ACTA ENDOCRINOLOGICA (BUC)

Context. Phosphoinositide-3-kinase (PI3K) pathway inhibitors are increasingly used as targeted therapy in malignancies. We discuss here three cases of PI3K inhibitor induced hyperglycemia and discuss the mechanism of action of these medications and treatment of this class side effect. Objectives. Alpelisib (Piqray) is the newest PI3K inhibitor used in conjunction with Fulvestrant to treat specific types of breast cancer. Since PI3K is a critical mediator of insulin signaling, hyperglycemia is an on-target, unfortunate side effect of this treatment. We present a case series of severe hyperglycemia induced by the alpelisib in three women without a history of diabetes. Design. All three women in this study had hormone receptor (HR) positive, human epidermal growth factor receptor 2 (Her2) negative, PI3K mutated breast cancer. They were referred to our clinic by Oncology for alpelisibinduced hyperglycemia. Subjects and Methods. Review of laboratory values and glucometer values were conducted during each visit allowing treatment decisions. Two of these women are actively managed by us for their diabetes. One woman recently died due to progression of malignancy. Results. All three women presented with new onset of severe hyperglycemia after the initiation of PI3K inhibitor, alpelisib. At least one case noted maximal glucose elevation in the hours following drug ingestion. In another, cessation of Alpelisib reversed the hyperglycemia within the span of one week. Conclusion. Hyperglycemia induced by PI3K inhibitors can be recalcitrant and might necessitate interruption of chemotherapy. Optimal glucose-lowering therapy remains unclear as exogenous insulin has the theoretical potential to overcome PI3K inhibition.

-

Background. Molecular defects in the SHOX gene including deletions, duplications or pathogenic point mutations are responsible for well-known pathologies involving short stature as a clinical manifestation: Léri–Weill dyschondrosteosis, Langer mesomelic dysplasia, Turner syndrome or idiopathic short stature. Duplications flanking the SHOX gene (upstream or downstream of the intact SHOX gene involving conserved non-coding cis-regulatory DNA elements - CNEs) have been described but their clinical involvement is still difficult to understand. Results. We describe two cases with short stature and normal GH-IGF1 status. Multiplex ligation-dependent probe amplification (MLPA) and array comparative genomic hybridization (arrayCGH) identified in both cases heterozygous duplications involving downstream regions of SHOX gene, within CNEs (CNE8, CNE9 and CNE4, CNE5, CNE6, ECR1, CNE8, CNE9 and surrounding areas, respectively). One of the cases showed a maternally inherited duplication. Although every case has several particularities, we consider that duplications in these non-coding regions of SHOX gene may explain the short stature phenotype. Conclusion. To our knowledge, these are the first Romanian-reported cases of ISS with a large duplication of downstream SHOX enhancers CNEs region. The spectrum of phenotypic consequences and the exact mechanism of the presumed clinical expression of these genetic alterations still needs to be evaluated and described.

Context. Neuroendocrine tumors are tumors developing from primitive cells in the intestinal walls, but can also affect the lungs, liver, pancreas, ovaries. Objective. We aim to describe the clinical, imagistic and biologic aspect of neuroendocrine tumors with different localizations and present the evolution, treatment options and prognosis. Design. Four patients either with previously known neuroendocrine tumors or with newly discovered tumors were studied. Subjects and methods. The first patient was diagnosed with primary liver carcinoid with pulmonary metastases by abdominal and thoracic CT scan, liver biopsy and determination of serologic markers. The second patient was diagnosed with primary lung neuroendocrine tumor using thoracoscopy biopsy and serologic markers The third patient was diagnosed with a large gastric neuroendocrine tumor with liver and spleen metastases. using CT scan, MRI and biopsy from the abdominal mass. The fourth patient was diagnosed with primary liver carcinoid using imagistic methods (CT scan) and liver biopsy. Results. The first patient died after 4 months due to the extent of the disease and comorbidities. The second patient had a good evolution, as the tumor was diagnosed in a localized stage. The third patient had a decreased survival due to the dimensions of the primary tumor and the multiple liver metastases which later caused obstructive jaundice requiring external biliary drainage. The fourth patient has had a good evolution, the tumor masses in the liver are being kept under control using transarterial chemoembolization. Conclusion. Neuroendocrine tumors are very versatile both in location and clinical aspect. The diagnosis requires imagistic methods but it is imperative to perform biopsy of the lesions with special histologic stains in order to be sure of the diagnosis.

There is increasing evidence that diabetes mellitus and its complication diabetic\r\nketoacidosis confer an increased risk of venous thromboembolism. Pulmonary embolism is\r\nthe most serious venous thromboembolic event that is rarely reported in association with\r\ndiabetic ketoacidosis. We report a case of saddle pulmonary embolism that presented\r\nsimultaneously with diabetic ketoacidosis. Though radiologically massive, saddle\r\npulmonary embolism does not confer any difference in management decisions or prognosis\r\nfrom other forms of pulmonary embolism. It is important to appreciate the relation between\r\ndiabetic ketoacidosis and venous thromboembolism in order to further evaluate the need for\r\nprophylactic anticoagulation and to increase the suspicion and recognition of venous\r\nthromboembolic events in patients with diabetic ketoacidosis.

A 55-year-old female patient was admitted for flushing and abdominal pain in the right upper quadrant. Her past medical history revealed high blood pressure and a recent echocardiography showed thickened appearance of tricuspid valve with coaptation defect and grade II tricuspid regurgitation. Contrast enhanced abdominal CT scan and MRI were subsequently performed and revealed a large macronodular liver mass, as well as other micronodular lesions disseminated in the liver parenchyma. CT guided biopsy from the main liver mass revealed neuroendocrine tumor of unknown origin (probably GI) with Ki-67 of 8%. Surgical exploration was decided. During laparotomy, the primary tumor was found in the proximal ileum and the patient underwent segmental enterectomy. Non-anatomical hepatectomy was also performed to remove the bulk of the tumor burden (more than 90%). Postoperative course was uneventful and the carcinoid syndrome relieved. At present, 15 months postoperatively, the patient is under treatment with somatostatin analogue for its antiproliferative effect, with good clinical, biochemical and tumoral control and stable heart disease. In patients with neuroendocrine liver metastases from unknown primary, surgical exploration could allow detection (and resection) of the primary tumor and surgical debulking of liver metastases to control carcinoid syndrome and carcinoid heart disease.

We present the case of a 32 yeas old male, diagnosed 7 years ago with Graves disease, with numerous recidives which needed anti-thyroid medication, with poor response (hypo to hyper-thyroid status, with high variations of TSH and FT4) whom after a period of remission (8 months, no treatment) came in for a polymorphic symptomatology sugestive for hyperthyroidism. The hyperthyroid state was confirmed he had high TRAb (31 UI/ml vs. <1.75 UI/ml) - on his last check in the detection rate of TRAb was under 0.3 UI/ml. The thyroid ultrasound revels on the left lobe a small mass of 0.8/0.8 cm, with EU-TIRADS score of 4, that was newly diagnosed. Postoperative histopathology revealed papillary microcarcinoma developed on Hashitoxicosis- pT1aN0, of 1 mm in the middle of left thyroid lobe. The particularity of this case consists in a long evolution of Graves disease with numerous relapses, the appearance of a thyroid nodule after 7 years in which they identified a papillary microcacinoma associated with Hashimoto thyroiditis and also the postoperative recovery that was slowed by the parathyreoprive tetany.

Context. Learn the growth hormone dynamics and discuss the issues of growth hormone therapy in subjects with 45,X/46XY. Objective. To study the growth hormone dynamics in children with 45,X/46,XY karyotyping and mixed gonadal dysgenesis (MGD). Design. Descriptive clinical study. Participants. Five subjects with karyotype 45,X / 46,XY with or without genital ambiguity and somatic features of SHOX haploinsufficiency. Interventions. Growth hormone dynamic study and gonadectomy. Main outcome. IGF-1, peak GH levels, Turner’s stigmata and histology of gonadal tissue. Results. Five cases of MGD with both male and female phenotype were studies. IGF-1 levels and GH levels showed both features of growth hormone deficiency and growth hormone insensitivity. One study subject has gonadal germ cell tumour (dysgerminoma). We discuss here the issues regarding the GH therapy in MGD subjects. Conclusion. Growth deceleration in MGD subjects is partly due to defective growth hormone secretion and partly due to growth hormone insensitivity. MGD subjects are at high risk for occurrence of gonadal tumours. Gonadectomy or biopsy of underlying dysgenetic gonads is essential prior GH therapy. Close surveillance for second neoplasm is to be considered in subjects with history of gonadal tumors prior starting GH for short stature.

-