Early Experience of the First Single-Room Gantry Mounted Active Scanning Proton Therapy System at an Integrated Cancer Center.

Introduction: Review the early experience with a single-room gantry mounted active scanning proton therapy system. Material and Methods: All patients treated with proton beam radiotherapy (PBT) were enrolled in an institutional review board-approved patient registry. Proton beam radiotherapy was delivered with a 250 MeV gantry mounted synchrocyclotron in a single-room integrated facility within the pre-existing cancer center. Demographic data, cancer diagnoses, treatment technique, and geographic patterns were obtained for all patients. Treatment plans were evaluated for mixed modality therapy. Insurance approval data was collected for all patients treated with PBT. Results: A total of 132 patients were treated with PBT between March 2018 and June 2019. The most common oncologic subsites treated included the central nervous system (22%), gastrointestinal tract (20%), and genitourinary tract (20%). The most common histologies treated included prostate adenocarcinoma (19%), non-small cell lung cancer (10%), primary CNS gliomas (8%), and esophageal cancer (8%). Rationale for PBT treatment included limitation of dose to adjacent critical organs at risk (67%), reirradiation (19%), and patient comorbidities (11%). Patients received at least one x-ray fraction delivered as prescribed (36%) or less commonly due to unplanned machine downtime (34%). Concurrent systemic therapy was administered to 57 patients (43%). Twenty-six patients (20%) were initially denied insurance coverage and required peer-to-peers (65%), written appeals (12%), secondary insurance approval (12%), and comparison x-ray to proton plans (8%) for subsequent approval. Proton beam radiotherapy approval required a median of 17 days from insurance submission. Discussion: Incorporation of PBT into our existing cancer center allowed for multidisciplinary oncologic treatment of a diverse population of patients. Insurance coverage for PBT presents as a significant hurdle and improvements are needed to provide more timely access to necessary oncologic care.

Prognostic significance of HPV status in postoperative squamous-cell carcinoma of the head and neck.

BACKGROUND: There are limited data on the prognostic significance of human papillomavirus (HPV) status in relation to traditional risk factors for head and neck squamous-cell carcinoma (HNSCC) in the postoperative setting. OBJECTIVE: To clarify the impact of HPV status on the risk for HNSCC in the postoperative setting. METHODS: We retrospectively evaluated an institutional cohort of 128 patients with HNSCC patients who had been treated with definitive surgery with or without adjuvant radiotherapy or chemoradiotherapy. Patient, disease, and treatment factors were analyzed as potential prognostic indicators. RESULTS: Lymph node extracapsular extension (ECE), perineural invasion (PNI), and lymphovascular space invasion (LVSI) positivity predicted poorer locoregional control (LRC), disease-free survival (DFS), and overall survival (OS). Positive margins related to poorer DFS and OS. HPV status alone did not predict LRC, DFS, or OS. Compared with patients who were HPV-positive and ECE-negative, both HPV-positive and HPV-negative patients with ECE experienced significantly poorer OS (78.6%, 60%, and 43.7%, respectively; 𝑃 = .010 and 𝑃 = .018, respectively). LIMITATIONS: Retrospective, single-institution study; small patient cohort; short follow-up time. CONCLUSION: The influence of HPV in postoperative HNSCC seems limited compared with traditional risk factors such as ECE, LVSI, and PNI. De-escalation of postoperative treatment based on HPV status alone should be approached with caution.

Mechanistic studies of anticancer aptamer AS1411 reveal a novel role for nucleolin in regulating Rac1 activation.

AS1411 is a G-rich quadruplex-forming oligodeoxynucleotide that binds specifically to nucleolin, a protein found on the surface and in the cytoplasm of most malignant cells but absent from the surface/cytoplasm of most normal cells. AS1411 has shown promising clinical activity and is being widely used as a tumor-targeting agent, but its mechanism of action is not fully understood. Previously, we showed that AS1411 is taken up in cancer cells by macropinocytosis (fluid phase endocytosis) and subsequently stimulates further macropinocytosis by a nucleolin-dependent mechanism. In the current study, we have investigated the significance and molecular mechanisms of AS1411-induced macropinocytosis. Our results indicate that the antiproliferative activity of AS1411 in various cell lines correlated with its capacity to stimulate macropinocytosis. In DU145 prostate cancer cells, AS1411 induced activation of EGFR, Akt, p38, and Rac1. Activation of Akt and p38 were not critical for AS1411 activity because Akt activation was not observed in all AS1411-responsive cell lines and knockdown of p38 had no effect on AS1411's ability to inhibit proliferation. On the other hand, activation of EGFR and Rac1 appeared to play a role in AS1411 activity in all cancer cell lines examined (DU145, MDA-MB-468, A549, LNCaP) and their inhibition significantly reduced AS1411-mediated macropinocytosis and AS1411 antiproliferative activity. Interestingly, downregulation of nucleolin expression by siRNA also produced a substantial increase in activated Rac1, revealing a previously unknown role for nucleolin as a negative regulator of Rac1 activation. Our results are consistent with a model whereby AS1411 binding to nucleolin leads to sustained activation of Rac1 and causes methuosis, a novel type of nonapoptotic cell death characterized by hyperstimulation of macropinocytosis. We speculate that methuosis is a tumor/metastasis suppressor mechanism that opposes the malignant functions of Rac1 and that cancer cells may overexpress nucleolin to surmount this barrier.