Context: Metastatic adrenocortical carcinoma (ACC) is an aggressive malignancy with a poor prognosis and limited therapeutic options. A subset of ACC is due to Lynch syndrome, an inherited tumor syndrome resulting from germline mutations in mismatch repair (MMR) genes. It has been demonstrated that several cancers characterized by MMR deficiency are sensitive to immune checkpoint inhibitors that target PD-1. Here, we provide the first report of PD-1 blockade with pembrolizumab in a patient with Lynch syndrome and progressive cortisol-secreting metastatic ACC. Case report: A 58-year-old female with known Lynch syndrome presented with severe Cushing's syndrome and was diagnosed with a cortisol-secreting ACC. Three months following surgical resection and adjuvant mitotane therapy the patient developed metastatic disease and persistent hypercortisolemia. She commenced pembrolizumab, but her second cycle was delayed due to a transient transaminitis. Computed tomography performed after 12 weeks and 2 cycles of pembrolizumab administration revealed significant disease progression and treatment was discontinued. After 7 weeks, the patient became jaundiced and soon died due to fulminant liver failure. Conclusion: Treatment of MMR-deficient cortisol-secreting ACC with pembrolizumab may be ineffective due to supraphysiological levels of circulating corticosteroids, which may in turn mask severe drug induced organ damage. (C) 2018 The Authors. Published by Elsevier Inc.

Primary aldosteronism is a curable cause of hypertension if the hypertension is due to an aldosterone-producing adenoma (APA) [1], [2]. The discovery of somatic mutations defining pathogenetic subtypes of this adenoma has increased recognition of common but small zona glomerulosa-like APAs [3], [4], [5], [6]. In this subtype, we have sought APAs with distinctive presentation or outcome, in which analysis of genotype–phenotype associations could help explain the low success rate and variability of adrenalectomy for curing hypertension. Ten zona glomerulosa-like APAs from three women with primary aldosteronism were analysed by exome sequencing and microarray analysis. Nine had a mutation of ATP1A1 or CACNA1D, and one had a distinctive genotype and transcriptome. Targeted sequencing of further zona glomerulosa-like APAs led to the finding of two with a similar genotype, and to the recognition that all three women presented in early pregnancy or menopause. Quantitative PCR and immunohistochemistry were performed for genes upregulated in the index case. Similar analyses and a TCF–LEF assay for Wnt signalling were performed on cells transfected with the mutant gene. All three APAs had novel mutations in exon 3 of CTNNB1, encoding β-catenin in the Wnt cell-differentiation pathway. The mutations prevented phosphorylation of β-catenin, resulting in an increase in total form of β-catenin and active to total ratio, as quantified by immunoblotting. Transfection of mutant constructs into HEK cells caused near doubling of Wnt signalling in a luciferase reporter assay. Microarray of the index case found a greater than 100-fold increase in expression of gonadal receptors LHCGR and GNRHR, confirmed by qPCR (both genes) and immunohistochemistry (LHCGR) in all three APAs. Increased GATA4 expression was further evidence of adrenocortical cell de-differentiation towards their common gonad-adrenal precursor cell-type. Transfection of LHCGR-negative APA cells with GFP-mutant-CTNNB1 switched on LHCGR expression in GFP-positive cells. The role of the Wnt system in adrenal physiology and tumour development is well recognised [7], [8]. De-differentiation of zona glomerulosa-cells after Wnt activation by the CTNNB1 mutation seems to cause aberrant gonadal receptor expression, which is also previously described [9], [10]. Our findings connect these observations, and explain the unmasking of small APAs by increases in luteinising hormone and human chorionic gonadotropin hormone in early pregnancy or menopause. Strikingly, all three women, including the treatment-resistant older woman, were clinically cured by adrenalectomy. This contrasts with the failure of adrenalectomy to completely cure hypertension in the majority of patients. This failure is attributable to decades of exposure to aldosterone excess, and the secondary consequences of fibrosis and remodelling in the cardiovascular system [11], [12]. CTNNB1 mutations have now been reported in 10% of APAs without a previously reported mutation [13]. Elucidation of APA subtypes could, with preoperative genotyping, permit recognition of patients in whom recent onset of primary aldosteronism is likely to be completely resolved by surgery.

Sobre os dunitos (olivina, serpentina, cromita e magnetita), foi estudado um perfil de alteracao de 38 m de profundidade, em posicao de meia encosta. Este perfil apresenta da base para o topo 3 niveis de alteracao: saprolito (serpentina, esmectita e quartzo), Si-boxwork (quartzo e goethita) e laterita (goethita, caolinita e quartzo). Quimicamente, ao longo do perfil, ocorre perda total de Mg, conservacao de Si e concentracao residual de Fe, AI, Cr, Ti, P e Zr encontram-se enriquecidos nos niveis superiores do perfil de Co, Ni, Mn, Ba e Ce mostram seus mais altos teores nos niveis intermediarios. A evolucao intemperica da rocha fresca ao saprolito e lateritica. O Si-boxwork representa um episodio de silicificacao e, finalmente, a cobertura lateritica, enriquecida em elementos nao tipicos de dunitos (AI, Ti, Zr, V e P), deve ser resultado de contribuicao aloctone. Foram analisados 2 perfis de alteracao sobre jacupiranguitos (titanoaugita, magnetita e perovskita), com 30 e 40 m de profundidade, situados no topo e na encosta de uma colina, respectivamente. Nestes perfis distinguem-se, da base para o topo: saprolito (titanoaugita, esmectita, rnagnetita e anatasio) e laterita (goethita, caolinita, anatasio e quartzo). Estes perfis, desenvolvidos essencialmente in situ, evoluem por perdas totais ou parciais de Ca, Mg e Si e concentracoes residuais de Fe, AI e Ti. V, Cr e Zr sao gradualmente enriquecidos da rocha fresca a laterita. Ba, Zn, Cu, Ni, Co, Ce e Mn concentram-se nos estagios iniciais do intemperismo, sendo, em seguida, lixiviados. O processo de alte racao foi de natureza laterItica, com uma fase inicial de formacao de argilo-minerais 2/1 que evoluem para 1/1. A porcao superior do nivel de laterita apresenta caracteristicas mineralogicas e quimicas que permitem identifica-Ia como proveniente de material parcialmente aloctone. O estudo dos perfis de alteracao sobre dunito e jacupiranguito permite emitir uma hipotese de evolucao supergena policiclica para o complexo alcalino de Jacupiranga. Assim, numa primeira fase de alteracao, sob clima marcado por episodios de relativa aridez, a evolucao dos dunitos conduziu a formacao de um perfil de alteracao silicificado em sua base, enquanto que os jacupiranguitos desenvolveram uma cobertura de natureza esmectitica. Numa fase posterior, processos erosivos relacionados a um soerguimento da regiao, provocaram a remocao das coberturas de alteracao ate o resistente boxwork silicoso, no caso dos dunitos, e mais profundamente, no caso dos jacupiranguitos. Num periodo seguinte, sob clima mais umido, semelhante ao atual, a alteracao, desta vez de carater lateritico, promoveu o desenvolvimento de espessos perfis. Neste periodo, um aporte coluvionar, a partir de Jitologias mais acidas, sobre as areas de dunito e jacupiranguito, forneceu material que misturado aquele derivado das rochas subjacentes gerou a cobertura que hoje capeia os perfis. Por analogia com a evolucao supergenica de outros macicos ultramaficos brasileiros, o ciclo erosivo acima citado pode ser correlacionado ao ciclo Velhas, do Terciario Superior, o que coloca um limite maximo para a idade do manto de alteracao em Jacupiranga.

In the semi-arid region of Central Bahia, the weathering cover above a concealed migmatite-diabase contact consisting of a loose sandy-clayey surface layer and an indurated gravelly laterite shows distinct chemical and mineralogical relationships to the underlying parent rocks. High concentrations of Fe, V, Mn, Cu, Co and Ni characterize the weathering material above the diabase. In the overlying laterite layer, a chemical dispersion of most of these elements towards the migmatite can be observed. On the other hand, the weathering material above the diabase shows abundance of primary quartz, zircon and rutile derived from the migmatite. The evolution of the weathering cover is believed to be controlled by colluvial intermixing and vertical homogenization of partly transported weathering material, being followed by lateral chemical dispersion during laterite formation. Thus, the weathering horizons obliterate the chemical signal of the parent rocks increasingly from the bottom to the top of the profile. Similar profiles can be expected in most savannah-type regions and, therefore their identification is relevant for geochemical exploration.

Laterites above ultramafic complexes in Brazil and the Philippines consist of in-situ (autochthonous) and partly transported (semi-autochthonous) horizons. Enrichment and distribution of minor and trace elements in the laterites are controlled by weathering processes and the morphology of the peridotite massifs. Mn and Co migrate towards the base of doline-like depressions of the peridotite karst where they precipitate in the ferruginous horizon above the saprolite, due to rising pH and concentration of the solution. Mass balance calculations reveal absolute enrichment of Mn and Co and depletion of Zn and Cr. Semi-autochthonous laterites represent a mixture of Fe-Cr-rich limonitic material derived from ultramafic rocks and Al-Si-Ti-Zr-rich kaolinitic material derived from sialic rocks. They may reveal unusually high contents of Al2O3, SiO2, TiO2 and Zr, thus camouflaging the underlying ultramafic bedrock. During and after deposition of semi-autochthonous laterites, acidic leaching under humid (sub-) tropical climate leads to the mobilization of rees from the weathering products of sialic rocks. Subsequent migration and precipitation of rees together with Mn at the base of depressions result in concentrations of predominantly Ce which under favourable conditions exceed 0.5 wt. %. High proportions of sialic weathering material in laterites can be expected in geological settings where ultramafic and sialic rocks occur in close spatial association. Enrichment of rees in weathering profiles above ultramafics is favoured by the abundance of weathering material from ree-rich alkaline rocks like those of the Alkaline Complex of Jacupiranga, Brazil.

Dexamethasone addition to cultured hepatocytes caused a 90-fold increase in mRNA for 6-phosphofructo 2-kinase/fructose-2, 6-bisphosphatase. Glucocorticoid administration invivo also increased the enzyme's mRNA in skeletal muscle by 3-4-fold. The sequence of the 5′-flanking region of the enzyme's gene revealed at least one consensus glucocorticoid response element. The amino acid sequence derived from a partial cDNA clone for the rat skeletal muscle bifunctional enzyme was identical to that of the liver isozyme except for an undetermined amount of N-terminal sequence. It is concluded that the rat muscle and liver isozymes, which are postulated to be identical except for the N-terminal region, are both regulated by glucocorticoids.