Search

Geeta Shroff Department of Stem Cell Therapy, Nutech Mediworld, New Delhi, India Abstract: Multiple sclerosis (MS), a complex disorder of the central nervous system (CNS), is characterized with axonal loss underlying long-term progressive disability. Currently available therapies for its management are able to slow down the progression but fail to treat it completely. Moreover, these therapies are associated with major CNS and cardiovascular adverse events, and prolonged use of these treatments may cause life-threatening diseases. Recent research has shown that cellular therapies hold a potential for CNS repair and may be able to provide protection from inflammatory damage caused after injury. Human embryonic stem cell (hESC) transplantation is one of the promising cell therapies; hESCs play an important role in remyelination and help in preventing demylenation of the axons. In this study, an overview of the current knowledge about the unique properties of hESC and their comparison with other cell therapies has been presented for the treatment of patients with MS. Keywords: multiple sclerosis, stem cells, human embryonic stem cells, remyelination, axonal loss, neurological disorder

BMS-986156 is a fully human IgG1 agonist mAb that binds GITR and promotes T effector cell activation and possible inactivation of T regulatory cells. Combined anti-GITR, anti-PD-1, anti-CLTA-4 antibodies and radiotherapy improve tumor control in pre-clinical studies. Here we describe the final results of safety and therapeutic efficacy of BMS-986156 + Ipilimumab or Nivolumab with/without Stereotactic Ablative Radiotherapy (SABR) in patients with advanced solid cancers. This is an open-label, multi-group and pan-cancer phase 1/2 study conducted in a single center. Patients with histologically confirmed stage IV solid cancer who failed to standard treatments but eligible for immunotherapy and SABR were prospectively enrolled. Group 1 (n=20) received four cycles of Ipilimumab (3 mg/kg) plus BMS-986156 (30 or 100mg), Q3W. Group 2 (n=10) received four cycles of Ipilimumab (3 mg/kg) plus BMS-986156 (dose as determined in Group 1),Q3W with SABR (50Gy/4fx or 60-70Gy/10fx, targeted at 1-4 liver/lung lesions). Group 3 (n=20) received four cycles of Nivolumab (480mg) plus BMS-986156 (30mg), Q3W with SABR. Maintenance Nivolumab could be given up to two years. Tumor responses were assessed every three months until progression, using Immune Related Response Criteria (irRC). Global, in-radiation field and out-of-field responses were assessed separately. Fifty patients were enrolled between Oct 9, 2019 and Dec 14, 2021. Median follow-up was 32.3 (95%CI 8.6-56.0) months. Median overall survival was 8.3 (95%CI 4.3-12.3) months. Patients received a median of three (IQR 2–4.25) treatment cycles. 100 mg BMS-986156 with Ipilimumab was tolerated well. Five discontinued BMS-986156 with Ipilimumab due to treatment-related adverse events (TRAEs). Twenty-two patients (44%) experienced grade (G) 1-3 TRAEs. Six (12%) had G3 TRAES, with elevated alanine aminotransferase (n=3) and aspartate aminotransferase (n=2) being the most common. There were no G4/5 TRAEs. Thirty-nine patients were eligible for efficacy assessment with adequate follow-up imaging before salvage therapy due to rapid progression. Overall, nineteen (48.7%) had stable disease and three (7.7%) achieved partial response. Among 26 patients receiving SABR, only one had in-field recurrence (3.8%). Out-of-field (abscopal) disease control rate (ACR) and out-of-field (abscopal) response rate (ARR) were 38.5% and 7.7%, respectively, with highest ACR (50%, 9/18) and ARR (11.1%, 2/18) in group 3. BMS-986156 was well-tolerated with Ipilimumab, Nivolumab, with or without SABR. Overall, more than half of patients had stable disease/partial response. The disease control rate and abscopal effect observed in those receiving SABR seem higher than reported in prior studies. (NCT04021043) [ABSTRACT FROM AUTHOR]

The article describes a case of air embolism involving the coronary and pulmonary circulation in a 58-year-old man. The patient, with a history of cirrhosis and hepatocellular carcinoma status post liver and kidney transplantation, and ventricular arrhythmia, underwent a fine-needle aspiration biopsy of a pulmonary nodule under computed tomography (CT) guidance at a hospital. His CT scan revealed evidence of massive cerebral air embolism, and a depressed left ventricular systolic function.

Introduction: Immune checkpoint inhibitor (ICI) pneumonitis causes substantial morbidity and mortality. Estimates of real-world incidence and reported risk factors vary substantially., Methods: We conducted a retrospective review of 419 patients with advanced non-small cell lung cancer (NSCLC) who were treated with anti-PD-(L)1 with or without anti-CTLA-4 therapy. Clinical, imaging, and microbiological data were evaluated by multidisciplinary adjudication teams. The primary outcome of interest was grade ≥2 (CTCAEv5) pneumonitis. Clinicopathologic variables, tobacco use, cancer therapies, and preexisting lung disease were assessed for univariate effects using Cox proportional hazards models. We created multivariate Cox proportional hazards models to assess risk factors for pneumonitis and mortality. Pneumonitis, pneumonia, and progression were modeled as time-dependent variables in mortality models., Results: We evaluated 419 patients between 2013 and 2021. The cumulative incidence of pneumonitis was 9.5% (40/419). In a multivariate model, pneumonitis increased the risk for mortality (HR 1.6, 95% CI, 1.0-2.5), after adjustment for disease progression (HR 1.6, 95% CI, 1.4-1.8) and baseline shortness of breath (HR 1.5, 95% CI, 1.2-2.0). Incomplete resolution was more common with more severe pneumonitis. Interstitial lung disease was associated with higher risk for pneumonitis (HR 5.4, 95% CI, 1.1-26.6), particularly in never smokers (HR 26.9, 95% CI, 2.8-259.0)., Conclusion: Pneumonitis occurred at a high rate and significantly increased mortality. Interstitial lung disease, particularly in never smokers, increased the risk for pneumonitis., (© The Author(s) 2023. Published by Oxford University Press.)

Aims: Pneumonitis is a common and potentially deadly complication of combined chemoradiation and immune checkpoint inhibition (CRT-ICI) in patients with locally advanced non-small cell lung cancer (LA-NSCLC). In this study we sought to identify the risk factors for pneumonitis with CRT-ICI therapy in LA-NSCLC cases and determine its impact on survival., Materials and Methods: We conducted a retrospective chart review of 140 patients with LA-NSCLC who underwent curative-intent CRT-ICI with durvalumab between 2018 and 2021. Pneumonitis was diagnosed by a multidisciplinary team of clinical experts. We used multivariable cause-specific hazard models to identify risk factors associated with grade ≥2 pneumonitis. We constructed multivariable Cox proportional hazard models to investigate the impact of pneumonitis on all-cause mortality., Results: The median age of the cohort was 67 years; most patients were current or former smokers (86%). The cumulative incidence of grade ≥2 pneumonitis was 23%. Among survivors, 25/28 patients had persistent parenchymal scarring. In multivariable analyses, the mean lung dose (hazard ratio 1.14 per Gy, 95% confidence interval 1.03-1.25) and interstitial lung disease (hazard ratio 3.8, 95% confidence interval 1.3-11.0) increased the risk for pneumonitis. In adjusted models, grade ≥2 pneumonitis (hazard ratio 2.5, 95% confidence interval 1.0-6.2, P = 0.049) and high-grade (≥3) pneumonitis (hazard ratio 8.3, 95% confidence interval 3.0-23.0, P < 0.001) were associated with higher all-cause mortality., Conclusions: Risk factors for pneumonitis in LA-NSCLC patients undergoing CRT-ICI include the mean radiation dose to the lung and pre-treatment interstitial lung disease. Although most cases are not fatal, pneumonitis in this setting is associated with markedly increased mortality., (Copyright © 2023. Published by Elsevier Ltd.)

Background: Immune checkpoint inhibitors (ICI) may cause pneumonitis, resulting in potentially fatal lung inflammation. However, distinguishing pneumonitis from pneumonia is time-consuming and challenging. To fill this gap, we build an image-based tool, and further evaluate it clinically alongside relevant blood biomarkers., Materials and Methods: We studied CT images from 97 patients with pneumonia and 29 patients with pneumonitis from acute myeloid leukemia treated with ICIs. We developed a CT-derived signature using a habitat imaging algorithm, whereby infected lungs are segregated into clusters ("habitats"). We validated the model and compared it with a clinical-blood model to determine whether imaging can add diagnostic value., Results: Habitat imaging revealed intrinsic lung inflammation patterns by identifying 5 distinct subregions, correlating to lung parenchyma, consolidation, heterogenous ground-glass opacity (GGO), and GGO-consolidation transition. Consequently, our proposed habitat model (accuracy of 79%, sensitivity of 48%, and specificity of 88%) outperformed the clinical-blood model (accuracy of 68%, sensitivity of 14%, and specificity of 85%) for classifying pneumonia versus pneumonitis. Integrating imaging and blood achieved the optimal performance (accuracy of 81%, sensitivity of 52% and specificity of 90%). Using this imaging-blood composite model, the post-test probability for detecting pneumonitis increased from 23% to 61%, significantly ( p = 1.5 E - 9) higher than the clinical and blood model (post-test probability of 22%)., Conclusion: Habitat imaging represents a step forward in the image-based detection of pneumonia and pneumonitis, which can complement known blood biomarkers. Further work is needed to validate and fine tune this imaging-blood composite model and further improve its sensitivity to detect pneumonitis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Aminu, Daver, Godoy, Shroff, Wu, Torre-Sada, Goizueta, Shannon, Faiz, Altan, Garcia-Manero, Kantarjian, Ravandi-Kashani, Kadia, Konopleva, DiNardo, Pierce, Naing, Kim, Kontoyiannis, Khawaja, Chung, Wu and Sheshadri.)

Background: Immune checkpoint inhibitors (ICI), combined with hypomethylating agents, can be used to treat acute myeloid leukemia (AML), but this strategy results in a high rate of pneumonitis. The authors sought to determine risk factors for pneumonitis development and whether pneumonitis increased mortality., Methods: The authors conducted a retrospective review of 258 AML patients who received ICI-containing regimens from 2016 to 2018. A multidisciplinary adjudication committee diagnosed pneumonia and pneumonitis by reviewing symptoms, imaging, microbiology, and response to therapies. To measure risk factors for pneumonitis and mortality, multivariate Cox proportional hazards models were constructed. Pneumonia, pneumonitis, and disease progression were modeled as a time-dependent variable and incorporated a standard risk set modifying variables into the models., Results: Thirty patients developed pneumonitis (12%). Of these, 17 had partial or complete resolution, whereas 13 patients died from pneumonitis. Increasing age (hazard ratio [HR], 1.04 per year; 95% confidence interval [CI], 1.00-1.08), and baseline shortness of breath increased pneumonitis risk (HR, 2.51; 95% CI, 1.13-5.55). Female sex (HR, 0.33; 95% CI, 0.15-0.70) and increasing platelet count (HR, 0.52 per log-unit increase; 95% CI, 0.30-0.92) decreased pneumonitis risk. In adjusted models, ICI-related pneumonitis significantly increased mortality (HR, 2.84; 95% CI, 1.84-4.37)., Conclusions: ICI-related pneumonitis occurs at a high rate in AML patients and increases mortality., Lay Summary: Immune checkpoint inhibitors (ICIs) remove inhibitory signals that reduce T-cell function and allow T-cells to better attack cancer cells. In acute myeloid leukemia (AML), the effectiveness of ICIs is limited in part by inflammation of the lung, called pneumonitis. This study reviewed 258 patients with AML who received ICIs and identified 30 patients who developed pneumonitis, nearly half of whom died. Older age and baseline shortness of breath increased pneumonitis risk, whereas female sex and higher baseline platelet counts decreased pneumonitis risk. Pneumonitis increased mortality by nearly 3-fold. This work highlights the significant harm imposed by pneumonitis after ICI therapies., (© 2022 American Cancer Society.)

Non-small-cell lung cancer (NSCLC) is frequently diagnosed when it is not amenable to local therapies; therefore, systemic agents are the mainstay of therapy for many patients. In recent years, treatment of advanced NSCLC has evolved from a general approach primarily involving chemotherapy to a more personalised strategy in which biomarkers such as the presence of genomic tumour aberrations and the expression of immune proteins such as programmed death-ligand 1 (PD-L1), in combination with other elements of clinical information such as histology and clinical stage, guide management. For instance, pathways resulting in uncontrolled growth and proliferation of tumour cells due to epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements may be targeted by tyrosine kinase inhibitors (TKIs). In this article, we review the current state of medical oncology, imaging characteristics of mutations, pitfalls in response assessments and the imaging of complications., (Copyright © 2021. Published by Elsevier Ltd.)

Radiation therapy using conventional fractionated external-beam or high-precision dose techniques including three-dimensional conformal radiotherapy, stereotactic body radiation therapy, intensity-modulated radiation therapy, and proton therapy, is a key component in the treatment of patients with lung cancer. Knowledge of the radiation technique used, radiation treatment plan, expected temporal evolution of radiation-induced lung injury and patient-specific parameters, such as previous radiotherapy, concurrent chemoradiotherapy, and/or immunotherapy, is important in imaging interpretation. This review discusses factors that affect the development and severity of radiation-induced lung injury and its radiological manifestations with emphasis on the differences between conventional radiation and high-precision dose radiotherapy techniques., (Copyright © 2021 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)