Locoregional delivery of IL-13Rα2-targeting CAR-T cells in recurrent high-grade glioma: a phase 1 trial.

Chimeric antigen receptor T cell (CAR-T) therapy is an emerging strategy to improve treatment outcomes for recurrent high-grade glioma, a cancer that responds poorly to current therapies. Here we report a completed phase I trial evaluating IL-13Rα2-targeted CAR-T cells in 65 patients with recurrent high-grade glioma, the majority being recurrent glioblastoma (rGBM). Primary objectives were safety and feasibility, maximum tolerated dose/maximum feasible dose and a recommended phase 2 dose plan. Secondary objectives included overall survival, disease response, cytokine dynamics and tumor immune contexture biomarkers. This trial evolved to evaluate three routes of locoregional T cell administration (intratumoral (ICT), intraventricular (ICV) and dual ICT/ICV) and two manufacturing platforms, culminating in arm 5, which utilized dual ICT/ICV delivery and an optimized manufacturing process. Locoregional CAR-T cell administration was feasible and well tolerated, and as there were no dose-limiting toxicities across all arms, a maximum tolerated dose was not determined. Probable treatment-related grade 3+ toxicities were one grade 3 encephalopathy and one grade 3 ataxia. A clinical maximum feasible dose of 200 × 106 CAR-T cells per infusion cycle was achieved for arm 5; however, other arms either did not test or achieve this dose due to manufacturing feasibility. A recommended phase 2 dose will be refined in future studies based on data from this trial. Stable disease or better was achieved in 50% (29/58) of patients, with two partial responses, one complete response and a second complete response after additional CAR-T cycles off protocol. For rGBM, median overall survival for all patients was 7.7 months and for arm 5 was 10.2 months. Central nervous system increases in inflammatory cytokines, including IFNγ, CXCL9 and CXCL10, were associated with CAR-T cell administration and bioactivity. Pretreatment intratumoral CD3 T cell levels were positively associated with survival. These findings demonstrate that locoregional IL-13Rα2-targeted CAR-T therapy is safe with promising clinical activity in a subset of patients. ClinicalTrials.gov Identifier: NCT02208362 .

CNS Efficacy of Osimertinib With or Without Chemotherapy in Epidermal Growth Factor Receptor-Mutated Advanced Non-Small-Cell Lung Cancer.

PURPOSE: We report CNS efficacy of first-line osimertinib plus chemotherapy versus osimertinib monotherapy in patients with epidermal growth factor receptor (EGFR)-mutated advanced non-small-cell lung cancer (NSCLC) from the phase III FLAURA2 study according to baseline CNS metastasis status. METHODS: Patients were randomly assigned to osimertinib plus platinum-pemetrexed (combination) or osimertinib monotherapy until disease progression or discontinuation. Brain scans were performed in all patients at baseline and progression and at scheduled assessments until progression for patients with baseline CNS metastases; scans were assessed by neuroradiologist CNS blinded independent central review (BICR). RESULTS: On the basis of baseline CNS BICR, 118 of 279 (combination) and 104 of 278 (monotherapy) randomly assigned patients had ≥one measurable and/or nonmeasurable CNS lesion and were included in the CNS full analysis set (cFAS); 40 of 118 and 38 of 104 had ≥one measurable target CNS lesion and were included in the post hoc CNS evaluable-for-response set (cEFR). In the cFAS, the hazard ratio (HR) for CNS progression or death was 0.58 (95% CI, 0.33 to 1.01). In patients without baseline CNS metastases, the HR for CNS progression or death was 0.67 (95% CI, 0.43 to 1.04). In the cFAS, CNS objective response rates (ORRs; 95% CI) were 73% (combination; 64 to 81) versus 69% (monotherapy; 59 to 78); 59% versus 43% had CNS complete response (CR). In the cEFR, CNS ORRs (95% CI) were 88% (73 to 96) versus 87% (72 to 96); 48% versus 16% had CNS CR. CONCLUSION: Osimertinib plus platinum-pemetrexed demonstrated improved CNS efficacy compared with osimertinib monotherapy, including delaying CNS progression, irrespective of baseline CNS metastasis status. These data support this combination as a new first-line treatment for patients with EGFR-mutated advanced NSCLC, including those with CNS metastases.

COVID and Cancer: A Complete 3D Advanced Radiological CT-Based Analysis to Predict the Outcome.

BACKGROUND: Cancer patients infected with COVID-19 were shown in a multitude of studies to have poor outcomes on the basis of older age and weak immune systems from cancer as well as chemotherapy. In this study, the CT examinations of 22 confirmed COVID-19 cancer patients were analyzed. METHODOLOGY: A retrospective analysis was conducted on 28 cancer patients, of which 22 patients were COVID positive. The CT scan changes before and after treatment and the extent of structural damage to the lungs after COVID-19 infection was analyzed. Structural damage to a lung was indicated by a change in density measured in Hounsfield units (HUs) and by lung volume reduction. A 3D radiometric analysis was also performed and lung and lesion histograms were compared. RESULTS: A total of 22 cancer patients were diagnosed with COVID-19 infection. A repeat CT scan were performed in 15 patients after they recovered from infection. Most of the study patients were diagnosed with leukemia. A secondary clinical analysis was performed to show the associations of COVID treatment on the study subjects, lab data, and outcome on mortality. It was found that post COVID there was a decrease of >50% in lung volume and a higher density in the form of HUs due to scar tissue formation post infection. CONCLUSION: It was concluded that COVID-19 infection may have further detrimental effects on the lungs of cancer patients, thereby, decreasing their lung volume and increasing their lung density due to scar formation.

RAGE ablation attenuates glioma progression and enhances tumor immune responses by suppressing galectin-3 expression.

BACKGROUND: Malignant gliomas consist of heterogeneous cellular components that have adopted multiple overlapping escape mechanisms that overcome both targeted and immune-based therapies. The receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin superfamily that is activated by diverse proinflammatory ligands present in the tumor microenvironment. Activation of RAGE by its ligands stimulates multiple signaling pathways that are important in tumor growth and invasion. However, treatment strategies that only target the interaction of RAGE with its ligands are ineffective as cancer therapies due to the abundance and diversity of exogenous RAGE ligands in gliomas. METHODS: As an alternative approach to RAGE ligand inhibition, we evaluated the genetic ablation of RAGE on the tumorigenicity of 2 syngeneic murine glioma models. RAGE expression was inhibited in the GL261 and K-Luc gliomas by shRNA and CRSPR/Cas9 techniques prior to intracranial implantation. Tumor growth, invasion, and inflammatory responses were examined by histology, survival, Nanostring, and flow cytometry. RESULTS: Intracellular RAGE ablation abrogated glioma growth and invasion by suppressing AKT and ERK1/2 activities and by downregulating MMP9 expression. Interestingly, RAGE inhibition in both glioma models enhanced tumor inflammatory responses by downregulating the expression of galectin-3 and potentiated immunotherapy responses to immune checkpoint blockade. CONCLUSIONS: We demonstrated that intracellular RAGE ablation suppresses multiple cellular pathways that are important in glioma progression, invasion, and immune escape. These findings strongly support the development of RAGE ablation as a treatment strategy for malignant gliomas.

Prognostic value of minimal residual disease among patients with classical Hodgkin lymphoma undergoing autologous stem cell transplantation.

Improved biomarkers are needed to guide patient selection for autologous stem cell transplantation (ASCT) and post-ASCT maintenance therapies in relapsed/refractory classical Hodgkin lymphoma (cHL). To assess the prognostic value of minimal residual disease (MRD) using immunoglobulin-based high-throughput sequencing (Ig-HTS), we analyzed pre- and post-ASCT peripheral blood and pre-ASCT apheresis stem cell (ASC) samples in 36 cHL patients. A tumor clonotype was detected in only 12 patients (33%). Among these patients, MRD within plasma samples was closely associated with impending relapse. All patients (n = 3) with detectable MRD in any post-ASCT plasma sample relapsed (100% specificity), and MRD was not detected in any patients in remission. MRD testing from cellular specimens (peripheral blood mononuclear cell or ASC samples) was not associated with relapse. In this small cohort, plasma-based MRD testing appeared to be a promising biomarker in cHL, but given low clonotype detection rates with Ig-HTS, alternative MRD approaches should be investigated.

Response-adapted anti-PD-1-based salvage therapy for Hodgkin lymphoma with nivolumab alone or in combination with ICE.

This phase 2 trial evaluated PET-adapted nivolumab alone or in combination with ifosfamide, carboplatin, and etoposide (NICE) as first salvage therapy and bridge to autologous hematopoietic cell transplantation (AHCT) in relapsed/refractory (RR) classical Hodgkin lymphoma (cHL). Patients with RR cHL received 240 mg nivolumab every 2 weeks for up to 6 cycles (C). Patients in complete response (CR) after C6 proceeded to AHCT, whereas patients with progressive disease at any point or not in CR after C6 received NICE for 2 cycles. The primary endpoint was CR rate per the 2014 Lugano classification at completion of protocol therapy. Forty-three patients were evaluable for toxicity; 42 were evaluable for response. Thirty-four patients received nivolumab alone, and 9 patients received nivolumab+NICE. No unexpected toxicities were observed after nivolumab or NICE. After nivolumab, the overall response rate (ORR) was 81%, and the CR rate was 71%. Among 9 patients who received NICE, all responded, with 8 (89%) achieving CR. At the end of protocol therapy, the ORR and CR rates were 93% and 91%. Thirty-three patients were bridged directly to AHCT, including 26 after Nivo alone. The 2-year progression-free survival (PFS) and overall survival in all treated patients (n = 43) were 72% and 95%, respectively. Among 33 patients who bridged directly to AHCT, the 2-year PFS was 94% (95% CI: 78-98). PET-adapted sequential salvage therapy with nivolumab/nivolumab+NICE was well tolerated and effective, resulting in a high CR rate and bridging most patients to AHCT without chemotherapy. This trial was registered at www.clinicaltrials.gov #NCT03016871.

Neuro-Behcet Disease and Ocular Inflammation: A Case Report and Literature Review.

Purpose: To describe a case of panuveitis with occlusive vasculitis leading to the diagnosis of neuro-Behcet disease (NBD) and discuss the relationship between uveitis and NBD.Methods: Case report with a literature review of ocular inflammation in NBD.Results: A 26-year-old woman with a seven-month history of recurrent cerebral venous sinus thromboses (CVST) and right-sided hemiparalysis secondary to rhombencephalitis presented with bilateral panuveitis and occlusive retinal vasculitis. Systemic evaluations were negative for hypercoagulability and infection. Although HLA-51 negative, the diagnosis was consistent with NBD.Conclusion: NBD is a rare subset of BD with a limited number of studies and patients. However, uveitis is more common in adults with parenchymal disease; may predate the development of neurological symptoms. The most common locations of ocular inflammation were posterior and panuveitis. MRI/V of the brain can identify enhancing lesions in the rhombencephalon or CVST in patients with uveitis with neurological findings.

Response criteria for immunotherapy and the radiologic patterns of immune-related adverse events.

Immunotherapy has revolutionized clinical outcomes in both early-stage and advanced-stage malignancies. Immunotherapy has improved patient survival in both solid and hematologic disorders with the potential added benefit of less toxicity compared to conventional cytotoxic chemotherapy. Imaging plays a fundamental role in monitoring treatment response and assessment of immune-related adverse events, e.g. pneumonitis, colitis, etc. Familiarity with the current strategies of immune-related response evaluation and their limitations is essential for radiologists to guide clinicians with their treatment decisions. Radiologists should be aware of the wide spectrum of immune-related adverse events and their various radiological features as well as the patterns of treatment response associated with immunotherapies.

Current update on vaginal malignancies.

Primary vaginal cancers are rare and account for 1-3% of all gynecologic malignancies. There are several histological subtypes that affect a wide range of the population. Imaging plays an important role in the diagnosis, staging, and treatment planning of vaginal cancers. This article reviews the relevant anatomy, clinical findings, imaging characteristics, and recent advances in the management of vaginal malignancies.

Diagnostic Utility of Radiomics in Thyroid and Head and Neck Cancers.

Radiomics is an emerging field in radiology that utilizes advanced statistical data characterizing algorithms to evaluate medical imaging and objectively quantify characteristics of a given disease. Due to morphologic heterogeneity and genetic variation intrinsic to neoplasms, radiomics have the potential to provide a unique insight into the underlying tumor and tumor microenvironment. Radiomics has been gaining popularity due to potential applications in disease quantification, predictive modeling, treatment planning, and response assessment - paving way for the advancement of personalized medicine. However, producing a reliable radiomic model requires careful evaluation and construction to be translated into clinical practices that have varying software and/or medical equipment. We aim to review the diagnostic utility of radiomics in otorhinolaryngology, including both cancers of the head and neck as well as the thyroid.

Utility of Preoperative Blood-Oxygen-Level-Dependent Functional MR Imaging in Patients with a Central Nervous System Neoplasm.

Functional neuroimaging provides means to understand the relationship between brain structure and associated functions. Functional MR (fMR) imaging can offer a unique insight into preoperative planning for central nervous system (CNS) neoplasms by identifying areas of the brain effected or spared by the neoplasm. BOLD (blood-oxygen-level-dependent) fMR imaging can be reliably used to map eloquent cortex presurgically and is sufficiently accurate for neurosurgical planning. In patients with brain tumors undergoing neurosurgical intervention, fMR imaging can decrease postoperative morbidity. This article discusses the applications, significance, and interpretation of BOLD fMR imaging, and its applications in presurgical planning for CNS neoplasms.

Role of cardiac nuclear stress perfusion exam after computed tomographic coronary angiogram for evaluation of obstructive coronary artery disease in patients with chest pain.

BACKGROUND: Clinical workup for chest pain varies among institutions. Acute coronary syndrome (ACS) is the primary diagnosis to rule out in the differential diagnosis, due to its associated mortality and morbidity. Although studies have demonstrated efficacy of coronary computed tomographic angiography (CCTA) in diagnosis obstructive coronary artery disease (CAD), there is limited evidence in the clinical value of performing cardiac nuclear stress perfusion imaging [myocardial perfusion imaging (MPI)] exam in patients with chest pain after undergoing CCTA. We aim to evaluate clinical value of follow-up nuclear cardiac MPI in patients with chest pain who have undergone recent CCTA. METHODS: A total of 1,000 patients were evaluated in this IRB approved retrospective study who presented with symptoms of ACS. Patients who had elevated troponin or abnormal electrocardiogram (ECG) findings at initial presentation or prior to cardiac nuclear MPI were excluded from the study. All patients who underwent 64- or 320-detector row ECG-gated CCTA as well as a follow-up nuclear MPI. Patients who had diagnostics studies limited by artifact [e.g., suboptimal intravenous (IV) contrast bolus in CCTA, motion artifact on CCTA or MPI, etc.] were excluded. RESULTS: One hundred patients met the inclusion criteria. Patient demographics include average age 64.3 [32-89] years, 59 male, 41 females. Ninety-five/100 patients had at least one vessel with 50-70% coronary artery diameter stenosis measured on CCTA. There were no focal perfusion abnormalities identified on cardiac nuclear MPI in patients with less than 70% stenosis diagnosed on CCTA. Five percent of patients were identified with coronary arterial narrowing greater than 70% on CCTA and all 5 of these patients have evidence of abnormal cardiac nuclear stress test (perfusion abnormalities, chest pain, abnormal ECG). CONCLUSIONS: In low-to-intermediate risk patients with chest pain and evidence of non-critical coronary artery stenosis (i.e., less than 70% stenosis) diagnosed on CCTA, a follow-up cardiac nuclear perfusion imaging is of limited value.

Radiogenomics of lung cancer.

Machine learning (ML) and artificial intelligence (AI) are aiding in improving sensitivity and specificity of diagnostic imaging. The rapid adoption of these advanced ML algorithms is transforming imaging analysis; taking us from noninvasive detection of pathology to noninvasive precise diagnosis of the pathology by identifying whether detected abnormality is a secondary to infection, inflammation and/or neoplasm. This is led to the emergence of "Radiobiogenomics"; referring to the concept of identifying biologic (genomic, proteomic) alterations in the detected lesion. Radiobiogenomic involves image segmentation, feature extraction, and ML model to predict underlying tumor genotype and clinical outcomes. Lung cancer is the most common cause of cancer related death worldwide. There are several histologic subtypes of lung cancer, e.g., small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC) (adenocarcinoma, squamous cell carcinoma). These variable histologic subtypes not only appear different at microscopic level, but these also differ at genetic and transcription level. This intrinsic heterogeneity reveals itself as different morphologic appearances on diagnostic imaging, such as CT, PET/CT and MRI. Traditional evaluation of imaging findings of lung cancer is limited to morphologic characteristics, such as lesion size, margins, density. Radiomics takes image analysis a step further by looking at imaging phenotype with higher order statistics in efforts to quantify intralesional heterogeneity. This heterogeneity, in turn, can be potentially used to extract intralesional genomic and proteomic data. This review aims to highlight novel concepts in ML and AI and their potential applications in identifying radiobiogenomics of lung cancer.

Thoracic imaging finding of rheumatic diseases.

In the era of Precision Medicine, diagnostic imaging plays a key role in initial diagnosis and treatment response assessment in thoracic manifestation of various rheumatic disorders; resulting in increased dependency on imaging for treatment planning. Chest radiographs serve as a good initial screening tool for assessment of emergent and urgent thoracic conditions, e.g., pneumothorax, pulmonary edema, consolidation and pleural effusions. Cross-sectional imaging techniques, e.g., computed tomography (CT) and positron emission tomography-computed tomography (PET-CT) are most commonly utilized to evaluate more detailed pulmonary and mediastinal manifestations of rheumatic conditions. Magnetic resonance imaging (MRI) and ultrasound are most commonly used in cardiovascular, neural and musculoskeletal structures. This review article aims to highly key common thoracic imaging findings of rheumatic disorders, highlighting imaging test of choice for the particular disorder.

Thyroid cancer diagnosis in the era of precision imaging.

Thyroid cancer affects 1.3% of the population with increasing rates of incidence over the last decade (approximately 2% per year). Although the overall prognosis is good in the differentiated subtypes, there has been a slow but steady increase in rate of deaths associated with thyroid cancer (approximately 0.7% per year over the last decade). Thyroid cancer is usually detected when: (I) patients feel a lump in the neck; (II) a routine clinical exam is performed; (III) an incidental thyroid nodule is identified on diagnostic imaging (e.g., CT neck or chest, carotid ultrasound, PET scan acquired for non-thyroid pathology). Identification of suspicious thyroid nodules results in further diagnostic work-up including laboratory assessment, further imaging, and biopsy. Accurate diagnosis is required for clinical staging and optimal patient treatment design. In this review, we aim to discuss utility of various imaging modalities and their role in thyroid cancer diagnosis and management. Additionally, we aim to highlight emerging diagnostic techniques that aim to improve diagnostic specificity and accuracy in thyroid cancer, thus paving way for precision medicine.

Role of theranostics in thoracic oncology.

Theranostics is a re-emerging field of medicine that aims to create targeted agents that can be used for diagnostic and/or therapeutic indications. In the past, theranostics has been used to treat neoplasms, such as thyroid cancer and neuroblastomas. More recently, theranostics has seen a resurgence with advent of new therapeutic antibodies and small molecules which can be transformed into Theranostic agents through radioconjugating with a radioactive isotope. Positron emitting radioisotopes can be used for diagnostic purposes while alpha- and beta-emitting radioisotopes can be used for therapy. The technique of radiolabeling an existing therapeutic agent (small molecule or antibody) leverages the existing qualities of that drug, and potentiates therapeutic effect by conjugating it with a cytotoxic-energy bearing radioisotope (e.g., 131-iodine, 177-lutetium). Theranostics have been used for a few decades now, starting with 131-iodine for therapy of autoimmune thyroiditis (Graves' disease, Hashimoto's thyroiditis) as well as for thyroid cancer. Additionally, 131-iodine-meta-iodobenzylguanidine (131-I-MIBG) initially had been used for gastroenteropancreatic neuroendocrine (carcinoid) tumors. However, recently clinical trials have start enrolling patients to evaluate efficacy of 131-I-MIBG in patients with small cell carcinoma of the lung. In the era of precision medicine and personalized targeted therapeutics, Theranostics can play a key pivotal in improving diagnostic and therapeutic specificity by increasing potency of these targeted small molecules and antibodies with radioisotopes. In this review, we will review various clinically relevant Theranostics agent and their utility in thoracic disorders, notably within oncology.

Identifying CD38+ cells in patients with multiple myeloma: first-in-human imaging using copper-64-labeled daratumumab.

18F-Fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) is one of the most widely used imaging techniques to detect multiple myeloma (MM). Intracellular FDG uptake depicts in vivo metabolic activity, which can be seen in both malignant and nonmalignant cells, resulting in limited sensitivity and specificity. Our group showed preclinically that tracing MM dissemination using a CD38-directed human antibody, daratumumab, that is radioconjugated with 64Cu via the chelator DOTA (64Cu-daratumumab), led to improved sensitivity and specificity over that of FDG. Here, we report the results of a phase 1 trial designed to (1) assess the safety and feasibility of 64Cu-daratumumab PET/CT and (2) preliminarily evaluate and characterize the ability of 64Cu-daratumumab to accurately detect or exclude MM lesions. A total of 12 daratumumab-naive patients were imaged. Prior to the injection of 15 mCi/5 mg of 64Cu-daratumumab, patients were treated with 0 (n = 3), 10 (n = 3), 45 (n = 3), or 95 mg (n = 3) of unlabeled daratumumab to assess its effect on image quality. No significant adverse events were observed from either unlabeled daratumumab or 64Cu-daratumumab. Of the dose levels tested, 45 mg unlabeled daratumumab was the most optimal in terms of removing background signal without saturating target sites. 64Cu-daratumumab PET/CT provided safe whole-body imaging of MM. A trial comparing the sensitivity and specificity of 64Cu-daratumumab PET/CT with that of FDG PET/CT is planned. This trial was registered at www.clinicaltrials.gov as #NCT03311828.

Molecular Biomarkers in Multiple Sclerosis and Its Related Disorders: A Critical Review.

Multiple sclerosis (MS) is a chronic autoimmune disease affecting the central nervous system (CNS) which can lead to severe disability. Several diseases can mimic the clinical manifestations of MS. This can often lead to a prolonged period that involves numerous tests and investigations before a definitive diagnosis is reached. As well as the possibility of misdiagnosis. Molecular biomarkers can play a unique role in this regard. Molecular biomarkers offer a unique view into the CNS disorders. They help us understand the pathophysiology of disease as well as guiding our diagnostic, therapeutic, and prognostic approaches in CNS disorders. This review highlights the most prominent molecular biomarkers found in the literature with respect to MS and its related disorders. Based on numerous recent clinical and experimental studies, we demonstrate that several molecular biomarkers could very well aid us in differentiating MS from its related disorders. The implications of this work will hopefully serve clinicians and researchers alike, who regularly deal with MS and its related disorders.