Italian Association of Clinical Endocrinologists (AME) 20th National Congress

The proceedings contain 9 papers. The topics discussed include: dulaglutide and NAFLD risk reduction;correlation between plasmatic long pentraxin PTX3 and nodular thyroid disease: a preliminary report;the fructose-bisphosphate aldolase a act as autoantigen in primary autoimmune hypophysitis;cortisol deficiency in Lenvatinib treatment;side effects of mitotane treatment: a retrospective study in 35 patients with adrenocortical carcinoma in adjuvant therapy;non-functioning pituitary adenoma: do predictor factors exist?;incidence and features of adrenal crisis in a series of 133 patients with Addison's disease;serological evidence and self-reported outcomes in patients with adrenal insufficiency during the first waves of COVID-19 in the North-East Italy;and persistent effects of spironolactone after its withdrawal in patients with hyperandrogenic skin disorders.

Patterns of Progression and Treatment Discontinuation in a Real Life Latin American Prospective Cohort Study of Intermediate-Advanced Hepatocellular Carcinoma: Second Interim Analysis

Introduction and Objectives: Previously published regional real-world results of overall survival (OS) in Barcelona Clinic Liver Cancer (BCLC) B and C patients demanded a prospective cohort study nested in a systematic and continuous medical educational networking group. This study aimed to describe and evaluate the treatment decisions in patients with hepatocellular carcinoma (HCC) within BCLC B and C stages. Material(s) and Method(s): A multicenter prospective cohort study, conducted in different Latin American centers from Argentina, Brazil and Colombia, started on 15th May 2018 (delayed recruitment during COVID locked-down period). Patients within BCLC B or C stages were included. Survival, tumor progression and patterns of treatment suspension were evaluated. Result(s): At this second interim analysis (projected final analysis March 2023), 390 HCC BCLC-B or C patients were included (n=15 excluded);mean age 65 years, 75.6% males and 89.5% cirrhotic. Median OS since HCC diagnosis was 27.2 months. Among BCLC-B patients, the most frequent therapy was transarterial chemoembolization (TACE, 42.3%);51.8% using drug-eluting beads and 47.4% conventional TACE;with a median OS since 1st TACE of 41.9 months. Similar radiological responses after 1st TACE were observed between both modalities. Overall, 48.2% of the cohort received systemic therapy for HCC (n=188), 23.7% still on BCLC-B stage. The most frequent systemic treatments were Sorafenib (74.5%), atezolizumab bevacizumab (17.5%), and lenvatinib (12.2%), with a median OS since systemic therapy of 15.7 months. Lenvatinib or atezolizumab bevacizumab was used as the second line following sorafenib in 5 and 3 patients, respectively. The most common causes of systemic treatment discontinuation were tumor progression and liver function deterioration (15% to 36.4%). Patterns of tumor progression were not specifically associated with prognosis or treatment discontinuation. Conclusion(s): Liver function deterioration occurs in a third of patients following systemic therapies. The complexity of treatment decisions underly the need for a multidisciplinary team and the role of hepatologists.Copyright © 2023

Thrombotic Events during Lenvatinib Treatment: A Single Institution Experience.

Lenvatinib is the standard treatment for radioiodine-refractory differentiated thyroid cancer (RR-DTC). Thromboembolic (TE) side effects are quite rare (1-3% of treated patients) in clinical trials. Nevertheless, patients with predisposing factors are at a higher risk of developing cardiovascular adverse events. Reduction of lenvatinib starting dose and cardiologic counselling to provide appropriate supportive therapies are usually recommended for high-risk patients. From 2016 to 2022, we analyzed a series of 16 patients who were consecutively treated at our institution. All except one patient received a reduction in their dosage after two cycles of therapy because of toxicities, and four patients (25%) suffered from TE. The observed incidence in our patient sample seemed to be higher than expected. We hypothesized that our patient sample might be at higher risk probably because of the heavy prior loco-regional treatments performed.

BELZUTIFAN-INDUCED HYPERSENSITIVITY PNEUMONITIS

SESSION TITLE: Using Imaging for Diagnosis Case Posters SESSION TYPE: Case Report Posters PRESENTED ON: 10/19/2022 12:45 pm - 01:45 pm INTRODUCTION: Immunotherapy is now a standard of care in solid-tumor oncology following the approvals of CTLA-4 and PD-1 inhibitors. Belzutifan, a small-molecule HIF-2a inhibitor, has recently gained FDA-approval for the treatment of advanced von Hippel-Lindau (VHL) associated renal cell carcinomas. CASE PRESENTATION: A 63-year-old female presented to our hospital with a one-day history of progressive dyspnea. Medical history is significant for metastatic renal cell carcinoma with pulmonary metastasis. Family and social history were noncontributory. Her cancer diagnosis was established in 2019 and had undergone cytoreductive nephrectomy and treatment with axitinib/pembrolizumab. As she had little improvement with immunotherapy, she was enrolled in a clinical trial at Memorial Sloan Kettering. Due to further disease progression, she was transitioned to lenvatinib/everolimus, though the treatment was discontinued due to anorexia and worsening pulmonary symptoms. Further work up revealed that she had ERG, MPL, VHL gene mutations. Thus, she was started on belzutifan two weeks prior to her presentation. Initial vitals were significant for hypoxia on room air that recovered with high flow nasal cannula (40L/80%). Physical examination was remarkable for severe respiratory distress with coarse breath sounds bilaterally. Laboratory studies revealed an acute leukocytosis with a neutrophilic prominence and a chronic metabolic alkalosis. COVID, flu PCR were negative. Chest x-ray demonstrated diffuse bilateral reticulonodular opacities. CTA revealed innumerable pulmonary nodules with areas of mass-like consolidation and a loculated left-sided pleural effusion. She was covered with azithromycin/ceftriaxone along with high-dose steroids and was admitted to the stepdown unit for further management. While in stepdown, she had a left PleurX catheter placed given her large effusion which was complicated by bloody output that required one unit of blood. Despite high-dose steroids, she had persistent hypoxia. As she remained unstable, goals of care discussions were held, which ultimately led to a change in code status to comfort measures. All aggressive measures were discontinued. She was started on comfort medications and ultimately passed away. DISCUSSION: Currently, neoplasms associated with VHL mutations are managed surgically to minimize the risk of metastatic disease. Nearly 70% of all patients with VHL mutations will develop renal cell carcinomas which means most patients undergo numerous surgical procedures. HIF-2a inhibition therefore offers an effective alternative that could reduce surgical burden and offer a new approach to management of VHL-associated disease. However due to its new approval, several adverse effects have yet to be documented. CONCLUSIONS: We report the only known case of Belzutifan-induced hypersensitivity pneumonitis and hope this case will become a useful contribution to the literature. Reference #1: Jonasch E, Donskov F, Iliopoulos O, Rathmell WK, Narayan VK, Maughan BL, Oudard S, Else T, Maranchie JK, Welsh SJ, Thamake S, Park EK, Perini RF, Linehan WM, Srinivasan R;MK-6482-004 Investigators. Belzutifan for Renal Cell Carcinoma in von Hippel-Lindau Disease. N Engl J Med. 2021 Nov 25;385(22):2036-2046. doi: 10.1056/NEJMoa2103425. PMID: 34818478. DISCLOSURES: No relevant relationships by Garrett Fiscus No relevant relationships by Niala Moallem No relevant relationships by Raj Parikh

Lenvatinib-induced hypocalcaemia due to transient primary hypoparathyroidism.

CONTEXT: Radioiodine refractory differentiated thyroid cancer can be effectively treated with multi-tyrosine-kinase inhibitors (MKIs). Hypocalcaemia has been reported among the side effects of these drugs, but little is known about its pathophysiology and clinical relevance. CASE REPORT: We report the case of a 78-years-old woman with an aggressive papillary thyroid cancer infiltrating perithyroidal structures. The extent of surgery was limited to hemithyroidectomy, RAI treatment could not be performed, and she started lenvatinib treatment. After 4 months of therapy, the patient accessed the Emergency Department for a grade III hypocalcaemia (corrected serum calcium: 6.6 mg/dL, n.v. 8.1-10.4 mg/dL), due to primary hypoparathyroidism (serum PTH: 12.6 ng/L, n.v. 13-64 ng/L). The patient was treated with intravenous calcium infusions and vitamin D supplementation. After discharge, the oral dose of carbonate calcium (CaCO3) was of 6 g/day, and was titrated according to blood exams. Two weeks after discharge, while taking CaCO3 at the dose of 3 g/day, the patient experienced symptomatic grade II hypercalcemia (corrected serum calcium: 11.6 mg/dL), associated to the spontaneous reprise of PTH secretion, and leading to oral calcium withdrawal. During the subsequent follow-up, the patient remained eucalcemic without calcium supplementation. CONCLUSIONS: Though hypocalcaemia has been described as potential side effect of MKI treatment, this is the first report of a lenvatinib-induced primary hypoparathyroidism, in a patient with a documented normal parathyroid function after surgery. The periodical assessment of calcium-phosphorus metabolism is thus warranted to prevent this potentially lethal side effect, in both post-surgical hypoparathyroid and euparathyroid patients.

Unusual presentation of hepatocellular carcinoma-cannonball pulmonary metastasis

Objectives: Cannonball metastasis refers to well-circumscribed, spherical nodules scattered over both lungs, usually occur due to hematogenous spread of tumor, classically seen in germ cell tumor, renal cell carcinoma, choriocarcinoma, endometrial cancer but it is a rare and an unusual phenomenon in hepatocellular carcinoma. Materials and Methods: Case description: Results: We report a case of hepatocellular carcinoma with unusual presentation of pulmonary cannonball lesions. A 41-year-old Chinese man who attended to ED on 8.10.2021 with one month duration of abdominal discomfort and progressive dyspnea. He has past history of chronic hepatitis B infection since the age of 16 years but he did not receive any treatment. He denied fever and no history of TB contact. His oxygen saturation was 89% on room air. On examination, he was dyspneic, tachypneic, few crepitations in both lungs, hepatomegaly was noted. Covid PCR test was negative. Imaging tests revealed cannonball lesions were seen in both CXR and CECT chest (Figure-1) and infiltrative type of hepatocellular carcinoma both lobes of liver with portal vein thrombosis detected in CECT Liver (Figure-1). Blood tests showed elevated bilirubin (3.5 g/dl), AST 122, ALT 30, hypoalbuminemia (3.2), AFP 8421, HBeAg negative, antiHBeAb negative, qHBsAg 2793 IU/ml. His Child Pugh stage B (score 9), MELDNa 12 and BCLC stage C. Therefore, we diagnosed him to have advanced hepatocellular carcinoma with cannonball pulmonary metastasis with underlying chronic hepatitis B infection, for which we started Tenofovir (TDF) 300 mg OD and Lenvatinib 4 mg OD. Unfortunately, he expired on 17.10.2021. Conclusion: Hepatocellular carcinoma is one of the commonest cancers in the world with chronic hepatitis B and C infection. Extrahepatic spread to lung is common and about one third of these patients developed pulmonary metastasis. However, cannonball pulmonary metastasis is rare and is an unusual presentation in hepatocellular carcinoma. Moreover, prognosis of these patients is poor and survival is usually only days. (Figure Presented).

Phase Ib study of BI 836880 (VEGF/Ang2 inhibitor) plus ezabenlimab (BI 754091;anti-PD-1 antibody) in patients (pts) with advanced hepatocellular carcinoma (HCC)

Background: Combination of anti-VEGF compounds and immune checkpoint inhibitors is an approved therapy across multiple solid tumors, including advanced HCC. This phase Ib study (NCT03468426) is assessing BI 836880 (bispecific VEGF/Ang2 nanobody) + ezabenlimab (anti-PD-1 antibody) in pts with advanced solid tumors. The recommended phase 2 dose (RP2D) of BI 836880 720 mg + ezabenlimab 240 mg given IV every 3 weeks was determined in Part 1. In Part 2, RP2D was assessed in 7 expansion cohorts. We report data from cohorts in HCC after prior sorafenib/lenvatinib (cohort F) and untreated unresectable HCC (cohort G). Methods: Pts with locally advanced or metastatic HCC, Child-Pugh class A, not eligible for surgical or locoregional therapies were enrolled. Cohort F enrolled pts who had progressed on or after first-line treatment with sorafenib or lenvatinib or who had discontinued due to poor tolerability after ≥2 weeks of treatment. Cohort G enrolled pts who had received no prior systemic therapy for HCC. Treatment continued until disease progression, undue toxicity or consent withdrawal. Primary endpoint is objective response rate (ORR) by RECIST 1.1. Results: As of Aug 2021, 30/31 pts have been treated in cohorts F/G: 87/77% male;median age 65/64 yrs. Follow-up is ongoing in both cohorts. 9/19 pts in cohorts F/G remain on treatment;median (range) duration of treatment is 175 (42-532)/ 169 (42-336) days in cohorts F/G. All pts were evaluable for response in cohort F: confirmed ORR to date is 40% (1 complete response;11 partial responses [PRs]). Of 28 evaluable pts in cohort G, confirmed ORR to date is 21% (6 PRs). 12 (40%) pts in cohort F and 18 (64%) in cohort G have stable disease. In cohort F, AEs were reported in 28 (93%) pts, most frequently hypertension and proteinuria (each 30%). In cohort G, AEs occurred in 26 (84%) pts, most frequently ascites (26%) and thrombocytopenia (19%). 24 (80%) pts in cohort F and 15 (48%) in cohort G had treatmentrelated AEs (TRAEs). Most frequent TRAEs were proteinuria (27%), infusion-related reactions (IRRs) and hypertension (each 20%) in cohort F, and hypertension (13%), IRRs, hypothyroidism and diarrhea (each 10%) in cohort G. There were 3 pts with G5 AEs in cohort F (COVID-19 pneumonia [n = 1];low Glasgow coma score and dyspnea [n = 1];hepatic cirrhosis [n = 1]) and 1 G5 AE in cohort G (hepatic failure);none were considered related to treatment. AEs leading to discontinuation occurred in 2 pts in cohort F (G3 hepatic encephalopathy and G2 duodenal ulcer) and 3 in cohort G (G5 hepatic failure [n = 1];G2 acute kidney injury and G1 decreased appetite [n = 1];G2 diarrhea [n = 1]). Conclusions: BI 836880 + ezabenlimab had a manageable safety profile and showed promising activity in pts with untreated and second-line post-sorafenib/lenvatinib advanced HCC. Data continue to mature, particularly in cohort G. Cohort F has been expanded by a further 30 pts.

Pulmonary cavitation in a patient with coronavirus disease 2019 during lenvatinib treatment for thyroid carcinoma: a case report.

Lenvatinib, a multi-tyrosine kinase inhibitor, is used for the treatment of thyroid carcinoma. However, it can cause pneumonia and pulmonary cavitation leading to pneumothorax. The mechanism underlying the occurrence of cavitation and pneumothorax is not well understood. Coronavirus disease 2019 (COVID-19), which is an infectious condition characterized primarily by pneumonia, is sometimes accompanied by pulmonary cavitation. Patients with COVID-19 who present with pulmonary cavitation may have a poor prognosis. In the present case, a patient with papillary thyroid carcinoma presented with multiple pulmonary metastatic tumors that were treated with lenvatinib. After 9 weeks from treatment initiation, he experienced fever and presented with pulmonary consolidation and ground-glass opacity (GGO). Pneumonia improved after the withdrawal of lenvatinib. After 21 weeks from treatment initiation, he developed fever again and the clinical tests led to the diagnosis of COVID-19. Computed tomography (CT) showed new GGO in both sides of the lung. Therefore, the patient was diagnosed with moderate COVID-19. He was treated with dexamethasone plus remdesivir, and GGO due to COVID-19 disappeared. However, the previous pulmonary shadow associated with lenvatinib became a cavitary lesion. The initial CT findings of COVID-19 and pneumonia associated with lenvatinib are similar. Thus, both conditions must be considered for a differential diagnosis in patients presenting with GGO during lenvatinib treatment.