Molecular characterization of epithelial-mesenchymal transition and medical treatment related-genes in non-functioning pituitary neuroendocrine tumors.

Introduction: Different medical therapies have been developed for pituitary adenomas. However, Non-Functioning Pituitary Neuroendocrine Tumors (NF-PitNET) have shown little response to them. Furthermore, epithelial-mesenchymal transition (EMT) has been linked to resistance to medical treatment in a significant number of tumors, including pituitary adenomas. Methods: We aimed to evaluate the expression of EMT-related markers in 72 NF-PitNET and 16 non-tumoral pituitaries. To further explore the potential usefulness of medical treatment for NF-PitNET we assessed the expression of somatostatin receptors and dopamine-associated genes. Results: We found that SNAI1, SNAI2, Vimentin, KLK10, PEBP1, Ki-67 and SSTR2 were associated with invasive NF-PitNET. Furthermore, we found that the EMT phenomenon was more common in NF-PitNET than in GH-secreting pituitary tumors. Interestingly, PEBP1 was overexpressed in recurrent NF-PitNET, and could predict growth recurrence with 100% sensitivity but only 43% specificity. In parallel with previously reported studies, SSTR3 is highly expressed in our NF-PitNET cohort. However, SSTR3 expression is highly heterogeneous among the different histological variants of NF-PitNET with very low levels in silent corticotroph adenomas. Conclusion: NF-PitNET showed an enhanced EMT phenomenon. SSTR3 targeting could be a good therapeutic candidate in NF-PitNET except for silent corticotroph adenomas, which express very low levels of this receptor. In addition, PEBP1 could be an informative biomarker of tumor regrowth, useful for predictive medicine in NF-PitNET.

Data mining analyses for precision medicine in acromegaly: a proof of concept.

Predicting which acromegaly patients could benefit from somatostatin receptor ligands (SRL) is a must for personalized medicine. Although many biomarkers linked to SRL response have been identified, there is no consensus criterion on how to assign this pharmacologic treatment according to biomarker levels. Our aim is to provide better predictive tools for an accurate acromegaly patient stratification regarding the ability to respond to SRL. We took advantage of a multicenter study of 71 acromegaly patients and we used advanced mathematical modelling to predict SRL response combining molecular and clinical information. Different models of patient stratification were obtained, with a much higher accuracy when the studied cohort is fragmented according to relevant clinical characteristics. Considering all the models, a patient stratification based on the extrasellar growth of the tumor, sex, age and the expression of E-cadherin, GHRL, IN1-GHRL, DRD2, SSTR5 and PEBP1 is proposed, with accuracies that stand between 71 to 95%. In conclusion, the use of data mining could be very useful for implementation of personalized medicine in acromegaly through an interdisciplinary work between computer science, mathematics, biology and medicine. This new methodology opens a door to more precise and personalized medicine for acromegaly patients.

Cerebral Microbleeds, Cerebral Amyloid Angiopathy, and Their Relationships to Quantitative Markers of Neurodegeneration.

BACKGROUND AND OBJECTIVES: Age-related cognitive impairment is driven by the complex interplay of neurovascular and neurodegenerative disease. There is a strong relationship between cerebral microbleeds (CMBs), cerebral amyloid angiopathy (CAA), and the cognitive decline observed in conditions such as Alzheimer disease. However, in the early, preclinical phase of cognitive impairment, the extent to which CMBs and underlying CAA affect volumetric changes in the brain related to neurodegenerative disease remains unclear. METHODS: We performed cross-sectional analyses from 3 large cohorts: The Northern Manhattan Study (NOMAS), Alzheimer's Disease Neuroimaging Initiative (ADNI), and the Epidemiology of Dementia in Singapore study (EDIS). We conducted a confirmatory analysis of 82 autopsied cases from the Brain Arterial Remodeling Study (BARS). We implemented multivariate regression analyses to study the association between 2 related markers of cerebrovascular disease-MRI-based CMBs and autopsy-based CAA-as independent variables and volumetric markers of neurodegeneration as dependent variables. NOMAS included mostly dementia-free participants age 55 years or older from northern Manhattan. ADNI included participants living in the United States age 55-90 years with a range of cognitive status. EDIS included community-based participants living in Singapore age 60 years and older with a range of cognitive status. BARS included postmortem pathologic samples. RESULTS: We included 2,657 participants with available MRI data and 82 autopsy cases from BARS. In a meta-analysis of NOMAS, ADNI, and EDIS, superficial CMBs were associated with larger gray matter (ß = 4.49 ± 1.13, p = 0.04) and white matter (ß = 4.72 ± 2.1, p = 0.03) volumes. The association between superficial CMBs and larger white matter volume was more evident in participants with 1 CMB (ß = 5.17 ± 2.47, p = 0.04) than in those with ≥2 CMBs (ß = 1.97 ± 3.41, p = 0.56). In BARS, CAA was associated with increased cortical thickness (ß = 6.5 ± 2.3, p = 0.016) but not with increased brain weight (ß = 1.54 ± 1.29, p = 0.26). DISCUSSION: Superficial CMBs are associated with larger morphometric brain measures, specifically white matter volume. This association is strongest in brains with fewer CMBs, suggesting that the CMB/CAA contribution to neurodegeneration may not relate to tissue loss, at least in early stages of disease.

Implications of Heterogeneity of Epithelial-Mesenchymal States in Acromegaly Therapeutic Pharmacologic Response.

Acromegaly is caused by excess growth hormone (GH) produced by a pituitary tumor. First-generation somatostatin receptor ligands (SRLs) are the first-line treatment. Several studies have linked E-cadherin loss and epithelial-mesenchymal transition (EMT) with resistance to SRLs. Our aim was to study EMT and its relationship with SRLs resistance in GH-producing tumors. We analyzed the expression of EMT-related genes by RT-qPCR in 57 tumors. The postsurgical response to SRLs was categorized as complete response, partial response, or nonresponse if IGF-1 was normal, had decreased more than 30% without normalization, or neither of those, respectively. Most tumors showed a hybrid and variable EMT expression profile not specifically associated with SRL response instead of a defined epithelial or mesenchymal phenotype. However, high SNAI1 expression was related to invasive and SRL-nonresponsive tumors. RORC was overexpressed in tumors treated with SRLs before surgery, and this increased expression was more prominent in those cases that normalized postsurgical IGF-1 levels under SRL treatment. In conclusion, GH-producing tumors showed a heterogeneous expression pattern of EMT-related genes that would partly explain the heterogeneous response to SRLs. SNAI1 and RORC may be useful to predict response to SRLs and help medical treatment decision making.

Assessing the perioperative complications and outcomes of robotic pancreaticoduodenectomy using the National Cancer Database: is it ready for prime time?

Robotic pancreaticoduodenectomy has generated significant interest in recent years. Our study aimed to evaluate the difference in surgical, oncological, and survival outcomes after pancreaticoduodenectomy (PD) by either a robotic (RPD) or open approach (OPD). Using the National Cancer Database, we identified patients from 2010 and 2017 diagnosed with pancreatic adenocarcinoma and underwent pancreaticoduodenectomy by either robotic PD or open approach. Patients who underwent robotic PD during 2010 were compared to patients receiving the same procedure in 2017. In addition, a secondary analysis was performed to assess outcomes of robotic PD to open PD for the 2017 patient cohorts. Our primary outcomes included 30-day and 90-day mortality, length of stay, as well as 30-day readmission. Secondary outcome measures were surgical margins, lymph node yield, and adjuvant chemotherapy initiation within 12 weeks of surgery. When we compared the 2017 data to 2010 data, we found that robotic pancreaticoduodenectomy had lower 30- and 90-day mortality rates in 2017 compared to 2010. Additionally, we found that the lymph node yield in robotic PD increased during the study period. When we compared robotic PD to open PD for 2017, we found no statistically significant differences in readmission rates (10.1% vs. 9.7%: p-0.4), lymph node yield, or negative margin between the groups. Outcomes of robotic PD have improved over the years. In 2017, outcomes of robotic PD were similar to open PD.

The Black Esophagus.

Acute esophageal necrosis (AEN), commonly referred to as black esophagus, is a rare clinical condition resulting from a combination of ischemic insult and thromboembolic injury to the esophagus. It is characterized by the circumferential black appearance of the esophagus. The risk factors for the development of AEN include coronary artery disease (CAD), diabetes mellitus, hypertension, malignancy, and alcohol use disorder. The treatment is directed at correcting the underlying medical conditions, supportive measures, and gastric acid suppression. We present the case of a 60-year-old female with multiple medical comorbidities who was detected to have a black esophagus during the evaluation of anemia.

Molecular determinants of enhanced response to somatostatin receptor ligands after debulking in large GH-producing adenomas.

OBJECTIVE: Large somatotrophic adenomas depict poor response to somatostatin receptor ligands (SRLs). Debulking has shown to enhance SRLs effect in some but not all cases and tumour volume reduction has been proposed as the main predictor of response. No biological studies have been performed so far in this matter. We aimed to identify molecular markers of response to SRLs after surgical debulking in GH-secreting adenomas. DESIGN: We performed a multicenter retrospective study. PATIENTS: 24 patients bearing large GH-producing tumours. MEASUREMENTS: Clinical data and SRLs response both before and after surgical debulking were collected, and 21 molecular biomarkers of SRLs response were studied in tumour samples by gene expression. RESULTS: From the 21 molecular markers studied, only two of them predicted enhanced SRLs response after surgery. Tumours with improved response to SRLs after surgical debulking showed lower levels of Ki-67 (MKI67, FC = 0.17 and P = .008) and higher levels of RAR-related orphan receptor C (RORC) (FC = 3.1 and P Ë‚ .001). When a cut-off of no detectable expression was used for Ki-67, the model provided a sensitivity of 100% and a specificity of 52.6% with an area under the curve of 65.8%. Using a cut-off of 2 units of relative expression of RORC, the prediction model showed 100% of sensitivity and specificity. CONCLUSIONS: High levels of RORC and low levels of Ki-67 identify improved SRLs response after surgical debulking in large somatotropic adenomas. To determine their expression would facilitate medical treatment decision-making after surgery.

Molecular profiling for acromegaly treatment: a validation study.

Pharmacologic treatment of acromegaly is currently based upon assay-error strategy, the first-generation somatostatin receptor ligands (SRL) being the first-line treatment. However, about 50% of patients do not respond adequately to SRL. Our objective was to evaluate the potential usefulness of different molecular markers as predictors of response to SRL. We used somatotropinoma tissue obtained after surgery from a national cohort of 100 acromegalic patients. Seventy-one patients were treated with SRL during at least 6 months under maximal therapeutic doses according to IGF1 values. We analyzed the expression of SSTR2, SSTR5, AIP, CDH1 (E-cadherin), MKI67 (Ki-67), KLK10, DRD2, ARRB1, GHRL, In1-Ghrelin, PLAGL1 and PEBP1 (RKIP) by RT-qPCR and mutations in GNAS gene by Sanger sequencing. The response to SRL was categorized as complete response (CR), partial (PR) or non-response (NR) if IGF1 was normal, between >2<3 SDS or >3 SDS IGF1 at 6 months of follow-up, respectively. From the 71 patients treated, there were 27 CR (38%), 18 PR (25%) and 26 NR (37%). SSTR2, Ki-67 and E-cadherin were associated with SRL response (P < 0.03, P < 0.01 and P < 0.003, respectively). E-cadherin was the best discriminator for response prediction (AUC = 0.74, P < 0.02, PPV of 83.7%, NPV of 72.6%), which was validated at protein level. SSTR5 expression was higher in patients pre-treated with SRL before surgery. We conclude that somatotropinomas showed heterogeneity in the expression of genes associated with SRL response. E-cadherin was the best molecular predictor of response to SRL. Thus, the inclusion of E-cadherin in subsequent treatment-decision after surgical failure may be useful in acromegaly.

Real-world GLP-1 RA therapy in type 2 diabetes: A long-term effectiveness observational study.

AIMS: To evaluate in a real-world setting the effectiveness and tolerability of available GLP-1 RA drugs in patients with type 2 diabetes after a prolonged follow-up. MATERIALS AND METHODS: Observational, retrospective, single-centre study in patients starting GLP-1 RA therapy. Change in HbA1c, fasting plasma glucose (FPG) and body mass index (BMI) along with gastrointestinal (GI) adverse events and withdrawal from GLP-1 RA therapy were evaluated. Lack of efficacy of GLP-1 RA therapy according to prespecified goals was also measured. RESULTS: A total of 735 patients were included, mean age 59.7 years, duration of diabetes 9.01 years, HbA1c 8.18% and BMI 38.56 kg/m2. Average follow-up was 18.97 months (range 4.2-39.09). All HbA1c (0.93%; P < 0.01), FPG (24 mg/dL; P < 0.01) and BMI (1.55 kg/m2; P < 0.05) were significantly reduced from baseline and maintained throughout follow-up, regardless of prescribed GLP-1 RA. GI adverse events were present in 13.81% of patients at first follow-up visit, 37.07% of patients discontinued GLP-1 RA treatment, and 38.63% did not meet efficacy goals. CONCLUSIONS: In a real-world setting, GLP-1 RA therapy is largely prescribed in severely obese patients with a long-standing and poorly controlled diabetes. All prescribed GLP-1 RAs significantly decreased HbA1c, FPG and BMI. GI adverse events affected a low proportion of patients. Inversely, a high proportion of patients did not meet efficacy goals and/or discontinued GLP-1 RA treatment. Baseline characteristics of patients and lack of adherence may represent important issues underlying differences in effectiveness in real-world studies versus randomized trials.

Síndrome hypoparathyroidism-deafness-renal dysplasia: descripción de un caso / The hypoparathyroidism-deafness-renal dysplasia syndrome: A case report

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Hypocalcemia due to 22q11.2 deletion syndrome diagnosed in adulthood.

Chromosome 22q11.2 deletion syndrome (22q11.2DS) is a genetic syndrome that may present with hypocalcemia due to primary hypoparathyroidism (PH) at any age. We report a new diagnosis of 22q11.2DS in a 57-year-old man who presented with symptomatic hypocalcemia. It is important to consider genetic causes of hypocalcemia due to PH regardless of age. LEARNING POINTS: It is important to discard genetic cause of primary hypoparathyroidism in a patient without autoimmune disease or prior neck surgery.A new diagnosis of a hereditary disease has familial implications and needs genetic counselling.It is also important to discard other syndrome's comorbidities.