Iron-Dependent Cell Death: A New Treatment Approach against Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a devastating tumor type where a very high proportion of people diagnosed end up dying from cancer. Surgical resection is an option for only about 20% of patients, where the 5-year survival increase ranges from 10 to 25%. In addition to surgical resection, there are adjuvant chemotherapy schemes, such as FOLFIRINOX (a mix of Irinotecan, oxaliplatin, 5-Fluorouraci and leucovorin) or gemcitabine-based treatment. These last two drugs have been compared in the NAPOLI-3 clinical trial, and the NALIRIFOX arm was found to have a higher overall survival (OS) (11.1 months vs. 9.2 months). Despite these exciting improvements, PDAC still has no effective treatment. An interesting approach would be to drive ferroptosis in PDAC cells. A non-apoptotic reactive oxygen species (ROS)-dependent cell death, ferroptosis was first described by Dixon et al. in 2012. ROS are constantly produced in the tumor cell due to high cell metabolism, which is even higher when exposed to chemotherapy. Tumor cells have detoxifying mechanisms, such as Mn-SOD or the GSH-GPX system. However, when a threshold of ROS is exceeded in the tumor cell, the cell's antioxidant systems are overwhelmed, resulting in lipid peroxidation and, ultimately, ferroptosis. In this review, we point out ferroptosis as an approach to consider in PDAC and propose that altering the cellular ROS balance by combining oxidizing agents or with inhibitors of the main cellular detoxifiers triggers ferroptosis in PDAC.

DLL3 Is a Prognostic and Potentially Predictive Biomarker for Immunotherapy Linked to PD/PD-L Axis and NOTCH1 in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive neoplasm with very poor patient survival outcomes despite available treatments. There is an urgent need for new potential treatment options and novel biomarkers for these patients. Delta-like canonical Notch ligand 3 (DLL3) interacts with the Notch receptor and causes inhibition of Notch signaling, which confers a survival advantage to PDAC cells. Thus, DLL3 expression could affect cell survival, and its inhibition could increase a patient's survival. To test this hypothesis, a survival analysis was conducted using the progression-free and overall survival from two independent datasets of PDAC patients, with one using mRNA z-score levels and the other using the Hscore protein expression level; both were carried out using a log-rank test and plotted using Kaplan-Meier curves. DLL3 at the mRNA expression level showed an association between high mRNA expression and both a longer progression-free survival (PFS) and overall survival (OS) of patients. Then, we designed a retrospective study with resected PDAC samples. Our primary objective with this dataset was to assess the relationship between PFS and OS and DLL3 protein expression. The secondary assessment was to provide a rationale for the use of anti-DLL3-based treatments in combination with immunotherapy that is supported by the link between DLL3 and other factors that are involved in immune checkpoints. The survival analyses revealed a protective effect of high DLL3 protein expression levels in both PFS and OS. Interestingly, high DLL3 protein expression levels were significantly correlated with PD-L1/2 and negatively correlated with NOTCH1. Therefore, DLL3 could be considered a biomarker for better prognosis in resectable PDAC patients as well as a therapeutic biomarker for immunotherapy response. These facts set a rationale for testing anti-DLL3-based treatments either alone or combined with immunotherapy or other NOTCH1 inhibitors.

Post-Chemotherapy Rebound Thymic Hyperplasia Mimicking Relapse in Breast Implant-Associated Anaplastic Large Cell Lymphoma: A Case Report.

INTRODUCTION: Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is an unusual form of T-cell non-Hodgkin lymphoma. Surgical management is essential; however, adjuvant therapy is recommended for advanced stages of cancer. CASE PRESENTATION: A 40-year-old woman with textured silicone implants placed 7 years earlier, presented with breast nodules. Physical examination and computed tomography (CT) revealed a left parasternal mass, 2 left-breast nodules, and axillary lymphadenopathies. A soft-tissue lesion in the anterior mediastinum consistent with thymic remnants was detected. BIA-ALCL was diagnosed based on ultrasound-guided core biopsies of an axillary lymph node and a breast nodule. She underwent total bilateral capsulectomy and received anthracycline-based adjuvant chemotherapy. End-of-treatment positron emission tomography-computed tomography (PET-CT) scan at 4 months showed no evidence of disease, except for the persistence of the mediastinal lesion (Deauville score 4). Three months later, a new PET-CT scan showed enlargement of the lesion and increased radiotracer uptake, suggesting metabolic progression. A mediastinal biopsy was performed and rebound thymic hyperplasia (RTH) was observed in the histopathologic study. Once complete remission (CR) was achieved, the patient was followed up continually and has shown no signs of relapse to date. CONCLUSIONS: Further studies are required to determine the best adjuvant therapy for advanced BIA-ALCL. RTH may be suspected when thymic enlargement without the involvement of other areas is observed in patients with cancer. Mediastinal biopsy is mandatory to rule out relapse.