Phase 1 study of cabozantinib in combination with topotecan-cyclophosphamide for patients with relapsed Ewing sarcoma or osteosarcoma.

PURPOSE: Phase 1 study assessing the safety and toxicity of cabozantinib in combination with topotecan and cyclophosphamide for relapsed osteosarcoma and Ewing sarcoma. METHODS: Oral cabozantinib (25 mg/m2 ) was administered daily for 21 (dose level 1) or 14 (dose level -1B) days. Topotecan (0.75 mg/m2 ) and cyclophosphamide (250 mg/m2 ) were administered intravenously (IV) on days 1-5. A modified 3+3 design based upon first cycle dose-limiting toxicities (DLT) was used for dose escalation. RESULTS: Twelve patients with a median age of 15 (12.9-33.2) years were enrolled (seven with Ewing sarcoma; five with osteosarcoma); all were evaluable for toxicity. At dose level 1, three of six patients developed first cycle DLT: grade 3 epistaxis, grade 3 transaminitis, and prolonged grade 2 thrombocytopenia. Six patients were enrolled on dose level -1B (interrupted cabozantinib, given days 8-21), with one first cycle DLT (grade 3 pneumothorax) observed. Of the 10 response evaluable patients, one had partial response (Ewing sarcoma), seven had stable disease, and two had progressive disease. CONCLUSIONS: The recommended phase 2 doses and schedules for this combination are topotecan 0.75 mg/m2 IV days 1-5, cyclophosphamide 250 mg/m2 IV days 1-5, and cabozantinib 25 mg/m2 days 8-21. Non-concomitant administration of cabozantinib with cytotoxic therapy in this population has acceptable toxicity, while allowing for potential disease control.

Phase 2 trial of palbociclib and ganitumab in patients with relapsed Ewing sarcoma.

BACKGROUND: Ewing sarcoma (EWS) is an aggressive sarcoma with few treatment options for patients with relapsed disease. Cyclin-dependent kinase 4 (CDK4) is a genomic vulnerability in EWS that is synergistic with IGF-1R inhibition in preclinical studies. We present the results of a phase 2 study combining palbociclib (CDK4/6 inhibitor) with ganitumab (IGF-1R monoclonal antibody) for patients with relapsed EWS. PATIENTS AND METHODS: This open-label, non-randomized, phase 2 trial enrolled patients ≥12 years with relapsed EWS. All patients had molecular confirmation of EWS and RECIST measurable disease. Patients initially received palbociclib 125 mg orally on Days 1-21 and ganitumab 18 mg/kg intravenously on Days 1 and 15 of a 28-day cycle. The primary endpoints were objective response (complete or partial) per RECIST and toxicity by CTCAE. An exact one-stage design required ≥4 responders out of 15 to evaluate an alternative hypothesis of 40% response rate against a null of 10%. The study was closed following enrollment of the 10th patient due to discontinuation of ganitumab supply. RESULTS: Ten evaluable patients enrolled [median age 25.7 years (range 12.3-40.1)]. The median duration of therapy was 2.5 months (range 0.9-10.8). There were no complete or partial responders. Three of 10 patients had stable disease for >4 cycles and 2 had stable disease at completion of planned therapy or study closure. Six-month progression-free survival was 30% (95% CI 1.6%-58.4%). Two patients had cycle 1 hematologic dose-limiting toxicities (DLTs) triggering palbociclib dose reduction to 100 mg daily for 21 days. Two subsequent patients had cycle 1 hematologic DLTs at the reduced dose. Eighty percent of patients had grade 3/4 AEs, including neutropenia (n = 8), white blood cell decreased (n = 7), and thrombocytopenia (n = 5). Serum total IGF-1 significantly increased (p = 0.013) and ctDNA decreased during the first cycle. CONCLUSIONS: This combination lacks adequate therapeutic activity for further study, though a subset of patients had prolonged stable disease.

Cross-platform dataset of multiplex fluorescent cellular object image annotations.

Defining cellular and subcellular structures in images, referred to as cell segmentation, is an outstanding obstacle to scalable single-cell analysis of multiplex imaging data. While advances in machine learning-based segmentation have led to potentially robust solutions, such algorithms typically rely on large amounts of example annotations, known as training data. Datasets consisting of annotations which are thoroughly assessed for quality are rarely released to the public. As a result, there is a lack of widely available, annotated data suitable for benchmarking and algorithm development. To address this unmet need, we release 105,774 primarily oncological cellular annotations concentrating on tumor and immune cells using over 40 antibody markers spanning three fluorescent imaging platforms, over a dozen tissue types and across various cellular morphologies. We use readily available annotation techniques to provide a modifiable community data set with the goal of advancing cellular segmentation for the greater imaging community.

CT Scan versus Saline Load Test for Detection of Traumatic Wrist Arthrotomy.

Background Traumatic arthrotomy of the wrist is most commonly detected using the saline load test (SLT); however, little data exists on the effectiveness of the SLT to this specific joint. The use of computed tomography (CT) scan has been validated as an alternative method to detect traumatic arthrotomy of the knee, as the presence of intra-articular air can be seen when there is violation of the joint capsule. Question/Purpose The purpose of this study was to determine the ability of CT scan to identify arthrotomy of the wrist capsule and compare the diagnostic performance of CT versus traditional SLT. Materials and Methods Ten fresh frozen cadavers which had undergone transhumeral amputation were initially used in this study. A baseline CT scan was performed to ensure no intra-articular air existed prior to intervention. After baseline CT, an arthrotomy was created at the 6R radiocarpal portal site. The wrists then underwent a postarthrotomy CT to identify the presence or absence of intra-articular air. Following CT, the wrists were subjected to the SLT to detect the presence of extravasation from the arthrotomy. Results Nine cadavers were included following baseline CT scan. Following arthrotomy, intra-articular air was visualized in eight of the nine cadavers in the postarthrotomy CT scan. Air was seen in the radiocarpal joint in eight of the nine wrists; midcarpal joint in seven of the nine wrists; and distal radioulnar joint in six of the nine wrists. All wrists (nine of the nine) demonstrated extravasation during the SLT. The mean volume of extravasation occurred at 3.7 mL (standard deviation = 2.6 mL), with a range of 1 to 7 mL. Conclusion CT scan correctly identified eight of the nine simulated traumatic arthrotomies. Injection of 7 mL during the SLT was necessary to identify 100% of the arthrotomies. Clinical Relevance CT scan is a sensitive modality for detection of traumatic arthrotomy of the wrist in a cadaveric model.

Resolution of donor non-alcoholic fatty liver disease following liver transplantation.

INTRODUCTION: Transplant surgeons conventionally select against livers displaying high degrees (>30%) of macrosteatosis (MaS), out of concern for primary non-function or severe graft dysfunction. As such, there is relatively limited experience with such livers, and the natural history remains incompletely characterized. We present our experience of transplanted livers with high degrees of MaS and microsteatosis (MiS), with a focus on the histopathologic and clinical outcomes. METHODS: Twenty-nine cases were identified with liver biopsies available from both the donor and the corresponding liver transplant recipient. Donor liver biopsies displayed either MaS or MiS ≥15%, while all recipients received postoperative liver biopsies for cause. RESULTS: The mean donor MaS and MiS were 15.6% (range 0%-60%) and 41.3% (7.5%-97.5%), respectively. MaS decreased significantly from donor (M=15.6%) to recipient postoperative biopsies (M=0.86%), P<.001. Similarly, MiS decreased significantly from donor biopsies (M=41.3%) to recipient postoperative biopsies (M=1.8%), P<.001. At a median of 68 days postoperatively (range 4-384), full resolution of MaS and MiS was observed in 27 of 29 recipients. CONCLUSIONS: High degrees of MaS and MiS in donor livers resolve in recipients following liver transplantation. Further insight into the mechanisms responsible for treating fatty liver diseases could translate into therapeutic targets.