procedures based on improvements in imaging, new technology and, consequently, novel surgical techniques. Multiple courses of action are possible, consistent with varying degrees of complexity. From the simplest scenario of a single adenoma localized by at least two preoperative tests in the context of sporadic primary hyperparathyroidism, to revision surgery related to recurrent, persistent or multiglandular disease, the surgeon has the opportunity to adapt his strategy. However, whatever surgical approach is used, even in the absence of formal guidelines, the clinical judgment of an experienced and skilled practitioner in endocrine surgery is the real guide and key of success in complex situations.

Nephro-oncology: a link in evolution.

A multidisciplinary approach represents the best method to interact with patients. Neoplastic and renal diseases are closely related to each other because of an increased risk of cancer among individuals with end-stage renal disease and because of the high prevalence of renal failure in cancer patients. Physicians should be able to know how to prevent and treat the possible complications which may appear during the course of neoplastic disease that may lead to kidney damage such as the Acute Tumor Lysis Syndrome, disorders of hydroelectrolitic balance, metabolic alterations in the calcium-phosphorus, anemia, interstitial and glomerular impairment due to chemotherapy. It is very important to know patients' renal function and directly monitor it, before and during treatment, using formulas for estimating glomerular filtration rate (GFR) and above all, specific biomarkers are more early and sensitive than the increase of creatinine, like neutrophil gelatinase-associated lipocalin. Additionally, physician should consider that alteration of GFR or substitutive renal treatments severely influence dosage of tumor markers and it could lead to wrong diagnosis of cancer. The aim of this article is to provide a review of problems related to cancer relevant in the development of renal failure and try to define the best therapeutic strategies to cope with possible kidney imbalances induced by cancer or its treatment.

Apelin beyond kidney failure and hyponatremia: a useful biomarker for cancer disease progression evaluation.

Apelin regulates angiogenesis, stimulating endothelial cell proliferation and migration. It is upregulated during tumor angiogenesis, and its overexpression was reported to increase tumor growth. Furthermore, apelin controls vasopressin release and body fluid homeostasis. The aim of this study was to examine the correlations between apelin expression and clinical outcomes in oncologic patients, such as cancer disease progression and patient's survival. Apelin levels were evaluated in a cohort of 95 patients affected by different varieties of cancer. Partial remission and stable disease were assigned to the 'no progression' group, comparing it with the progressor group. Patients were followed up for 2 years. Receiver operating characteristics analysis was employed for identifying the progression of the oncologic disease and Kaplan-Meier curves assessed the survival. Adjusted risk estimates for progression endpoint were calculated using Cox proportional hazard regression analysis. Oncologic patients had higher apelin levels compared with healthy subjects, and apelin was closely related to the stages of the disease. In the hyponatremia group, apelin values were significantly higher than patients with eunatremia. After the follow-up of 24 months, 41 patients (43%) reached the endpoint. Progressor subjects presented significantly increased apelin values at baseline compared with non-progressor. Univariate followed by multivariate Cox proportional hazard regression analysis showed that apelin predicted cancer progression independently of other potential confounders. In patients with cancer, apelin closely reflects the stage of the disease and represents a strong and independent risk marker for cancer progression.

Menstrual and reproductive factors in the risk of differentiated thyroid carcinoma in young women in France: a population-based case-control study.

The incidence of thyroid cancer has increased in eastern Europe since the Chernobyl nuclear power plant accident. Although the radioactive fallout was much less severe and the thyroid radiation dose was much lower in France, a case-control study was initiated in eastern France. The present study included 633 young women who were diagnosed with differentiated thyroid cancer before 35 years of age between 2002 and 2006 and matched with 677 controls. Face-to-face interviews were conducted from 2005 to 2010. Odds ratios were calculated using conditional logistic regressions and were reported in the total group and by histopathological type of cancer ("only papillary" and "excluding microcarcinomas"). The risk of thyroid cancer was higher in women who had a higher number of pregnancies, used a lactation suppressant, or had early menarche. Conversely, breastfeeding, oral contraceptive use, and late age at first pregnancy were associated with a lower risk of thyroid cancer. No association was observed between thyroid cancer and having irregular menstrual cycle, undergoing treatment for menstrual cycle regularity shortly after menarche, having a cessation of menstruation, use of another contraceptive, history of miscarriage or abortion for the first pregnancy, or having had gestational diabetes. This study confirms the role of hormonal and reproductive factors in thyroid cancer, and our results support the fact that exposure to estrogens increases thyroid cancer risk.

Is plasma and urine neutrophil gelatinase-associated lipocalin (NGAL) determination in donors and recipients predictive of renal function after kidney transplantation?

OBJECTIVES: Delayed graft function (DGF) is still a major issue in kidney transplantation. Plasma and urine neutrophil gelatinase-associated lipocalin (NGAL) were evaluated in a population of kidney donors and recipients to investigate their performance to predict early renal function. DESIGN AND METHODS: Plasma (pNGAL) and urine (uNGAL) samples were obtained from donors before organ procurement, and from recipients before transplantation, and then 6, 24 and 48h after the procedure. Kidney transplantations were performed from both living donors (LDs, n=17) and deceased donors (DDs, n=80). Recovery of renal function was evaluated as the time to reach serum creatinine <2mg/l or glomerular filtration rate (GFR)>40mL/min. Logistic regression was used to assess the ability of different variables to predict the occurrence of DGF. RESULTS: Plasma NGAL levels were significantly lower in LDs than in DDs. No episodes of DGF were recorded among LD kidney recipients, but DGF was observed in 25% of patients in the DD group. There was no correlation between donor pNGAL and uNGAL values and the occurrence of post-transplant DGF. Recipient pNGAL performed better than uNGAL in terms of predicting DGF occurrence. Donor pNGAL and uNGAL values did not influence the time needed to reach serum creatinine levels of <2mg/dl after transplantation. When time to reach eGFR of >40mL/min is considered, only donor uNGAL seems to be a predictor of graft function recovery. However, recipient pNGAL values obtained 24 and 48h after transplantation, but not uNGAL values, were found to be a significant predictor of graft function recovery. CONCLUSIONS: Plasma NGAL level determination in recipients, but not in donors, proved to be a reliable predictor of DGF occurrence and renal function restoration, but too long for an interval to be able to compete with biomarkers currently used in clinical practice.

Relaxin: new pathophysiological aspects and pharmacological perspectives for an old protein.

Human relaxin-2 (hereafter simply defined as "relaxin") is a 6-kDa peptidic hormone best known for the physiological role played during pregnancy in the growth and differentiation of the reproductive tract and in the renal and systemic hemodynamic changes. This factor can also be involved in the pathophysiology of arterial hypertension and heart failure, in the molecular pathways of fibrosis and cancer, and in angiogenesis and bone remodeling. It belongs to the relaxin peptide family, whose members comprehensively exert numerous effects through interaction with different types of receptors, classified as relaxin family peptide (RXFP) receptors (RXFP1, RXFP2, RXFP3, RXFP4). Research looks toward the in-depth examination and complete understanding of relaxin in its various pleiotropic actions. The intent is to evaluate the likelihood of employing this substance for therapeutic purposes, for instance in diseases where a deficit could be part of the underlying pathophysiological mechanisms, also avoiding any adverse effect. Relaxin is already being considered as a promising drug, especially in acute heart failure. A careful study of the different RXFPs and their receptors and the comprehension of all biological activities of these hormones will probably provide new drugs with a potential wide range of therapeutic applications in the near future.

Apelin and copeptin: two opposite biomarkers associated with kidney function decline and cyst growth in autosomal dominant polycystic kidney disease.

Vasopressin (AVP) plays a detrimental role in autosomal dominant polycystic kidney disease (ADPKD). Copeptin represents a measurable substitute for circulating AVP whereas apelin counteracts AVP signaling. The aim of this study was to investigate the predictive value of apelin and copeptin for the progression of ADPKD disease. 52 ADPKD patients were enrolled and followed until the end of the observation period or the primary study endpoint was reached, defined by the combined outcome of decrease of glomerular filtration rate associated with a total renal volume increase. Receiver operating characteristics (ROC) analysis was employed for identifying the progression of renal disease and Kaplan-Meier curves assessed the renal survival. Adjusted risk estimates for progression endpoint and incident renal replacement therapy (RRT) were calculated using Cox proportional hazard regression analysis. ADPKD patients were characterized by lower apelin levels and higher copeptin levels when compared with healthy subjects. These biomarkers were strictly correlated with osmolality and markers of renal function. At ROC analysis, apelin and copeptin showed a very good diagnostic profile in identifying ADPKD progression. After the follow up of 24 months, 33 patients reached the endpoint. Cox proportional hazard regression analysis showed that apelin predicted renal disease progression and incident RRT independently of other potential confounders. Apelin is associated with kidney function decline in ADPKD, suggesting that it may be a new marker to predict kidney outcome.

Distinctive features of melanoma and its management in elderly patients: a population-based study in France.

IMPORTANCE: Life expectancy is increasing in most developed countries, and elderly people have the highest incidence of melanoma. OBJECTIVE: To identify characteristics of melanoma and its management in the elderly compared with younger patients. DESIGN, SETTING, AND PARTICIPANTS: Retrospective population-based study of incident cases of primary melanoma in 1621 patients with stage I or II melanoma in 2004 and 2008. Questionnaires administered to physicians and a survey of cancer registries and pathology laboratories were used to obtain data. The study was conducted in 5 regions in northeastern France. MAIN OUTCOMES AND MEASURES: Characteristics of patients and tumors, circumstances of diagnosis, and further management in older patients (≥70 years, 487 patients [30.0%]) compared with younger ones (<70 years, 1134 [70.0%]). RESULTS: Older patients had more frequent melanomas of the head and neck (29.4% vs 8.7%; P < .001) and of the nodular, lentigo maligna, or acral lentiginous histologic subtypes. They had thicker and more frequently ulcerated tumors, categorized as T3 or T4 in 36.7% of cases vs 20.1% in younger patients. Diagnosis of melanoma occurred more frequently in a general practice setting and less frequently in direct consultation with a dermatologist or regular screening for skin cancer. Time to definitive excision was longer in older patients, and 16.8% of them compared with 5.0% of the younger population had insufficient excision margins (P < .001). A sentinel lymph node biopsy was performed in 23.3% of the older patients with melanoma thicker than 1 mm vs 41.4% in the younger patients (P < .001). Adjuvant therapy was less frequently started in older patients and was prematurely stopped in a higher proportion of that population. CONCLUSIONS AND RELEVANCE: Age-related variations are observed at every step of melanoma management. The most important concerns are access of elderly people to settings for early diagnosis and excision with appropriate margins.