Moisés Mercado

Purpose: Although cabergoline is the treatment of choice for prolactinomas, a non‐negligible proportion of patients show incomplete biochemical and/or tumoral response. Although several baseline factors have been associated with dopamine agonist resistance, their predictive value remains inconsistent. We aimed to evaluate whether baseline clinical, biochemical, and gross tumor burden variables are associated with incomplete biochemical and radiological response to cabergoline in prolactinomas using a predefined composite operational outcome. Methods: We conducted a retrospective observational cohort study at a tertiary care center in Mexico City. Adult patients with prolactinomas treated with cabergoline were included. The primary outcome was incomplete response to cabergoline, defined using a predefined operational composite endpoint requiring both prolactin normalization and at least 30% estimated tumor volume reduction during follow‐up. Follow‐up duration and cabergoline dose exposure were summarized descriptively and component analyses evaluated biochemical and radiological response separately. A sensitivity analysis used at least 30% tumor diameter reduction instead of volume reduction. Baseline characteristics were compared between responders and patients with incomplete response. Multivariable models including only baseline variables were constructed to identify independent baseline factors associated with incomplete response. Because maximal tolerated cabergoline dose and the reasons for dose non‐escalation were not uniformly available, this endpoint was used exclusively as a research classification; non‐attainment was not interpreted as clinical treatment failure or dopamine‐agonist resistance. Results: A total of 226 patients were included. Using the primary volume‐based definition, 140 patients (61.9%) were classified as responders and 86 (38.1%) as having incomplete response. Follow‐up duration from cabergoline initiation to the last clinical assessment was calculable in 225 patients, with a median duration of 107 months (IQR 56.5−153.5). The median cabergoline dose at 12 months was 1.5 mg/week (IQR 1.0−2.0), and 61 patients (27.0%) had received ≥ 2 mg/week at that time. In unadjusted analyses, age, sex, baseline estimated tumor volume, and tumor size category were not associated with incomplete response, whereas baseline prolactin showed only a weak non‐significant trend. In the primary multivariable model, none of the baseline variables independently identified patients with incomplete response. In exploratory component analyses, 140 patients (61.9%) achieved both prolactin normalization and ≥ 30% estimated tumor volume reduction, 14 (6.2%) achieved prolactin normalization only, 46 (20.4%) achieved ≥ 30% estimated tumor volume reduction only, and 26 (11.5%) achieved neither endpoint. Higher baseline prolactin was associated with incomplete biochemical response (adjusted OR 1.90 per log10 increase, 95% CI 1.11−3.25; p = 0.019; AUC 0.624), but no baseline variable was independently associated with incomplete radiological response. Conclusion: Using a composite operational definition of incomplete response to cabergoline, no routinely available baseline clinical, biochemical, or gross tumor burden variable was independently associated with the composite endpoint or with incomplete radiological response. Baseline prolactin was associated only with incomplete biochemical response, and discrimination remained limited. Conventional baseline variables appear insufficient for clinically useful prediction, highlighting the need for more comprehensive models incorporating dynamic treatment‐related, imaging features of tumor invasiveness, and molecular markers.

Background The development of a staple line or anastomotic leak after sleeve gastrectomy (SG) or gastric bypass (RYGB) continues to be one of the most feared complications after bariatric surgery. Such leaks do not only affect the immediate management but are also associated with a significant increase in morbidity and mortality. Methods Using the data from the MBSAQIP database, we carried out a multivariate analysis and identified the most common risk factors for a leak after a primary bariatric surgery. Using the odds ratio (OR) of those factors, a risk index was developed, and a subsequent analysis was performed upon the index itself to determine the risk of a leak according to the number of points. Results Data from 193,847 patients was analyzed, 140,605 had a SG (72.5%), and 53,242 had a RYGB (27.5%). A leak was present in 190 patients (0.1%) after SG and in 113 (0.2%) after RYGB. Statistically significant risk factors included: albumin < 3 g/dL (OR 3.196), previous foregut surgery (OR 2.827), preoperative therapeutic anticoagulation (OR 1.874), smoking (OR 1.776), hypertension (OR 1.404), sleep apnea (OR 1.322), and bypass surgery (OR 1.487). The risk of leak according to the number of points: 1 (OR 1.469), 2 (OR 2.066), 3 (OR 3.655), 4 (OR 3.609), 5 (OR 3.772), 6 (OR 4.075), 7 (OR 22.278). Conclusions As expected, the incremental number of factors increases exponentially the risk of a leak. Hypoalbuminemia, smoking, therapeutic anticoagulation and history of foregut surgery are the most significant risk factors. This score allows us to estimate more precisely the risk of a leak.

Clinically aggressive lactotroph pituitary neuroendocrine tumors (PitNET) are invasive tumors with an unusually rapid growth rate despite maximally tolerated doses of dopamine agonist (DA). We aimed to unravel the molecular heterogeneity of lactotroph PitNET and to identify biomarkers of aggressiveness and resistance to pharmacological treatment. A total of 13 patients harboring DA-resistant lactotroph PitNET were included in this study. Visium Spatial Transcriptomics (ST), whole transcriptome sequencing (WTS), and whole exome sequencing (WES) were performed in tumors from 4 of these patients; WTS and WES was carried out in 5; tumors from two patients underwent ST and WES and tumors from two other patients underwent only ST. Tumors were classified as null or partial responders according to their response to DA treatment. The eight PitNET analyzed by ST exhibited significant intratumoral heterogeneity, with clones showing alterations in PI3K/AKT and lipid metabolism pathways, particularly inositol phosphate, glycerophospholipid, and sphingolipid metabolism. The cell-cell communication analysis showed FGF-FGFR ligand receptor interaction whilst the transcription factors RXRA and CREM showed participation in both groups. A trajectory exploration was performed by including all PitNET together in a single analysis to determine whether there was a tendency or molecular pathway showing a differentiation pattern that would guide the transition from a partially responsive PitNET to a completely unresponsive one. We did not observe any such pattern. All of these findings were corroborated in the cohort of DA-resistant PitNETs in which only bulk WTS and WES were performed. The bulk WTS corroborated lipid metabolism and PI3K-AKT pathway alteration in PitNET, whereas the WES showed only SF3β1 and TP53 variants in one tumor each. Our work suggests that the PI3K/AKT pathway may constitute a molecular target at which to aim therapeutic strategies designed to treat aggressive and DA-resistant lactotroph PitNET.

A 25‐year‐old previously healthy man presents to the clinic with a severe headache after cocaine consumption. Physical examination revealed acromegaloid features, and the hormonal profile revealed an IGF‐1 of 308 ng/mL (40.8 nmol/L) (normal reference range 197–333 ng/mL; 17.8–45.6). An MRI showed a heterogeneous, cystic lesion of the pituitary gland with hematic contents, consistent with the diagnosis of a pituitary apoplexy. Considering the normal IGF‐1 level, the patient was classified to be in remission, which deems it unnecessary to initiate pharmacologic or surgical treatment. Remission of acromegaly after a pituitary apoplexy is an extremely rare event, and pituitary apoplexy after cocaine consumption is also anecdotal. We present the first case of remission of acromegaly after a cocaine‐induced pituitary apoplexy.

SUMMARY Familial partial lipodystrophy type 2 is a rare disease, particularly when it is caused by nonclassical gene variants. A high index of suspicion is essential for a timely diagnosis. We present the case of a 32-year-old woman, referred to evaluation of a possible Cushing syndrome, which was clinically and biochemically ruled out. Yet, due to the finding of a rather abnormal fat distribution during physical examination, the diagnosis of lipodystrophy was cogitated. Whole-exome sequencing revealed a missense variant of [...] SUMMARY Familial partial lipodystrophy type 2 is a rare disease, particularly when it is caused by nonclassical gene variants. A high index of suspicion is essential for a timely diagnosis. We present the case of a 32-year-old woman, referred to evaluation of a possible Cushing syndrome, which was clinically and biochemically ruled out. Yet, due to the finding of a rather abnormal fat distribution during physical examination, the diagnosis of lipodystrophy was cogitated. Whole-exome sequencing revealed a missense variant of

Acute remission of acromegaly after a cocaine-induced apoplexy of a GH-secreting pituitary tumorDalia Cuenca. Department of Medicine, American British Cowdray Medical Center.Latife Salame-Khouri. Department of Neurology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán.Daniela Shveid-Gerson. Department of Medicine, American British Cowdray Medical Center.Marco Antonio Alegría-Loyola. Department of Medicine, American British Cowdray Medical Center.Corresponding author: Moises Mercado. Endocrine Research Unit, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, IMSS, Mexico City, mmercadoa@yahoo.com

Introduction: MODY misdiagnosis remains widespread, existing remarkable variability within genetic variants across populations. While diagnostic tools are based on Caucasian cohorts, Whole Exome Sequencing (WES) studies are needed to identify new genes in non-Caucasians, as up to 77% of patients do not harbor variants of significance in MODY-known genes. In Latino populations, no WES studies have addressed MODY genomic landscape beyond its canonical genes. Methods: We carried out WES in 17 patients with MODY, 17 patients with type 2 diabetes (T2DM) and 17 healthy controls (HC). MODY diagnosis was established according to Exeter criteria (score ≥36%) in subjects with no or minimal insulin requirements. We compared the single nucleotide variant (SNV) landscape across groups. Results: Patients with MODY present a polygenic landscape with allelic variants in canonical and non-canonical genes. Canonical MODY genes used for routine genetic diagnosis showed low discrimination utility, having similar frequencies between MODY, T2DM and HC in the Mexican population. We propose 14 genes with variants that distinguish MODY from T2DM and HC, as we detected variants in genes as MAP2K3, SYT15, TPTE, KCNJ12, PEX5, and OR2A1 in 75-100% of MODY cases while were absent in T2DM and HC. Enrichment analysis revealed involvement in synaptic vesicle trafficking, insulin/IGF pathway-mitogen activated protein kinase kinase/MAPK cascade, and insulin/IGF pathway-protein kinase B/AKT signaling cascade. Discussion: MODY presents a polygenic landscape. Besides improving our understanding of glycemic regulation pathways, the candidate genes could serve as MODY diagnostic biomarkers in Latino populations. Funding: Supported by grant R-2019-785-052 from Instituto Mexicano del Seguro Social.