Simultaneous Bilateral Laparoscopic Adrenalectomy Is Safe for Synchronous Large Adrenal Tumors

Laparoscopy is now considered the gold standard for treating benign monolateral adrenal lesions. We present the case of a patient affected by Cushing's syndrome due to large bilateral adrenal adenomas (7.5cm) who underwent simultaneous laparoscopic bilateral adrenalectomy. An anterior, lateral transperitoneal approach was used. Operative time was 200 minutes, and blood loss was 200mL. No intraoperative complications were encountered. The postoperative course was uneventful, and the patient was discharged after 3 days. Laparoscopic bilateral adrenalectomy is a safe, effective procedure when performed by experienced hands and may be an alternative treatment for large adrenal lesions

Proteomic profiles in hyperandrogenic syndromes

Background: Polycystic ovary syndrome (PCOS) and congenital adrenal hyperplasia (CAH) represent the most common causes of hyperandrogenism. Although the etiopathogeneses of these syndromes are different, they share many clinical and biochemical signs, such as hirsutism, acne, and chronic anovulation. Experimental data have shown that peripheral T-lymphocytes function as molecular sensors, being able to record molecular signals either at staminal and mature cell levels, or hormones at systemic levels. Methods: Twenty PCOS women and 10 CAH with 21-hydroxylase deficiency, aged between 18-35 yr, were studied. T-cells purified from all patients and 20 healthy donors have been analyzed by 2-dimensional gel electrophoresis. Silver-stained proteomic map of each patient was compared with a control map obtained by pooling protein samples of the 20 healthy subjects. Results: Spots of interest were identified by peptide mass fingerprint. Computer analysis evidenced several peptidic spots significantly modulated in all patients examined. Some proteins were modulated in both syndromes, others only in PCOS or in CAH. These proteins are involved in many physiological processes as the functional state of immune system, the regulation of the cytoskeleton structure, the oxidative stress, the coagulation process, and the insulin resistance. Conclusion: Identification of the physiological function of these proteins could help to understand ethiopathogenetic mechanisms of hyperandrogenic syndromes and its complications. (J. Endocrinol. Invest. 33: 156-164, 2010) (C) 2010, Editrice Kurti

THU035 Impact Of Surgery Or Medical Treatment With The Selective Glucocorticoid Receptor Modulator Relacorilant On Hypercoagulopathy In Patients With Cushing Syndrome

In patients with Cushing syndrome (CS), hypercoagulability represents a significant concern, leading to an elevated risk for thrombotic events. Hypercoagulability persists for several months (mos) after curative surgery, and current CS treatment guidelines recommend anticoagulation therapy for up to 3 mos after surgery. In patients with Cushing disease, hemostatic parameters may even worsen after surgery, independent of surgical outcome, with improvements beginning about 3 mos after successful surgery (Casonato et al. Blood Coagul Fibrinolysis 1999). This transient worsening may be due to increased inflammation as cortisol levels, and hence cortisol’s anti-inflammatory effects, are reduced after successful surgery, leading to increased activity in the coagulation cascade, which normalizes over time. Here, we evaluate the impact of surgery or treatment with the selective glucocorticoid receptor modulator relacorilant (RELA) on the coagulation state in patients with CS, reporting findings from a retrospective, longitudinal, monocentric, surgical cohort study and an open-label phase 2 study of RELA (NCT02804750). In the surgical study, coagulation markers were assessed in 30 patients before curative surgery and in remission. In the RELA study, patients received either RELA 100-200 mg for 12 weeks or RELA 250-400 mg for 16 weeks; coagulation markers were assessed in 34 patients throughout the study. In the surgical study, baseline (BL) mean 24-h urinary free cortisol (UFC) was 615.6 mcg/day (by immunoassay; 2.1x upper limit of normal [ULN]); mean and median time to hemostasis assessment after remission were 6.2 and 6 mos, respectively. Significant mean changes from BL were observed in activated partial thromboplastin time (aPTT; +2.0 sec, P=0.031), factor VIII (fVIII; -24.2%, P=0.044), and von Willebrand factor (vWF; -20.6%, P=0.018), whereas platelet count was unchanged. In the RELA study, BL mean UFC was 211.9 mcg/day (by tandem mass spectrometry; 4.2x ULN). Similar to the surgical study, significant mean changes from BL to last observed visit were reported in aPTT (+1.5 sec, P=0.046), fVIII (-18.9%, P=0.022), and platelet count (-68.8*109/L, P<0.0001), while vWF was unchanged. Significant improvements in other coagulation factors, eg, fIX and fX, were seen in patients with abnormal values at BL. These studies showed that coagulation markers in patients with CS improve 6 mos after curative surgery, and that treatment with RELA may have similar effects after 3-4 mos. The previously observed transient increase in fVIII immediately after surgery was absent with RELA, where negative mean changes from BL were seen throughout the study. This is presumably due to the less abrupt reduction of cortisol activity with RELA compared to surgery. RELA’s effects on hypercoagulopathy support further investigation of preoperative use and in patients with CS who are not eligible for surgery

Correlation between mutations and mRNA expression of APC and MUTYH genes: new insight into hereditary colorectal polyposis predisposition.

BACKGROUND: Transcript dosage imbalance may influence the transcriptome. To gain insight into the role of altered gene expression in hereditary colorectal polyposis predisposition, in the present study we analyzed absolute and allele-specific expression (ASE) of adenomatous polyposis coli (APC) and mutY Homolog (MUTYH) genes. METHODS: We analyzed DNA and RNA extracted from peripheral blood mononuclear cells (PBMC) of 49 familial polyposis patients and 42 healthy blood donors selected according similar gender and age. Patients were studied for germline alterations in both genes using dHPLC, MLPA and automated sequencing. APC and MUTYH mRNA expression levels were investigated by quantitative Real-Time PCR (qRT-PCR) analysis using TaqMan assay and by ASE assays using dHPLC-based primer extension. RESULTS: Twenty out of 49 patients showed germline mutations: 14 in APC gene and six in MUTYH gene. Twenty-nine patients did not show mutations in both genes. Results from qRT-PCR indicated that gene expression of both APC and MUTYH was reduced in patients analyzed. In particular, a significant reduction in APC expression was observed in patients without APC germline mutation vs control group (P\u2009<\u20090.05) while APC expression in the mutation carrier patients, although lower compared to control individuals, did not show statistical significance. On the other hand a significant reduced MUTYH expression was detected in patients with MUTYH mutations vs control group (P\u2009<\u20090.05). Altered ASE of APC was detected in four out of eight APC mutation carriers. In particular one case showed a complete loss of one allele. Among APC mutation negative cases, 4 out of 13 showed a moderate ASE. ASE of MUTYH did not show any altered expression in the cases analyzed. Spearman's Rho Test analysis showed a positive and significant correlation between APC and MUTYH genes both in cases and in controls (P\u2009=\u20090.020 and P\u2009<\u20090.001). CONCLUSIONS: APC and MUTYH showed a reduced germline expression, not always corresponding to gene mutation. Expression of APC is decreased in mutation negative cases and this appears to be a promising indicator of FAP predisposition, while for MUTYH gene, mutation is associated to reduced mRNA expression. This study could improve the predictive genetic diagnosis of at-risk individuals belonging to families with reduced mRNA expression regardless of presence of mutation

Additional file 2: Table S2. of Correlation between mutations and mRNA expression of APC and MUTYH genes: new insight into hereditary colorectal polyposis predisposition

Mean and median ASE values of cases and controls after combining both MUTYH assays. (DOCX 18 kb

Additional file 1: Table S1. of Correlation between mutations and mRNA expression of APC and MUTYH genes: new insight into hereditary colorectal polyposis predisposition

qRT-PCR and ASE results from 50 cases investigated. (DOCX 37 kb

Basal and one-month differed neutrophil, lymphocyte and platelet values and their ratios strongly predict the efficacy of checkpoint inhibitors immunotherapy in patients with advanced BRAF wild-type melanoma

Background To evaluate the capability of basal and one-month differed white blood cells (WBC), neutrophil, lymphocyte and platelet values and their ratios (neutrophils-to-lymphocytes ratio, NLR, and platelets-to-lymphocytes ratio, PLR) in predicting the response to immune checkpoint inhibitors (ICI) in metastatic melanoma (MM). Methods We performed a retrospective study of 272 BRAF wild-type MM patients treated with first line ICI. Bivariable analysis was used to correlate patient/tumor characteristics with clinical outcomes. Variations between time 1 and time 0 (Delta) of blood parameters were also calculated and dichotomized using cut-off values assessed by ROC curve. Results At baseline, higher neutrophils and NLR negatively correlated with PFS, OS and disease control rate (DCR). Higher PLR was also associated with worse OS. In multivariable analysis, neutrophils (p = 0.003), WBC (p = 0.069) and LDH (p = 0.07) maintained their impact on PFS, while OS was affected by LDH (p &lt; 0.001), neutrophils (p &lt; 0.001) and PLR (p = 0.022), while DCR by LDH (p = 0.03) and neutrophils (p = 0.004). In the longitudinal analysis, PFS negatively correlated with higher Delta platelets (p = 0.039), Delta WBC (p &lt; 0.001), and Delta neutrophils (p = 0.020), and with lower Delta lymphocytes (p &lt; 0.001). Moreover, higher Delta NLR and Delta PLR identified patients with worse PFS, OS and DCR. In the multivariable model, only Delta NLR influenced PFS (p = 0.004), while OS resulted affected by higher Delta WBC (p &lt; 0.001) and lower Delta lymphocytes (p = 0.038). Higher Delta WBC also affected the DCR (p = 0.003). When clustering patients in 4 categories using basal LDH and Delta NLR, normal LDH/lower Delta NLR showed a higher PFS than high LDH/higher Delta NLR (20 vs 5 months). Moreover, normal LDH/higher Delta lymphocytes had a higher OS than high LDH/lower Delta lymphocytes (50 vs. 10 months). Conclusions Baseline and early variations of blood cells, together with basal LDH, strongly predict the efficacy of ICI in MM. Our findings propose simple, inexpensive biomarkers for a better selection of patient treatments. Prospective multicenter studies are warranted to confirm these data

No Impact of NRAS Mutation on Features of Primary and Metastatic Melanoma or on Outcomes of Checkpoint Inhibitor Immunotherapy: An Italian Melanoma Intergroup (IMI) Study

Aims: It is debated whether the NRAS-mutant melanoma is more aggressive than NRAS wildtype. It is equally controversial whether NRAS-mutant metastatic melanoma (MM) is more responsive to checkpoint inhibitor immunotherapy (CII). 331 patients treated with CII as first-line were retrospectively recruited: 162 NRAS-mutant/BRAF wild-type (mut/wt) and 169 wt/wt. We compared the two cohorts regarding the characteristics of primary and metastatic disease, disease-free interval (DFI) and outcome to CII. No substantial differences were observed between the two groups at melanoma onset, except for a more frequent ulceration in the wt/wt group (p = 0.03). Also, the DFI was very similar in the two cohorts. In advanced disease, we only found lung and brain progression more frequent in the wt/wt group. Regarding the outcomes to CII, no significant differences were reported in overall response rate (ORR), disease control rate (DCR), progression free survival (PFS) or overall survival (OS) (42% versus 37%, 60% versus 59%, 12 (95% CI, 7–18) versus 9 months (95% CI, 6–16) and 32 (95% CI, 23–49) versus 27 months (95% CI, 16–35), respectively). Irrespectively of mutational status, a longer OS was significantly associated with normal LDH, &lt;3 metastatic sites, lower white blood cell and platelet count, lower neutrophil-to-lymphocyte (N/L) ratio. Our data do not show increased aggressiveness and higher responsiveness to CII in NRAS-mutant MM