Ectopic Cushing's syndrome from an ACTH-producing pheochromocytoma with a non-functioning pituitary adenoma.

Summary: An adrenocorticotropic hormone (ACTH)-producing pheochromocytoma (PCC)/paraganglioma is the cause of ectopic Cushing's syndrome (CS) in 5.2% of cases reported in the literature. We present a previously healthy 43-year-old woman admitted to our hospital with cushingoid features and hypertensive urgency (blood pressure = 200/120 mmHg). Her 24-h urinary free cortisol was >4270 nmol/day (reference range (RR) = 100-380 nmol/day) with a plasma ACTH of 91.5 pmol/L (RR: 2.0-11.5 pmol/L). Twenty-four-hour urinary metanephrines were increased by 30-fold. Whole-body CT demonstrated a 3.7-cm left adrenal mass with a normal-appearing right adrenal gland. Sellar MRI showed a 5-mm sellar lesion. MIBG scan revealed intense uptake only in the left adrenal mass. She was managed pre-operatively with ketoconazole and phenoxybenzamine and underwent an uneventful left laparoscopic adrenalectomy, which resulted in biochemical resolution of her hypercortisolemia and catecholamine excess. Histology demonstrated a PCC (Grading System for Adrenal Pheochromocytoma and Paraganglioma score 5) with positive ACTH staining by immunohistochemistry. A PCC gene panel showed no mutations and there has been no evidence of recurrence at 24 months. This case highlights the difficult nature of localizing the source of CS in the setting of a co-existing PCC and sellar mass. Learning points: An adrenocorticotropic hormone (ACTH)-producing pheochromocytoma (PCC) is an important item to be considered in all patients presenting with ectopic Cushing's syndrome (CS). In exceptionally rare cases, patients with ectopic CS may present with multiple lesions, and a systematic approach considering all potential sources is crucial to avoid misdiagnosis. CS with a large adrenal mass but lacking contralateral adrenal atrophy should raise suspicion of an ACTH-dependent process. In patients with clinical suspicion of PCC, clinicians should be mindful of the use of steroids and beta-blockers without appropriate alpha blockade as they may precipitate an adrenergic crisis.

Patterns of Left-Ventricular Function Assessment in Patients With Acute Coronary Syndromes.

BACKGROUND: In patients with acute coronary syndromes (ACS), guidelines recommend the assessment of left-ventricular ejection fraction (LVEF). Many patients with ACS undergo multiple assessments of LVEF, the clinical value of which is unknown. METHODS: Patients with ACS undergoing cardiac catheterization between 2012 and 2016 were evaluated and assessments of LV function identified. To evaluate changes in LVEF over time, available echocardiograms were reviewed in a subsample of patients with LVEF data available (n = 3221). Patients with ACS were classified into 3 groups: group 1 (LVEF > 50%), group 2 (LVEF 35% to 50%), and group 3 (LVEF < 35%). RESULTS: Our cohort consisted of 8327 patients with ACS (76% men), presenting with a mean age of 62.4 ± 12.4 years. At index presentation, 66% of patients had an LVEF > 50%, 27% had an LVEF between 35% and 50%, and 7% had severely reduced LVEF of < 35%. More than half of the cohort (n = 4600) had follow-up assessment of LV function, performed over an average of 2.71 ± 1.31 years. In the subsample of 3221 patients, only 1.1% of those in group 1, and 5.1% of those in group 2, deteriorated to an LVEF < 35%. CONCLUSIONS: Patients with ACS often undergo multiple assessments of LV function. Those with initially preserved EF rarely demonstrate a decline in EF to < 35%. A reduction in low-value cardiac tests may be an important first step in improving the quality of care for patients with ACS.

CONTEXTE: En cas de syndrome coronarien aigu (SCA), les lignes directrices recommandent d'évaluer la fraction d'éjection ventriculaire gauche (FEVG). Beaucoup de patients présentant un SCA subissent plusieurs évaluations de la FEVG, une pratique dont on ne connaît pas la valeur clinique. MÉTHODOLOGIE: Nous avons examiné les dossiers de patients atteints d'un SCA ayant subi un cathétérisme cardiaque entre 2012 et 2016 afin de relever les évaluations de la fonction ventriculaire gauche. Pour évaluer l'évolution de la FEVG au fil du temps, nous avons examiné les échocardiogrammes d'un sous-échantillon de patients pour lesquels des données sur la FEVG étaient disponibles (n = 3 221). Les patients présentant un SCA ont été divisés en trois groupes : groupe 1 (FEVG > 50 %), groupe 2 (FEVG de 35 à 50 %) et groupe 3 (FEVG < 35 %). RÉSULTATS: Notre cohorte comprenait 8 327 patients présentant un SCA (proportion d'hommes : 76 %), dont l'âge moyen était de 62,4 ± 12,4 ans. Au moment de la manifestation de référence, 66 % des patients avaient une FEVG > 50 %, 27 %, une FEVG de 35 à 50 % et 7 %, une FEVG gravement réduite < 35 %. Plus de la moitié des patients de la cohorte (n = 4 600) ont subi une évaluation de suivi de la fonction ventriculaire gauche, effectuée sur une période de 2,71 ± 1,31 ans en moyenne. Dans le sous-échantillon de 3 221 patients, seulement 1,1 % des patients du groupe 1 et 5,1 % de ceux du groupe 2 ont vu leur FEVG se détériorer à une valeur < 35 %. CONCLUSIONS: Les patients présentant un SCA subissent souvent plusieurs évaluations de la fonction ventriculaire gauche. Ceux dont la fraction d'éjection était initialement préservée ont rarement présenté une réduction de la fraction d'éjection en deçà de 35 %. Une réduction du nombre d'évaluations cardiaques offrant peu de valeur pourrait constituer un premier pas important vers l'amélioration de la qualité des soins prodigués aux patients présentant un SCA.

Evidence for adequate thymic function but impaired naive T-cell survival following allogeneic hematopoietic stem cell transplantation in the absence of chronic graft-versus-host disease.

Allogeneic hematopoietic stem cell transplantation (AHSCT) leads to a prolonged state of immunodeficiency characterized by low peripheral naive T-cell counts. To identify the mechanisms leading to this defect we quantitatively and qualitatively analyzed thymic function through quantification of T-cell receptor excision circle (TREC) frequencies (both the signal-joint TREC [sjTREC] and 6 different DbetaJbeta TRECs, by-products of T-cell receptor [TCR] alpha and beta gene rearrangement, respectively), in conjunction with immunophenotype and spectratype analyses in a cohort of patients sampled from 1 to 10 years following AHSCT. In this cohort, reduced thymic function was associated only with ongoing clinical chronic graft-versus-host disease (cGVHD). Nonetheless, the diversity of thymic production remained unchanged irrespective of the patient's cGVHD status. Interestingly, increased homeostatic proliferation was found in the naive T-cell compartment of cGVHD- patients who underwent transplantation. However, reduced expression of both the interleukin-7 receptor alpha (IL-7Ralpha) (CD127) chain and the antiapoptotic protein Bcl-2 was observed. Taken together, these data indicate that the inability to reconstitute the naive T-cell compartment for several years after AHSCT, in the absence of cGVHD, is a consequence of impaired naive T-cell survival rather than thymic dysfunction.

Estimate of the total number of CD8+ clonal expansions in healthy adults using a new DNA heteroduplex-tracking assay for CDR3 repertoire analysis.

A T-cell receptor heteroduplex-tracking assay (TCR-HTA) was developed to analyze the sequence diversity of the TCR beta-chain mRNA of each of the 24 T-cell receptor beta-chain variable region (TRBV). TCR-HTA allowed an estimation of the number of expanded CD8 T-cell clones whose distinct CDR3 domain mRNA made up 2% or more of the transcript of each TRBV subfamily. An average of 40 CD8+ clonal expansions (range 34-49) was detected in three healthy adults. Correct sampling of the complex mRNA transcript populations was documented by the reproducible generation of TCR-HTA patterns using independently generated PCR amplicons. The CDR3 sequence of expanded T-cell clones could be rapidly determined by direct sequencing of DNA heteroduplex bands. CD4+ and CD8+ clonal expansions were found predominantly although not exclusively in CD45RO+ CD62L- effector/memory cells and the majority of expanded T-cell clones were stable over a period of at least 6 months. Fewer CD4+ than CD8+ clonal expansions were detected in peripheral blood cells. By providing a high-resolution method for the detection of clonally expanded T-cell clones and by simplifying the pattern generated using traditional DNA heteroduplex analysis, TCR-HTA is shown to be a sensitive method for assessing levels of oligoclonality and changes in TRBV repertoires.

Analysis of HIV-1- and CMV-specific memory CD4 T-cell responses during primary and chronic infection.

CD4 T-cell-specific memory antiviral responses to human immunodeficiency virus type 1 (HIV-1) and cytomegalovirus (CMV) were investigated in 16 patients with documented primary HIV-1 infection (4 of the 16 subjects also had primary CMV infection) and compared with those observed in patients with chronic HIV-1 and CMV coinfection. Virus-specific memory CD4 T cells were characterized on the basis of the expression of the chemokine receptor CCR7. HIV-1- and CMV-specific interferon-gamma-secreting CD4 T cells were detected in patients with primary and chronic HIV-1 and CMV coinfection and were mostly contained in the cell population lacking expression of CCR7. The magnitude of the primary CMV-specific CD4 T-cell response was significantly greater than that of chronic CMV infection, whereas there were no differences between primary and chronic HIV-1-specific CD4 T-cell responses. A substantial proportion of CD4(+)CCR7(-) T cells were infected with HIV-1. These results advance the characterization of antiviral memory CD4 T-cell response and the delineation of the potential mechanisms that likely prevent the generation of a robust CD4 T-cell immune response during primary infection.

Treatment of primary HIV-1 infection with cyclosporin A coupled with highly active antiretroviral therapy.

Primary HIV-1 infection causes extensive immune activation, during which CD4(+) T cell activation supports massive HIV-1 production. We tested the safety and the immune-modulating effects of combining cyclosporin A (CsA) treatment with highly active antiretroviral therapy (HAART) during primary HIV-1 infection. Nine adults with primary HIV-1 infection were treated with CsA along with HAART. At week 8, all patients discontinued CsA but maintained HAART. Viral replication was suppressed to a comparable extent in the CsA + HAART cohort and in 29 control patients whose primary infection was treated with HAART alone. CsA restored normal CD4(+) T cell levels, both in terms of percentage and absolute numbers. The increase in CD4(+) T cells was apparent within a week and persisted throughout the study period. CsA was not detrimental to virus-specific CD8(+) or CD4(+) T cell responses. At week 48, the proportion of IFN-gamma-secreting CD4(+) and CD4(+)CCR7(-) T cells was significantly higher in the CsA + HAART cohort than in the HAART-alone cohort. In conclusion, rapid shutdown of T cell activation in the early phases of primary HIV-1 infection can have long-term beneficial effects and establish a more favorable immunologic set-point. Appropriate, immune-based therapeutic interventions may represent a valuable complement to HAART for treating HIV infection.

Distribution and functional analysis of memory antiviral CD8 T cell responses in HIV-1 and cytomegalovirus infections.

In the present study, we have investigated the anatomic distribution and the function of different populations of HIV-1- and cytomegalovirus (CMV)-specific memory CD8 T cells. The different populations of virus-specific memory CD8 T cells were distinguished on the basis of the expression of CD45RA and CCR7, and the composition of HIV-1- and CMV-specific memory CD8 T cell pools were compared in subjects with chronic HIV-1 and CMV co-infection. The distribution of HIV-1-specific CD8 T cells was similar between blood and lymph node. However, CMV-specific CD8 T cells were accumulated predominantly in the blood away from the lymphoid tissue. The majority (>70%) of HIV-1- and CMV-specific CD8 T cells in both blood and lymph node had a phenotype, e.g. CCR7-, typical of effector T cells. HIV-1-specific memory CD8 T cells were mostly (>80%) pre-terminally differentiated cells, e.g. CD45RA-CCR7-, in both blood and lymph node while 30-50% of CMV-specific CD8 T cells were terminally differentiated, e.g. CD45RA+CCR7-. Therefore, consistently with studies in mice, antigen-specific effector memory CD8 T cells accumulate predominantly in the target organ of the pathogen in humans, and the differences in the composition of HIV-1- and CMV-specific CD8 T cell pools were also present in the lymphoid tissue. A substantial proportion (30-40%) of virus-specific CD8+CCR7+ T cells produced IFN-gamma. Thus, indicating that the expression of CCR7 does not provide a clear-cut separation of memory CD8 T cells with distinct functional capacities. Taken together, these results provide further advances in the characterization of human memory CD8 T cells.