Prorenin and diabetes mellitus

The renin-angiotensin system (RAS) plays an important role in the regulation of arterial blood pressure and water and salt regulation. Until recently this system was considered to be exclusively a circulating endocrine system. Circulating renin, released by the renal juxtaglomerular cells, reacts with hepatically derived angiotensinogen (renin substrate) to form the inactive decapeptide angiotensin I (Ang 1). Ang I, in turn, is converted to the biologically active octapeptide angiotensin II (Ang II) by angiotensin converting enzyme (ACE) which is bound to the endothelial cell membrane. Ang II formed in the circulation diffuses to the tissues where it stimulates specific receptors on the surface of vascular smooth muscle cells as well as on the surface of the aldosterone-producing cells in the adrenal glands. More recent evidence, however, suggests that, in addition to the circulating endocrine RAS, there exist local or tissue renin-angiotensin systems in which Ang I and Ang II are formed in the tissues ratherthan in the circulation. Tissue production of these peptides may be catalyzed either by locally synthesized renin and renin substrate or by renin and renin substrate that are taken up from the plasma. Local renin-angiotensin systems have both autocrine and paracrinefunctions. Messenger RNA (mRNA) for renin has been demonstrated not only in the kidney but also in such organs as the adrenals, ovaries, testes, and brain, and mRNA for angiotensinogen has been found in all of these tissues as well. On the other hand, renin in the heart and blood vessel wall probably originates mainly in the kidneys and is then taken up from the circulation. Human plasma contains not only renin but also its enzymatically inactive precursor prorenin. Virtually all plasma renin is derived from the kidney, as evidenced by the observation that circulating renin levels are extremely low or not demonstrable in anephric patients. The kidney is also an important source of circulating prorenin. However the finding that anephric patients have plasma prorenin levels that are 30-40% of normal indicates that a proportion of circulating prorenin is clearly of extrarenal origin. It is likely that such organs as the adrenals, testes, and ovaries release not renin but prorenin into the circulation. For example, the increased plasma prorenin levels seen in pregnant women are largely derived from the ovaries. Unlike plama renin, plasma prorenin is increased in patients with diabetes mellitus who have microvascular complications. The mechanisms that account for the elevations in plasma prorenin levels seen in these patients are yet unknown. In patients receiving a beta-adrenoreceptor antagonist (beta-blocker), plasma renin levels fall and plasma prorenin levels rise. Thus, it has been proposed that the development of autonomic neuropathy in patients with diabetes mellitus may be responsible for the increase in plasma pro renin. Loss of sympathetic stimulation ofthe beta-adrenoreceptors on the juxtaglomerular cells might result in diminished secretion of renin and, as a compensatory mechanism, the synthesis and secretion of prorenin in the juxtaglomerular apparatus might be augmented According to an alternative hypothesis, when the juxtaglomerular cells are affected by diabetic micrangiopathy, conversion of prorenin to renin in these cells decreases and secretion of prorenin consequently increase

Fractures in pituitary adenoma patients from the Dutch National Registry of Growth Hormone Treatment in Adults

Purpose: The effects of growth hormone (GH) replacement therapy on fracture risk in adult GH deficient (GHD) patients with different etiologies of pituitary GHD are not well known, due to limited data. The aim of this study was to investigate characteristics and fracture occurrence at start of (baseline) and during long-term GH replacement therapy in GHD adults previously treated for Cushing’s disease (CD) or acromegaly, compared to patients with previous nonfunctioning pituitary adenoma (NFPA). Methods: From the Dutch National Registry of Growth Hormone Treatment in Adults, a nationwide surveillance study in severe GHD adults, all patients using ≥30 days of GH replacement therapy with previous NFPA (n = 783), CD (n = 180) and acromegaly (n = 65) were selected. Patient characteristics, fractures and potential influencing factors were investigated. Results: At baseline, patients with previous CD were younger, more often female and had more often a history of osteopenia or osteoporosis, whereas patients with previous acromegaly had more often received cranial radiotherapy and a longer duration between treatment of their pituitary tumor and start of adult GH replacement therapy. During follow-up, a fracture occurred in 3.8 % (n = 39) of all patients. Compared to patients with previous NFPA, only patients with previous acromegaly had an increased fracture risk after 6 years of GH replacement therapy. Conclusions: During GH replacement therapy, an increased fracture risk was observed in severe GHD adult patients previously treated for acromegaly, but not in those previously treated for CD, compared to severe GHD adult patients using GH replacement therapy because of previous NFPA. Further studies are needed to confirm these findings and to elucidate potential underlying mechanisms

Surgery for unresectable stage IIIC and IV melanoma in the era of new systemic therapy

Opportunities for surgical treatment in metastatic melanoma patients have re-emerged due to the development of novel systemic therapeutics over the past decade. The aim of this study is to present data on outcomes of surgery in patients with unresectable stage IIIC and IV melanoma, who have previously been treated with immunotherapy or targeted therapy. Data was extracted from the Dutch Melanoma Treatment Registry (DMTR) on 154 patients obtaining disease control to systemic therapy and undergoing subsequent surgery. Disease control was defined as a complete response (CR), which was seen in 3.2% of patients; a partial response (PR), seen in 46.1% of patients; or stable disease (SD), seen in 44.2% of patients. At a median follow-up of 10.0 months (interquartile range 4-22) after surgery, the median overall survival (OS) had not been reached in our cohort and median progression-free survival (PFS) was 9.0 months (95% CI 6.3-11.7). A CR or PR at first follow-up after surgery was associated with both a better OS and PFS compared to stable or progressive disease (p < 0.001). We conclude that selected patients can benefit from surgery after achieving disease control with systemic therapy

Healthcare costs of metastatic cutaneous melanoma in the era of immunotherapeutic and targeted drugs

Immunotherapeutic and targeted drugs improved survival of patients with metastatic melanoma. There is, however, a lack of evidence regarding their healthcare costs in clinical practice. The aim of our study was to provide insight into real-world healthcare costs of patients with metastatic cutaneous melanoma. Data were obtained from the Dutch Melanoma Treatment Registry for patients who were registered between July 2012 and December 2018. Mean total/monthly costs per patient were reported for all patients, patients who did not receive systemic therapy, and patients who received systemic therapy. Furthermore, mean episode/monthly costs per line of therapy and drug were reported for patients who received systemic therapy. Mean total/monthly costs were € 89,240/€ 6809: € 7988/€ 2483 for patients who did not receive systemic therapy (n = 784) and € 105,078/€ 7652 for patients who received systemic therapy (n = 4022). Mean episode/monthly costs were the highest for nivolumab plus ipilimumab (€ 79,675/€ 16,976), ipilimumab monotherapy (€ 79,110/€ 17,252), and dabrafenib plus trametinib (€ 77,053/€ 12,015). Dacarbazine yielded the lowest mean episode/monthly costs (€ 6564/€ 2027). Our study showed that immunotherapeutic and targeted drugs had a large impact on real-world healthcare costs. As new drugs continue entering the treatment landscape for (metastatic) melanoma, it remains crucial to monitor whether the benefits of these drugs outweigh their costs

Dutch Oncology COVID-19 consortium:Outcome of COVID-19 in patients with cancer in a nationwide cohort study

Aim of the study: Patients with cancer might have an increased risk for severe outcome of coronavirus disease 2019 (COVID-19). To identify risk factors associated with a worse outcome of COVID-19, a nationwide registry was developed for patients with cancer and COVID-19. Methods: This observational cohort study has been designed as a quality of care registry and is executed by the Dutch Oncology COVID-19 Consortium (DOCC), a nationwide collaboration of oncology physicians in the Netherlands. A questionnaire has been developed to collect pseudonymised patient data on patients' characteristics, cancer diagnosis and treatment. All patients with COVID-19 and a cancer diagnosis or treatment in the past 5 years are eligible. Results: Between March 27th and May 4th, 442 patients were registered. For this first analysis, 351 patients were included of whom 114 patients died. In multivariable analyses, age ≥65 years (p < 0.001), male gender (p = 0.035), prior or other malignancy (p = 0.045) and active diagnosis of haematological malignancy (p = 0.046) or lung cancer (p = 0.003) were independent risk factors for a fatal outcome of COVID-19. In a subgroup analysis of patients with active malignancy, the risk for a fatal outcome was mainly determined by tumour type (haematological malignancy or lung cancer) and age (≥65 years). Conclusion: The findings in this registry indicate that patients with a haematological malignancy or lung cancer have an increased risk of a worse outcome of COVID-19. During the ongoing COVID-19 pandemic, these vulnerable patients should avoid exposure to severe acute respiratory syndrome coronavirus 2, whereas treatment adjustments and prioritising vaccination, when available, should also be considered

Tumor Recurrence or Regrowth in Adults With Nonfunctioning Pituitary Adenomas Using GH Replacement Therapy

Context: GH replacement therapy (GH-RT) is a widely accepted treatment in GH-deficient adults with nonfunctioning pituitary adenoma (NFPAs). However, some concerns have been raised about the safety of GH-RT because of its potentially stimulating effect on tumor growth. Objective: The aim of this study was to evaluate tumor progression in NFPA patients using GH-RT. Design, Setting, and Patients: From the Dutch National Registry of Growth Hormone Treatment in Adults, a nationwide surveillance study in severely GH-deficient adults (1998-2009), all NFPA patients with >= 30 days of GH-RT were selected (n = 783). Data were retrospectively collected from the start of GH-RT in adulthood (baseline). Main Outcome Measure: Tumor progression, including tumor recurrence after complete remission at baseline and regrowth of residual tumor. Results: Tumor progression developed in 12.1% of the patients after a median (range) time of 2.2 (0.1-14.9) years. Prior radiotherapy decreased tumor progression risk compared tonoradiotherapy (hazard ratio = 0.16; 95% confidence interval, 0.09-0.26). Analysis in 577 patients with available baseline imaging data showed that residual tumor at baseline increased tumor progression risk compared to no residual tumor (hazard ratio = 4.5; 95% confidence interval, 2.4-8.2). Conclusions: The findings in this large study were in line with those reported in literature and provide further evidence that GH-RT does not appear to increase tumor progression risk in NFPA patients. Although only long-term randomized controlled trials will be able to draw firm conclusions, our data support the current view that GH-RT is safe in NFPA patients

Effect of long-term GH replacement therapy on cardiovascular outcomes in GH-deficient patients previously treated for acromegaly: a sub-analysis from the Dutch National Registry of Growth Hormone Treatment in Adults

Objective: The effect of GH deficiency (GHD) on the metabolic profile of acromegaly patients is unclear in patients previously treated for acromegaly, as are the efficacy and safety of GH treatment in this particular group. The aim of the study is to describe the characteristics of patients with severe GHD who were previously treated for acromegaly, and to investigate the effects of long-term GH treatment on cardiovascular risk factors and morbidity, compared with patients who were treated for a nonfunctioning pituitary adenoma (NFPA). Design: A nationwide surveillance study. Methods: Sixty-five patients from the Dutch National Registry of Growth Hormone Treatment in Adults with previous acromegaly were compared with 778 patients with previous NFPA. Cardiovascular indices, including body composition, lipid profile, glucose metabolism, blood pressure, and morbidity were investigated. Results: GHD patients with previous acromegaly had an unfavorable metabolic profile comparable with or more than GHD patients with previous NFPA. GH treatment led to improvement of the lipid profile in both groups, also after excluding patients using lipid-lowering medication. In patients with previous acromegaly, HbA1c levels increased more than in patients with previous NFPA (estimate 0.03, 95% CI 0.002-0.06, P=0.04). The risk for developing cardiovascular diseases was not different between the groups. Conclusions: The patients with GHD after previous acromegaly have an unfavorable metabolic profile comparable with patients with GHD after previous NFPA. In both groups, the lipid profile improves during GH treatment. Changes in glucose metabolism should be monitored closely. GH treatment in patients with GHD previously treated for acromegaly had no deleterious effect on cardiovascular morbidity

Cerebrovascular Events, Secondary Intracranial Tumors, and Mortality After Radiotherapy for Nonfunctioning Pituitary Adenomas: A Subanalysis From the Dutch National Registry of Growth Hormone Treatment in Adults

Context: Radiotherapy is frequently administered as adjuvant treatment in patients with clinically nonfunctioning pituitary adenomas (NFPAs). However, concerns have been raised about potential long-term side effects, including cerebrovascular events (CVEs) and secondary intracranial tumors. Objective: The aim of this study was to analyze the risk of CVEs, secondary intracranial tumors, and mortality in irradiated (IRR) NFPA patients, compared with NFPA patients who were not irradiated (non-IRR). Design, Setting, and Patients: The study cohort included 806 patients with a NFPA from the Dutch National Registry of Growth Hormone Treatment in Adults, a nationwide long-term surveillance study in severe GH-deficient adult patients. IRR patients (n = 456) were compared with non-IRR patients (n = 350). Main Outcome Measures: CVEs, secondary intracranial tumors, and mortality were measured. Results: Sixty-nine subjects developed a CVE. In men, but not in women, the incidence of a CVE was significantly higher in IRR patients than in non-IRR patients (hazard ratio 2.99, 95% confidence interval 1.31-6.79). A secondary intracranial tumor developed in five IRR patients and two non-IRR patients. After adjustment for age, radiotherapy was not associated with mortality. Conclusions: The incidence of secondary intracranial tumors and mortality did not differ between IRR and non-IRR patients. However, a CVE was found significantly more frequently in IRR men but not in women. Further research into the long-term effects of cranial radiotherapy seems mandatory. The potential risks of radiotherapy have to be taken into account when radiotherapy is considered in NFPA patients, and long-term follow-up is recommended