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Melanoma is the most aggressive form of skin cancer, with tendency to spread to any organ of the human body, including the gastrointestinal tract (GIT). The diagnosis of metastases to the GIT can be difficult, as they may be clinically silent for somewhile and may occur years after the initial melanoma diagnosis. CT imaging remains the standard modality for staging and surveillance of melanoma patients, and in most cases, it will be the first imaging modality to identify GIT lesions. However, interpretation of CT studies in patients with melanoma can be challenging as lesions may be subtle and random in distribution, as well as sometimes mimicking other conditions. Even so, early diagnosis of GIT metastases is critical to avoid emergency hospitalisations, whilst surgical intervention can be curative in some cases. In this review, we illustrate the various imaging presentations of melanoma metastases within the GIT, discuss the clinical aspects and offer advice on investigation and management. We offer tips intended to aid radiologists in their diagnostic skills and interpretation of melanoma imaging scans., (© 2022. The Author(s).)

Background: Melanoma is the most aggressive form of skin cancer, with a tendency to metastasise to any organ of the human body. While the most common body organs affected include liver, lungs, brain and soft tissues, spread to the gastrointestinal tract is not uncommon. In the bowel, it can present with a multitude of imaging appearances, more rarely as an aneurysmal dilatation. This appearance is classically associated with lymphoma, but it has more rarely been associated with other forms of malignancy., Case Presentation: We report a case series of three patients with aneurysmal dilatation in the small bowel (SB) confirmed to be due to metastatic melanoma (MM). All patients had non-specific symptoms; most times being attributed initially to causes other than melanoma. On CT the identified aneurysmal SB dilatations were diagnosed as presumed lymphoma in all cases. In two cases, the aneurysmal dilatation was the first presentation of metastatic disease and in two of the cases more than one site of the gastrointestinal tract was concomitantly involved. All patients underwent surgical resection with histological confirmation of MM., Conclusions: Recognition of unusual SB presentation of MM, such as aneurysmal SB dilatation, is important to expedite diagnosis, provide appropriate treatment, and consequently improve quality of life and likely survival of these patients. As the most common cancer to metastasise to the SB and as a known imaging mimicker, MM should remain in any radiologist's differential diagnosis for SB lesions with aneurysmal dilatation., (© 2022. The Author(s).)

Objectives: To investigate the relationship between magnetization transfer (MT) imaging and tissue macromolecules in high-grade serous ovarian cancer (HGSOC) and whether MT ratio (MTR) changes following neoadjuvant chemotherapy (NACT)., Methods: This was a prospective observational study. 12 HGSOC patients were imaged before treatment. MTR was compared to quantified tissue histology and immunohistochemistry. For a subset of patients ( n = 5), MT imaging was repeated after NACT. The Shapiro-Wilk test was used to assess for normality of data and Spearman's rank-order or Pearson's correlation tests were then used to compare MTR with tissue quantifications. The Wilcoxon signed-rank test was used to assess for changes in MTR after treatment., Results: Treatment-naïve tumour MTR was 21.9 ± 3.1% (mean ± S.D.). MTR had a positive correlation with cellularity, rho = 0.56 ( p < 0.05) and a negative correlation with tumour volume, ρ = -0.72 ( p = 0.01). MTR did not correlate with the extracellular proteins, collagen IV or laminin ( p = 0.40 and p = 0.90). For those patients imaged before and after NACT, an increase in MTR was observed in each case with mean MTR 20.6 ± 3.1% (median 21.1) pre-treatment and 25.6 ± 3.4% (median 26.5) post-treatment ( p = 0.06)., Conclusion: In treatment-naïve HGSOC, MTR is associated with cellularity, possibly reflecting intracellular macromolecular concentration. MT may also detect the HGSOC response to NACT, however larger studies are required to validate this finding., Advances in Knowledge: MTR in HGSOC is influenced by cellularity. This may be applied to assess for cell changes following treatment., Competing Interests: Competing interests: The authors have no conflicts of interest to declare., (© 2022 The Authors. Published by the British Institute of Radiology.)

The aim of this study was to assess the feasibility of rapid sodium MRI ( 23 Na-MRI) for the imaging of peritoneal cancer deposits in high grade serous ovarian cancer (HGSOC) and to evaluate the relationship of 23 Na-MRI with tumour cellularity. 23 Na-MRI was performed at 3 T on twelve HGSOC patients using a 3D-cones acquisition technique. Tumour biopsies specimens were collected after imaging and cellularity was measured from histology. Total 23 Na-MRI scan time for each patient was approximately 11 min. At an isotropic resolution of 5.6 mm, signal-to-noise ratios (SNRs) of 82.2 ± 15.3 and 15.1 ± 7.1 (mean ± standard deviation) were achieved for imaging of tumour tissue sodium concentration (TSC) and intracellular weighted sodium concentration (IWS) respectively. Tumour TSC and IWS concentrations were: 56.8 ± 19.1 mM and 30.8 ± 9.2 mM respectively and skeletal muscle TSC and IWS concentrations were 33.2 ± 16.3 mM and 20.5 ± 9.9 mM respectively. There were significant sodium concentration differences between cancer and skeletal muscle, Wilcoxon signed-rank test, P  <  0.001 for TSC and P  =  0.01 for IWS imaging. Tumour cellularity displayed a strong negative correlation with TSC, Spearman's rho = -0.92, P  <  0.001, but did not correlate with IWS. This study demonstrates that 23 Na-MRI using 3D-cones can rapidly assess sodium concentration in peritoneal deposits of HGSOC and that TSC may serve as a biomarker of tumour cellularity.

Existing methods to improve detection of circulating tumor DNA (ctDNA) have focused on genomic alterations but have rarely considered the biological properties of plasma cell-free DNA (cfDNA). We hypothesized that differences in fragment lengths of circulating DNA could be exploited to enhance sensitivity for detecting the presence of ctDNA and for noninvasive genomic analysis of cancer. We surveyed ctDNA fragment sizes in 344 plasma samples from 200 patients with cancer using low-pass whole-genome sequencing (0.4×). To establish the size distribution of mutant ctDNA, tumor-guided personalized deep sequencing was performed in 19 patients. We detected enrichment of ctDNA in fragment sizes between 90 and 150 bp and developed methods for in vitro and in silico size selection of these fragments. Selecting fragments between 90 and 150 bp improved detection of tumor DNA, with more than twofold median enrichment in >95% of cases and more than fourfold enrichment in >10% of cases. Analysis of size-selected cfDNA identified clinically actionable mutations and copy number alterations that were otherwise not detected. Identification of plasma samples from patients with advanced cancer was improved by predictive models integrating fragment length and copy number analysis of cfDNA, with area under the curve (AUC) >0.99 compared to AUC <0.80 without fragmentation features. Increased identification of cfDNA from patients with glioma, renal, and pancreatic cancer was achieved with AUC > 0.91 compared to AUC < 0.5 without fragmentation features. Fragment size analysis and selective sequencing of specific fragment sizes can boost ctDNA detection and could complement or provide an alternative to deeper sequencing of cfDNA., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Ovarian cancer is a heterogeneous group of cancers that differ by cell of origin and genomic features. High-grade serous ovarian cancer (HGSOC) is the commonest histiotype and is characterized by extreme genomic complexity and dysregulation of DNA damage repair pathways, particularly homologous recombination deficiency. New insights from molecular profiling into homologous recombination deficiency now offers the credible possibility of personalizing treatment choices for women with HGSOC using poly(ADP-ribose) polymerase inhibitor (PARP) therapy. Although the presence of tumour infiltrating lymphocytes (TILs) in the microenvironment is associated with improved survival in HGSOC, the role of anti-angiogenic and immune checkpoint inhibitor therapy remains unclear. PARP inhibition combined with immunotherapy is an exciting combination strategy for future therapeutic development for women with advanced HGSOC., (Copyright © 2018 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Introduction: Hepatotoxicity from T-cell checkpoint blockade is an increasingly common immune-related adverse event, but remains poorly characterised and can be challenging to manage. Such toxicity is generally considered to resemble autoimmune hepatitis, although this assumption is extrapolated from limited clinicopathological reports of anti-cytotoxic T-lymphocyte-associated protein 4-induced hepatotoxicity., Methods: Here we report, with full clinicopathological correlation, three cases of T-cell checkpoint inhibitor-induced hepatotoxicity associated with anti-programmed cell death protein 1 agents., Results: We find that a major feature of these cases is biliary injury, including a unique case of vanishing bile duct syndrome, and that such toxicity was poorly responsive to long-term immunosuppression (corticosteroids and mycophenolate mofetil). Any potential benefits of long-term immunosuppression in these cases were outweighed by therapy-related complications., Discussion: We discuss potential aetiologies and risk factors for immune-mediated biliary toxicity in the context of the limited literature in this field, and provide guidance for the investigation and supportive management of affected patients., Competing Interests: Competing interests: None declared.

Current research identifies advanced dementia to be the terminal phase of this progressive and incurable condition. However, there has been relatively little investigation into how family members of people with advanced dementia understand their relative's condition. In this article, we report on semi-structured interviews with 10 family members of people with advanced dementia, in a residential aged care facility. Using a qualitative, descriptive design, we explored family members' understandings of dementia, whether they were aware that it was a terminal condition, and the ways they developed their understandings. Findings revealed that the majority of family members could not recognize the terminal nature of dementia. Relying on predominantly lay understandings, they had little access to formal information and most failed to conceptualize a connection between dementia and death. Moreover, family members engaged in limited dialogue with aged care staff about such issues, despite their relatives being in an advanced stage of the disease. Findings from our study suggest that how family members understand their relative's condition requires greater attention. The development of staff/family partnerships that promote shared communication about dementia and dying may enhance family members' understandings of the dementia trajectory and the types of decisions they may be faced with during the more advanced stages of the disease.

Background: Circulating tumour DNA (ctDNA) carrying tumour-specific sequence alterations may provide a minimally invasive means to dynamically assess tumour burden and response to treatment in cancer patients. Somatic TP53 mutations are a defining feature of high-grade serous ovarian carcinoma (HGSOC). We tested whether these mutations could be used as personalised markers to monitor tumour burden and early changes as a predictor of response and time to progression (TTP)., Methods and Findings: We performed a retrospective analysis of serial plasma samples collected during routine clinical visits from 40 patients with HGSOC undergoing heterogeneous standard of care treatment. Patient-specific TP53 assays were developed for 31 unique mutations identified in formalin-fixed paraffin-embedded tumour DNA from these patients. These assays were used to quantify ctDNA in 318 plasma samples using microfluidic digital PCR. The TP53 mutant allele fraction (TP53MAF) was compared to serum CA-125, the current gold-standard response marker for HGSOC in blood, as well as to disease volume on computed tomography scans by volumetric analysis. Changes after one cycle of treatment were compared with TTP. The median TP53MAF prior to treatment in 51 relapsed treatment courses was 8% (interquartile range [IQR] 1.2%-22%) compared to 0.7% (IQR 0.3%-2.0%) for seven untreated newly diagnosed stage IIIC/IV patients. TP53MAF correlated with volumetric measurements (Pearson r = 0.59, p < 0.001), and this correlation improved when patients with ascites were excluded (r = 0.82). The ratio of TP53MAF to volume of disease was higher in relapsed patients (0.04% per cm3) than in untreated patients (0.0008% per cm3, p = 0.004). In nearly all relapsed patients with disease volume > 32 cm3, ctDNA was detected at ≥20 amplifiable copies per millilitre of plasma. In 49 treatment courses for relapsed disease, pre-treatment TP53MAF concentration, but not CA-125, was associated with TTP. Response to chemotherapy was seen earlier with ctDNA, with a median time to nadir of 37 d (IQR 28-54) compared with a median time to nadir of 84 d (IQR 42-116) for CA-125. In 32 relapsed treatment courses evaluable for response after one cycle of chemotherapy, a decrease in TP53MAF of >60% was an independent predictor of TTP in multivariable analysis (hazard ratio 0.22, 95% CI 0.07-0.67, p = 0.008). Conversely, a decrease in TP53MAF of ≤60% was associated with poor response and identified cases with TTP < 6 mo with 71% sensitivity (95% CI 42%-92%) and 88% specificity (95% CI 64%-99%). Specificity was improved when patients with recent drainage of ascites were excluded. Ascites drainage led to a reduction of TP53MAF concentration. The limitations of this study include retrospective design, small sample size, and heterogeneity of treatment within the cohort., Conclusions: In this retrospective study, we demonstrated that ctDNA is correlated with volume of disease at the start of treatment in women with HGSOC and that a decrease of ≤60% in TP53MAF after one cycle of chemotherapy was associated with shorter TTP. These results provide evidence that ctDNA has the potential to be a highly specific early molecular response marker in HGSOC and warrants further investigation in larger cohorts receiving uniform treatment., Competing Interests: We have read the journal's policy and the authors of this manuscript have the following competing interests: DG, NR and JDB are co-founders, shareholders and officers/consultants of Inivata Ltd, a cancer genomics company that commercialises ctDNA analysis.

Background: The major clinical challenge in the treatment of high-grade serous ovarian cancer (HGSOC) is the development of progressive resistance to platinum-based chemotherapy. The objective of this study was to determine whether intra-tumour genetic heterogeneity resulting from clonal evolution and the emergence of subclonal tumour populations in HGSOC was associated with the development of resistant disease., Methods and Findings: Evolutionary inference and phylogenetic quantification of heterogeneity was performed using the MEDICC algorithm on high-resolution whole genome copy number profiles and selected genome-wide sequencing of 135 spatially and temporally separated samples from 14 patients with HGSOC who received platinum-based chemotherapy. Samples were obtained from the clinical CTCR-OV03/04 studies, and patients were enrolled between 20 July 2007 and 22 October 2009. Median follow-up of the cohort was 31 mo (interquartile range 22-46 mo), censored after 26 October 2013. Outcome measures were overall survival (OS) and progression-free survival (PFS). There were marked differences in the degree of clonal expansion (CE) between patients (median 0.74, interquartile range 0.66-1.15), and dichotimization by median CE showed worse survival in CE-high cases (PFS 12.7 versus 10.1 mo, p = 0.009; OS 42.6 versus 23.5 mo, p = 0.003). Bootstrap analysis with resampling showed that the 95% confidence intervals for the hazard ratios for PFS and OS in the CE-high group were greater than 1.0. These data support a relationship between heterogeneity and survival but do not precisely determine its effect size. Relapsed tissue was available for two patients in the CE-high group, and phylogenetic analysis showed that the prevalent clonal population at clinical recurrence arose from early divergence events. A subclonal population marked by a NF1 deletion showed a progressive increase in tumour allele fraction during chemotherapy., Conclusions: This study demonstrates that quantitative measures of intra-tumour heterogeneity may have predictive value for survival after chemotherapy treatment in HGSOC. Subclonal tumour populations are present in pre-treatment biopsies in HGSOC and can undergo expansion during chemotherapy, causing clinical relapse.

Unlabelled: Malignant ovarian germ cell tumors are rare, highly curable cancers of young women. The majority of patients can be cured with either fertility-preserving surgery alone or a combination of surgery and chemotherapy. Relapses occur in 10% to 20% of patients, and the significant proportion of them can be salvaged with chemotherapy. There is no evidence that treatment for malignant ovarian germ cell tumors will adversely affect menstrual or reproductive functions, increase future pregnancy loss, or increase the risk of congenital malformations of the fetus. Late effects, such as secondary leukemia, from chemotherapy are reported but rare., Target Audience: Obstetricians & Gynecologists and Family Physicians., Learning Objective: After completing this CME activity, physicians should be better able to diagnose ovarian germ cell tumors, outline management of malignant ovarian germ cell tumors, and understand the impact of treatment on fertility and late effects.

Objectives: Malignant ovarian germ cell tumours (MOGCT) are rare cancers of young women. Limited prospective trials exist from which evidence-based management can be developed. This review summarizes the available literature concerning MOGT in order to provide the clinician with information relevant to their multidisciplinary management., Methods: MEDLINE was searched between 1966 and 2010 for all publications in English where the studied population included women diagnosed with malignant ovarian germ cell tumours., Results: The majority of patients can be cured with fertility-preserving surgery with or without combination chemotherapy. Long term survival approaches 100% in early stage disease and is approximately 75% in advanced stage disease. Most studies suggest that the treatment has little, if any, effect on future fertility and limited data suggest that there is no adverse effect on the future quality of life., Conclusion: MOGCTs are rare tumours of young women the majority of which can be successfully treated with fertility-preserving surgery with or without chemotherapy with preservation of reproductive function. Minimisation of chemotherapy in good prognostic groups and improved treatment in resistant and relapsed MOGCT are important goals for the future. Further studies are needed to quantify the late adverse effects of treatment in long term survivors., (Copyright © 2010. Published by Elsevier Inc.)

Background: Granulosa-cell tumors (GCTs) are the most common type of malignant ovarian sex cord-stromal tumor (SCST). The pathogenesis of these tumors is unknown. Moreover, their histopathological diagnosis can be challenging, and there is no curative treatment beyond surgery., Methods: We analyzed four adult-type GCTs using whole-transcriptome paired-end RNA sequencing. We identified putative GCT-specific mutations that were present in at least three of these samples but were absent from the transcriptomes of 11 epithelial ovarian tumors, published human genomes, and databases of single-nucleotide polymorphisms. We confirmed these variants by direct sequencing of complementary DNA and genomic DNA. We then analyzed additional tumors and matched normal genomic DNA, using a combination of direct sequencing, analyses of restriction-fragment-length polymorphisms, and TaqMan assays., Results: All four index GCTs had a missense point mutation, 402C-->G (C134W), in FOXL2, a gene encoding a transcription factor known to be critical for granulosa-cell development. The FOXL2 mutation was present in 86 of 89 additional adult-type GCTs (97%), in 3 of 14 thecomas (21%), and in 1 of 10 juvenile-type GCTs (10%). The mutation was absent in 49 SCSTs of other types and in 329 unrelated ovarian or breast tumors., Conclusions: Whole-transcriptome sequencing of four GCTs identified a single, recurrent somatic mutation (402C-->G) in FOXL2 that was present in almost all morphologically identified adult-type GCTs. Mutant FOXL2 is a potential driver in the pathogenesis of adult-type GCTs., (2009 Massachusetts Medical Society)

Malignancy is a well-recognised complication of transplantation and can occur de novo, as a recurrence of a pre-existing malignancy, or from transmission of malignancy from the donor. Common de-novo malignancies are those of the skin and the lymphoreticular system. Various solid-organ cancers have also been reported in transplant recipients and each poses a unique management challenge in view of the unusual setting. We review solid-organ cancers in transplant recipients and their management, including surveillance and prevention.

This study describes the first use of a classroom environment questionnaire with a class in nursing education. An instructor of nursing students monitored classes using such a questionnaire. The questionnaire used was the College and University Classroom Environment Inventory and it was used to obtain practical and useful information about the learning environment in two different classes. Collaborative changes were made in the classes to improve the classroom environment and consequently the learning situation. Any instructor of nursing students could use this same process with this instrument.

Potassium and angiotensin (AII) show interdependence as stimuli of aldosterone production. However, potassium stimulates in vitro in the absence of AII. In the present study we examined for a contribution by AII to the in vitro stimulatory potential of potassium, an AII effect mediated on the adrenal before killing of the animal. Captopril, an angiotensin converting-enzyme inhibitor, was administered orally and by sc injection for 3 days so as to decrease levels of AII. Aldosterone secretory responses by adrenal capsules to graded increments in potassium were measured subsequently using a perifusion system. It was found that captopril pretreatment significantly reduced the magnitude of aldosterone secretory response to increments in potassium of 0.5 to 6.0 mM, from a baseline potassium concentration of 3.5 mM. Responses to the lowest increment in potassium, 0.5 and 1.0 mM, were virtually abolished by captopril treatment. The results suggest that AII sensitizes the adrenal glomerulosa such that very small changes in potassium concentration can affect aldosterone production.

The present study undertook to examine aldosterone excretion during sleep as an integrated measurement of aldosterone production. A 24-hour urine collection was divided into awake and sleep fractions. Urinary aldosterone and electrolyte excretion were measured in 26 healthy children (mean age, 8.9 +/- 1.9 [SD] years) and 28 adults (mean age, 29.9 +/- 9.5 years). Aldosterone excretion in children was 5.6 +/- 3.9 (SD) micrograms/g creatinine during the awake period, which was significantly different from the 3.9 +/- 4.1 micrograms/g creatinine value recorded during sleep (p less than 0.002). In adults, awake aldosterone excretion was significantly greater than that during sleep; 4.9 +/- 2.7 versus 3.2 +/- 1.6 micrograms/g creatinine (p less than 0.001). Sleep aldosterone excretion values were highly correlated with the corresponding 24-hour aldosterone excretion values (r = 0.85, p less than 0.001) in children and in adults (r = 0.64, p less than 0.001). Sleep aldosterone excretion was correlated with 24-hour potassium excretion (p less than 0.02) only in children. Sleep aldosterone excretion correlated with neither sleep nor 24-hour sodium excretion in children or adults. Sleep electrolyte excretion rates were highly correlated with 24-hour excretion rates in both children and adults. Dexamethasone, 1 mg, administered the night before to suppress the normally high morning levels of endogenous adrenocorticotropic hormone, had no discernible effect on sleep aldosterone excretion. These results indicate that measurement of aldosterone excretion in an easily collected sleep urine sample provides a reliable index of aldosterone production in children and adults.

Since minoxidil was previously shown to raise plasma renin activity (PRA) but not the plasma aldosterone concentration (PAC), the effect of minoxidil on the rate of aldosterone metabolic clearance was studied. After the addition of minoxidil to the antihypertensive regimen of 7 hypertensive patients, the aldosterone metabolic clearance rate increased from 1,110 +/- 91 to 1,570 +/- 180 liters/day (p less than 0.01), an overall increase of 41%. Hepatic blood flow, estimated from the clearance from plasma of indocyanine green, was increased in a group of minoxidil-treated patients compared to a comparable group not treated with minoxidil (p less than 0.01). Thus, although minoxidil induces an increase in PRA, PAC does not change, since aldosterone metabolic clearance increases. Minoxidil increased hepatic blood flow, and it was probably by this mechanism that the drug accelerated the rate of aldosterone clearance.

Although propranolol administration produces a lowering of PRA, PAC does not decrease in a similar fashion. In the present study the effects of propranolol on the aldosterone MCR were examined. Eight patients with essential hypertension were studied while receiving treatment with a diuretic and again after propranolol (160 to 320 mg/day) was added to the therapeutic regimen. Propranolol therapy was associated with a 25% decrease in PRA (p less than 0.05) and changes in PACs that were variable but not significantly different from diuretic therapy alone. The aldosterone MCR decreased from 1420 +/- 120 to 1120 +/- 90 L/24 hr in response to propranolol (p less than 0.01). The average production rate of aldosterone (MCR X PAC) did not change after propranolol treatment despite a decrease in PRA. There were no changes in plasma concentrations of potassium or in ACTH secretion (as reflected by levels of cortisol) to explain a role for propranolol to sustain aldosterone secretion. Thus propranolol administered to hypertensive patients pretreated with a diuretic can affect circulating levels of aldosterone apart from changes in PRA. Propranolol therapy produces a moderate reduction in aldosterone MCR and appears to augment aldosterone production by a mechanism exclusive of known stimuli.

The effect in the rat of alloxan diabetes (with and without insulin treatment) on renin and aldosterone secretion was examined. Rats with diabetes for 7 weeks were found to have lower PRA than nondiabetic controls. The decrease in PRA appeared to result from insulin deficiency since PRA was normal in diabetic rats given insulin. In a second set of animals, which were killed after 3 weeks, in vitro measurements of aldosterone production by perifused adrenal capsular tissue were carried out. Production of aldosterone was greatest by adrenal capsular tissue from insulin-treated diabetic rats where both basal and potassium-stimulated aldosterone production were higher than diabetic rats not given insulin. Although the reduced aldosterone production associated with untreated diabetes may have been a result of reduced in vivo exposure of adrenal tissue to angiotensin II, a chronic adrenotrophic influence of insulin could not be ruled out. In summary, insulin appears to be necessary for normal renin and aldosterone secretion in the diabetic rat.

A new method for the assessment of endogenous formation of aldosterone in anephric patients is described. (1, 2-3H) aldosterone was administered i.v. to patients 1-2 days before hemodialysis, and then the specific activity (SA) of tetrahydroaldosterone glucosiduronate, the major aldosterone metabolite, was measured in the dialysate using a specific radioimmunoassay. The aldosterone secretion rate was determined from the extent of isotope dilution by endogenous metabolite. Aldosterone secretion rates measured in 10 patients were for the most part low. The secretion rate determined in blood from the aldosterone metabolic clearance rate and plasma aldosterone concentration closely approximate secretion rate values obtained by the isotope dilution method in 3 of 4 patients. In 2 patients in whom ACTH was administered chronically, radio-labeled aldosterone was administered at the start of the study and then the day to day aldosterone secretory response to ACTH was determined from the SA of tetrahydroaldosterone in blood. Aldosterone secretion continuously increased for as long as ACTH was administered.

It has been shown that despite an effect of minoxidil to increase PRA, plasma levels of aldosterone do not change. We observed similar findings in seven hypertensive patients undergoing treatment with minoxidil; PRA activity increased markedly, whereas the plasma aldosterone concentration showed no consistent change. The aldosterone MCRs in these patients increased by 41% in response to minoxidil, from 1110 +/- 91 to 1570 +/- 180 (SEM) liters/day; this appeared to explain why plasma aldosterone levels did not increase in parallel with renin activity. Hepatic blood flow (estimated from the clearance of indocyanine green) in a group of patients receiving minoxidil was greater than that in an otherwise comparable group (P less than 0.02). This increase in hepatic perfusion may, at least in part, have accounted for the increase in aldosterone MCR.

Metoclopramide (MP), a dopamine antagonist, stimulates secretion of aldosterone by a mechanism which has not been defined. We examined a potential role for either the kidney or the pituitary to mediate MPs effect on aldosterone secretion. Responses to MP administered i.v. were measured in six anephric and six hypopituitary patients as well as in six normal subjects. MP increased the plasma aldosterone concentration (PAC) in normal subjects in a fashion similar to what had previously been reported. MP produced no increase in plasma levels of renin activity (PRA), cortisol, potassium, or sodium. Three of six anephric patients (all of whom had undetectable PRA) responded to MP with increases in PAC; the magnitude of these responses correlated with the plasma potassium concentration. All six hypopituitary patients showed increases in PAC after MP administration. MP increased plasma prolactin levels in normal subjects and anephric patients; one hypopituitary patient had high basal plasma prolactin levels which increased with MP. In conclusion, neither the kidney nor the pituitary is involved in the mechanism for MP stimulated aldosterone production. These observations suggest that MP may act on the adrenal to evoke secretion of aldosterone.

The effect of sodium intake on the aldosterone metabolic clearance rate (MCR) was examined in 5 normal subjects. Measurements were made under conditions where dietary sodium ranged from 10 to 1500 meq/day. There were no consistent changes in MCR over these extremes of sodium intake, and the plasma level of aldosterone correlated only with the aldosterone urinary excretion rate. In an additional group of 6 normal subjects, a single dose of 100 meq sodium administered orally had no effect on the aldosterone MCR. The findings indicate that aldosterone metabolism is unaffected by sodium intake.