Primary Results of NRG-RTOG1106/ECOG-ACRIN 6697: A Randomized Phase II Trial of Individualized Adaptive (chemo)Radiotherapy Using Midtreatment F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography in Stage III Non-Small Cell Lung Cancer.

Purpose: NRG-RTOG0617 demonstrated a detrimental effect of uniform high-dose radiation in stage III non-small cell lung cancer. NRG-RTOG1106/ECOG-ACRIN6697 (ClinicalTrials.gov identifier: NCT01507428), a randomized phase II trial, studied whether midtreatment F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) can guide individualized/adaptive dose-intensified radiotherapy (RT) to improve and predict outcomes in patients with this disease.

Imaging with [Zr]Zr-DFO-SC16.56 anti-DLL3 antibody in patients with high-grade neuroendocrine tumours of the lung and prostate: a phase 1/2, first-in-human trial.

Background: Delta-like ligand 3 (DLL3) is aberrantly expressed on the surface of small-cell lung cancer (SCLC) and neuroendocrine prostate cancer cells. We assessed the safety and feasibility of the DLL3-targeted imaging tracer [Zr]Zr-DFO-SC16.56 (composed of the anti-DLL3 antibody SC16.

First-in-human imaging with [Zr]Zr-DFO-SC16.56 anti-DLL3 antibody in patients with high-grade neuroendocrine tumors of the lung and prostate.

Background: Delta-like ligand 3 (DLL3) is aberrantly expressed on the cell surface in many neuroendocrine cancers including small cell lung cancer (SCLC) and neuroendocrine prostate cancer (NEPC). Several therapeutic agents targeting DLL3 are in active clinical development. Molecular imaging of DLL3 would enable non-invasive diagnostic assessment to inform the use of DLL3-targeting therapeutics or to assess disease treatment response.

Sex differences in brain tumor glutamine metabolism reveal sex-specific vulnerabilities to treatment.

Background: Brain cancer incidence and mortality rates are greater in males. Understanding the molecular mechanisms that underlie those sex differences could improve treatment strategies. Although sex differences in normal metabolism are well described, it is currently unknown whether they persist in cancerous tissue.

Treatment Response and Clinical Outcomes of Well-Differentiated High-Grade Neuroendocrine Tumors to Lutetium-177-DOTATATE.

Introduction: Lutetium-177 (177Lu)-DOTATATE received FDA approval in 2018 to treat somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (NETs). Little data are available on response and outcomes for well-differentiated (WD) high-grade (HG) NETs treated with 177Lu-DOTATATE.

Materials And Methods: Patients with WD HG NETs treated with 177Lu-DOTATATE at MSK from 2018 to 2020 were identified.

Optimizing Y Particle Density Improves Outcomes After Radioembolization.

Purpose: To determine how particle density affects dose distribution and outcomes after lobar radioembolization.

Methods: Matched pairs of patients, treated with glass versus resin microspheres, were selected by propensity score matching (114 patients), in this single-institution retrospective study. For each patient, tumor and liver particle density (particles/cm) and dose (Gy) were determined.

A Phase I Dose-Escalation and Expansion Study of Telaglenastat in Patients with Advanced or Metastatic Solid Tumors.

Purpose: Glutamine is a critical fuel for solid tumors. Interference with glutamine metabolism is deleterious to neoplasia in preclinical models. A phase I study of the oral, first-in-class, glutaminase (GLS) inhibitor telaglenastat was conducted in treatment-refractory solid tumor patients to define recommended phase II dose (RP2D) and evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity.

Preclinical and first-in-human-brain-cancer applications of [F]poly (ADP-ribose) polymerase inhibitor PET/MR.

Background: We report preclinical and first-in-human-brain-cancer data using a targeted poly (ADP-ribose) polymerase 1 (PARP1) binding PET tracer, [F]PARPi, as a diagnostic tool to differentiate between brain cancers and treatment-related changes.

Methods: We applied a glioma model in p53-deficient nestin/tv-a mice, which were injected with [F]PARPi and then sacrificed 1 h post-injection for brain examination. We also prospectively enrolled patients with brain cancers to undergo dynamic [F]PARPi acquisition on a dedicated positron emission tomography/magnetic resonance (PET/MR) scanner.

Measuring Tumor Epichaperome Expression Using [I] PU-H71 Positron Emission Tomography as a Biomarker of Response for PU-H71 Plus Nab-Paclitaxel in HER2-Negative Metastatic Breast Cancer.

Purpose: Epichaperome network maintenance is vital to survival of tumors that express it. PU-H71 is an epichaperome inhibitor that binds to the ATP-binding site of HSP90 and has demonstrated antitumor activity in breast cancer xenograft models and clinical safety in patients. PU-positron emission tomography (PET) is a theragnostic imaging tool that allows visualization of the epichaperome target.

Phase 1 Trial of MLN0128 (Sapanisertib) and CB-839 HCl (Telaglenastat) in Patients With Advanced NSCLC (NCI 10327): Rationale and Study Design.

Introduction: There are currently no approved targeted therapies for lung squamous-cell carcinoma (LSCC) and KRAS-mutant lung adenocarcinoma (LUAD). About 30% of LSCC and 25% of KRAS-mutant LUAD exhibit hyperactive NRF2 pathway activation through mutations in NFE2L2 (the gene encoding NRF2) or its negative regulator, KEAP1. Preclinical data demonstrate that these tumors are uniquely sensitive to dual inhibition of glycolysis and glutaminolysis via mammalian target of rapamycin (mTOR) and glutaminase inhibitors.

The Unique Pharmacometrics of Small Molecule Therapeutic Drug Tracer Imaging for Clinical Oncology.

Translational development of radiolabeled analogues or isotopologues of small molecule therapeutic drugs as clinical imaging biomarkers for optimizing patient outcomes in targeted cancer therapy aims to address an urgent and recurring clinical need in therapeutic cancer drug development: drug- and target-specific biomarker assays that can optimize patient selection, dosing strategy, and response assessment. Imaging the in vivo tumor pharmacokinetics and biomolecular pharmacodynamics of small molecule cancer drugs offers patient- and tumor-specific data which are not available from other pharmacometric modalities. This review article examines clinical research with a growing pharmacopoeia of investigational small molecule cancer drug tracers.

Value of [F]-FDG positron emission tomography in patients with recurrent glioblastoma receiving bevacizumab.

Background: Treatment of recurrent glioblastoma (GBM) with bevacizumab can induce MRI changes that confound the determination of progression. We sought to determine the value of [F]-fluorodeoxyglucose (FDG) positron emission tomography (PET) in GBM patients receiving bevacizumab at the time of suspected progression and, thereby, its utility as a potential prognostic adjunct in progressive disease.

Methods: This retrospective study included patients who underwent brain FDG PET within 4 weeks of receiving bevacizumab for recurrent GBM with suspected progression.

Safety and Feasibility of PARP1/2 Imaging with F-PARPi in Patients with Head and Neck Cancer.

Purpose: We performed a first-in-human clinical trial. The aim of this study was to determine safety and feasibility of PET imaging with F-PARPi in patients with head and neck cancer.

Patients And Methods: Eleven patients with newly diagnosed or recurrent oral and oropharyngeal cancer were injected with F-PARPi (331 ± 42 MBq), and dynamic PET/CT imaging was performed between 0 and 25 minutes postinjection.

First-in-Humans Trial of Dasatinib-Derivative Tracer for Tumor Kinase-Targeted PET.

We developed a first-of-kind dasatinib-derivative imaging agent, F-SKI-249380 (F-SKI), and validated its use for noninvasive in vivo tyrosine kinase-targeted tumor detection in preclinical models. In this study, we assessed the feasibility of using F-SKI for PET imaging in patients with malignancies. Five patients with a prior diagnosis of breast cancer, renal cell cancer, or leukemia underwent whole-body PET/CT imaging 90 min after injection of F-SKI (mean, 241.

Circulating Tumor DNA Analysis to Assess Risk of Progression after Long-term Response to PD-(L)1 Blockade in NSCLC.

Purpose: Treatment with PD-(L)1 blockade can produce remarkably durable responses in patients with non-small cell lung cancer (NSCLC). However, a significant fraction of long-term responders ultimately progress and predictors of late progression are unknown. We hypothesized that circulating tumor DNA (ctDNA) analysis of long-term responders to PD-(L)1 blockade may differentiate those who will achieve ongoing benefit from those at risk of eventual progression.

The epichaperome is a mediator of toxic hippocampal stress and leads to protein connectivity-based dysfunction.

Optimal functioning of neuronal networks is critical to the complex cognitive processes of memory and executive function that deteriorate in Alzheimer's disease (AD). Here we use cellular and animal models as well as human biospecimens to show that AD-related stressors mediate global disturbances in dynamic intra- and inter-neuronal networks through pathologic rewiring of the chaperome system into epichaperomes. These structures provide the backbone upon which proteome-wide connectivity, and in turn, protein networks become disturbed and ultimately dysfunctional.

Off-the-shelf EBV-specific T cell immunotherapy for rituximab-refractory EBV-associated lymphoma following transplantation.

BACKGROUNDAdoptive transfer of donor-derived EBV-specific cytotoxic T-lymphocytes (EBV-CTLs) can eradicate EBV-associated lymphomas (EBV-PTLD) after transplantation of hematopoietic cell (HCT) or solid organ (SOT) but is unavailable for most patients.METHODSWe developed a third-party, allogeneic, off-the-shelf bank of 330 GMP-grade EBV-CTL lines from specifically consented healthy HCT donors. We treated 46 recipients of HCT (n = 33) or SOT (n = 13) with established EBV-PTLD, who had failed rituximab therapy, with third-party EBV-CTLs.

Paradigms for Precision Medicine in Epichaperome Cancer Therapy.

Alterations in protein-protein interaction networks are at the core of malignant transformation but have yet to be translated into appropriate diagnostic tools. We make use of the kinetic selectivity properties of an imaging probe to visualize and measure the epichaperome, a pathologic protein-protein interaction network. We are able to assay and image epichaperome networks in cancer and their engagement by inhibitor in patients' tumors at single-lesion resolution in real time, and demonstrate that quantitative evaluation at the level of individual tumors can be used to optimize dose and schedule selection.

Pharmacokinetic Assessment of F-(24)-4-Fluoroglutamine in Patients with Cancer.

F-(2S,4R)-4-fluoroglutamine (F-FGln) is an investigational PET radiotracer for imaging tumor glutamine flux and metabolism. The aim of this study was to investigate its pharmacokinetic properties in patients with cancer. Fifty lesions from 41 patients (21 men and 20 women, aged 54 ± 14 y) were analyzed.

Chaperome heterogeneity and its implications for cancer study and treatment.

The chaperome is the collection of proteins in the cell that carry out molecular chaperoning functions. Changes in the interaction strength between chaperome proteins lead to an assembly that is functionally and structurally distinct from each constituent member. In this review, we discuss the epichaperome, the cellular network that forms when the chaperome components of distinct chaperome machineries come together as stable, functionally integrated, multimeric complexes.

Detection of recurrent pancreatic cancer: value of second-opinion interpretations of cross-sectional images by subspecialized radiologists.

Purpose: To investigate the value of second-opinion interpretation of cross-sectional images by subspecialized radiologists to diagnose recurrent pancreatic cancer after surgery.

Methods: The IRB approved and issued a waiver of informed consent for this retrospective study. Initial and second-opinion interpretations of 69 consecutive submitted MRI or CT follow-up after pancreatic cancer resection between January 1, 2009 and December 31, 2013 were evaluated by one oncologic imaging radiologist, who was blinded to patient's clinical details and histopathologic data.

Specialized second-opinion radiology review of PET/CT examinations for patients with diffuse large B-cell lymphoma impacts patient care and management.

To identify discrepancies in fludeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) reports generated by general radiologists and subspecialized oncological radiologists for patients with diffuse large B-cell lymphoma (DLBCL), and to assess if such discrepancies impact patient management.Two radiologists retrospectively reviewed 72 PET/CT scans of patients with DLBCL referred to our institutions between 2009 and 2011, and recorded the discrepancies between the outside and second-opinion reports regarding multiple preset criteria using kappa statistic (Κ), including the disease stage. A multidisciplinary staging that considered all patient clinical data, pathology, and follow up radiological scans, was considered as standard of reference.