Successful salvage of a severe COVID-19 patient previously with lung cancer and radiation pneumonitis by mesenchymal stem cells: a case report and literature review.

During the COVID-19 pandemic, elderly patients with underlying condition, such as tumors, had poor prognoses after progressing to severe pneumonia and often had poor response to standard treatment. Mesenchymal stem cells (MSCs) may be a promising treatment for patients with severe pneumonia, but MSCs are rarely used for patients with carcinoma. Here, we reported a 67-year-old female patient with lung adenocarcinoma who underwent osimertinib and radiotherapy and suffered from radiation pneumonitis. Unfortunately, she contracted COVID-19 and that rapidly progressed to severe pneumonia. She responded poorly to frontline treatment and was in danger. Subsequently, she received a salvage treatment with four doses of MSCs, and her symptoms surprisingly improved quickly. After a lung CT scan that presented with a significantly improved infection, she was discharged eventually. Her primary disease was stable after 6 months of follow-up, and no tumor recurrence or progression was observed. MSCs may be an effective treatment for hyperactive inflammation due to their ability related to immunomodulation and tissue repair. Our case suggests a potential value of MSCs for severe pneumonia that is unresponsive to conventional therapy after a COVID-19 infection. However, unless the situation is urgent, it needs to be considered with caution for patients with tumors. The safety in tumor patients still needs to be observed.

Liposome-anchored mesenchymal stem cells for radiation pneumonia/fibrosis treatment.

The effectiveness of mesenchymal stem cells (MSCs) on inflammation-related disease is limited and the pharmaceutical preparation that was used to enhance the efficacy of MSCs cannot reach the diseased tissue in large quantities. Herein, antioxidant liposome (Lipo-OPC) is designed to anchor onto the surface of MSCs membrane via click chemical reaction (MSC-Lipo-OPC) without affecting the viability and physiological characteristics of MSCs, thus allowing efficient accumulation of MSC-Lipo-OPC in X-ray irradiated lung sites. More importantly, MSC-Lipo-OPC promotes the change of the quantity and polarity of innate immunocytes, mainly including neutrophils, macrophages and Tregs, in favor of anti-inflammatory, finally preventing the formation of radioactive pulmonary fibrosis. Therefore, it could enhance the treatment outcome of both of MSCs and drugs to radiation-induced lung injury via modifying the drug-loaded nanoparticle on the surface of MSCs membrane, further promoting the application of MSCs in radiation damage and protection.

Network pharmacology-based strategy to investigate the active ingredients and molecular mechanisms of Scutellaria Barbata D. Don against radiation pneumonitis.

INTRODUCTION: Herbal medicines combined with radiotherapy significantly reduced the incidence of radiation pneumonitis (RP), and the Scutellaria barbata D. Don (SBD) is a perennial herb that has been reported to protect against radiation-induced pneumonitis. However, the exact molecular mechanism is not known. The objective of this research was to investigate the against radiation pneumonitis ingredients and their functional mechanisms in SBD. METHODS: Based on the network pharmacology approaches, we collected active ingredients and target genes in SBD against RP through Traditional Chinese Medicine System Pharmacology (TCMSP) Database, and the "Herb-Ingredients-Target Genes-Disease" Network was constructed by using of Cytoscape. STRING analysis was performed to reveal the protein-protein interactions, and then we applied enrichment analysis on these target proteins, gene function, and pathways. RESULTS: A total of 18 ingredients in SBD regulate 65 RP related target proteins, which show that quercetin, luteolin, baicalein, wogonin may be the key active ingredients, while IL6, AKT1, VEGFA, MMP9, CCL2, prostaglandin-endoperoxide synthase 2 (PTGS2) (cyclooxygenase-2 [COX-2]), CXCL8, IL1B, mitogen-activated protein kinase (MAPK1), and IL10 were identified as critical targets. Besides, the results of Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis indicated that predicted targets of SBD are mostly associated with the pathological process of oxidative stress and inflammation. AGE- Receptor of Advanced Glycation Endproducts (RAGE) signaling pathway in diabetic complications, IL-17 signaling pathway, hypoxia-inducible factor-1 (HIF-1) signaling pathway, NF-kappa B signaling pathway might serve as the principal pathways for RP treatment. CONCLUSION: In our study, the pharmacological and molecular mechanism of SBD against RP was predicted from a holistic perspective, and the results provided theoretical guidance for researchers to explore the mechanism in further research.

Urgent lung transplantation for thymic neoplasm-associated severe constrictive bronchiolitis with bronchiectasis and radiotherapy-induced organizing pneumonia: A case report.

Here, we present the case of a 28-year-old woman who developed severe and progressive thymoma-associated constrictive bronchiolitis with bronchiectasis, despite undergoing thymectomy. The disease was further complicated by radiation-induced organizing pneumonia (RIOP), which developed after adjuvant radiotherapy (RT) for Masaoka stage II thymoma. The patient was successfully treated with an urgent lung transplantation (LTx) for irreversible respiratory failure.

Radiation-induced lung injury: current evidence.

Chemo-radiotherapy and systemic therapies have proven satisfactory outcomes as standard treatments for various thoracic malignancies; however, adverse pulmonary effects, like pneumonitis, can be life-threatening. Pneumonitis is caused by direct cytotoxic effect, oxidative stress, and immune-mediated injury. Radiotherapy Induced Lung Injury (RILI) encompasses two phases: an early phase known as Radiation Pneumonitis (RP), characterized by acute lung tissue inflammation as a result of exposure to radiation; and a late phase called Radiation Fibrosis (RF), a clinical syndrome that results from chronic pulmonary tissue damage. Currently, diagnoses are made by exclusion using clinical assessment and radiological findings. Pulmonary function tests have constituted a significant step in evaluating lung function status during radiotherapy and useful predictive tools to avoid complications or limit toxicity. Systemic corticosteroids are widely used to treat pneumonitis complications, but its use must be standardized, and consider in the prophylaxis setting given the fatal outcome of this adverse event. This review aims to discuss the clinicopathological features of pneumonitis and provide practical clinical recommendations for prevention, diagnosis, and management.

Radiation-induced lung toxicity - cellular and molecular mechanisms of pathogenesis, management, and literature review.

Lung, breast, and esophageal cancer represent three common malignancies with high incidence and mortality worldwide. The management of these tumors critically relies on radiotherapy as a major part of multi-modality care, and treatment-related toxicities, such as radiation-induced pneumonitis and/or lung fibrosis, are important dose limiting factors with direct impact on patient outcomes and quality of life. In this review, we summarize the current understanding of radiation-induced pneumonitis and pulmonary fibrosis, present predictive factors as well as recent diagnostic and therapeutic advances. Novel candidates for molecularly targeted approaches to prevent and/or treat radiation-induced pneumonitis and pulmonary fibrosis are discussed.

A Likely Role for a Novel Cell Therapeutic Target of Transforming Growth Factor-ß1 on Radiation Pneumonitis in Lung and Nasopharyngeal Cancer Patients.

The association between the polymorphism of transforming growth factor (TGF)-ß1 and risk of radiation pneumonitis has been extensively investigated; however, conclusive results were unavailable. Eligible studies were identified from the database of Medline, Web of Science, EMBASE, and CNKI (China Knowledge Resource Integrated Database) up to September 2019. The odds ratio (OR) and 95% confidence interval (95% CI) were used to assess the strength of the relationship. The results showed that there were associations between TGF 869 T/C (rs1982073) and risks of radiation pneumonitis. Subgroup analyses showed that TGF 869 T/C was associated with risk of radiation pneumonitis in Caucasians (OR [95% CI]: 0.45 [0.31 to 0.67] for C carriers vs. TT). In addition, subgroup analyses also suggested that the C allele was associated with decreased risks of radiation pneumonitis among hospital-based case-control studies (0.56 [0.39 to 0.82] for C carriers vs. TT). Meanwhile, C allele was also suggested to be associated with decreased risk of radiation pneumonitis among PCC (0.60 [0.38 to 0.96] for C carriers vs. TT). Especially, C allele was also found to be associated with decreased risk of radiation pneumonitis from the participants with lung cancer (0.57 [0.37 to 0.90] for C carriers vs. TT). Our meta-analysis shows that T allele in TGF 869 T/C is significantly associated with the increased risk of radiation pneumonitis, especially for Caucasians, and for the participants with lung cancer.

Clinical Evaluation and Management of Cancer Survivors with Radiation Fibrosis Syndrome.

OBJECTIVES: To define radiation fibrosis and radiation fibrosis syndrome; review the basics of radiotherapy, the pathophysiology of radiation injury, and the principles of clinical evaluation and management of the common late effects resulting from radiation therapy for cancer treatment. DATA SOURCES: Peer-reviewed journal articles, book chapters, Internet. CONCLUSION: There is no cure for radiation fibrosis syndrome, but supportive treatment of its clinical sequelae can potentially result in improved function and quality of life. IMPLICATIONS FOR NURSING PRACTICE: The sequelae of radiation fibrosis syndrome can often be improved with early detection and supportive care by a multidisciplinary team including cancer rehabilitation physiatrists, oncologists, oncology nurses, nurse practitioners, physical therapists, occupational therapists, and speech and language pathologists.

Radiation-Induced Lung Injury: Assessment and Management.

Radiation-induced lung injury (RILI) encompasses any lung toxicity induced by radiation therapy (RT) and manifests acutely as radiation pneumonitis and chronically as radiation pulmonary fibrosis. Because most patients with thoracic and breast malignancies are expected to undergo RT in their lifetime, many with curative intent, the population at risk is significant. Furthermore, indications for thoracic RT are expanding given the advent of stereotactic body radiation therapy (SBRT) or stereotactic ablative radiotherapy (SABR) for early-stage lung cancer in nonsurgical candidates as well as oligometastatic pulmonary disease from any solid tumor. Fortunately, the incidence of serious pulmonary complications from RT has decreased secondary to advances in radiation delivery techniques. Understanding the temporal relationship between RT and injury as well as the patient, disease, and radiation factors that help distinguish RILI from other etiologies is necessary to prevent misdiagnosis. Although treatment of acute pneumonitis is dependent on clinical severity and typically responds completely to corticosteroids, accurately diagnosing and identifying patients who may progress to fibrosis is challenging. Current research advances include high-precision radiation techniques, an improved understanding of the molecular basis of RILI, the development of small and large animal models, and the identification of candidate drugs for prevention and treatment.

Thoracic Radiation Normal Tissue Injury.

Thoracic malignancies are often a difficult group of tumors to treat definitively as the radiation doses needed to achieve a high probability for tumor control are often associated with high rates of radiation-induced toxicities. The lungs are particularly radiosensitive and are susceptible to radiation pneumonitis in the acute and subacute settings and pulmonary fibrosis in the late setting. Acute esophagitis is common and affects patient quality of life. Beyond acute pericarditis, late cardiac toxicities are increasingly being recognized as clinically relevant when delivering thoracic radiotherapy and can affect overall survival. This review details the common and dose-limiting acute and late toxicities associated with thoracic radiation therapy. As radiation-induced toxicities are often amplified with concurrent chemotherapy, this article focuses on the toxicities associated with irradiation for lung cancer, the most common thoracic malignancy, which is often treated with multimodality therapy. The management of radiation-induced toxicities and the changing patterns of toxicities with advanced radiation delivery modalities are also described.

[Medical prevention and treatment of radiation-induced pulmonary complications]. / Prévention médicale et traitement des complications pulmonaires secondaires à la radiothérapie.

Radiation-induced lung injuries mainly include the (acute or sub-acute) radiation pneumonitis, the lung fibrosis and the bronchiolitis obliterans organizing pneumonia (BOOP). The present review aims at describing the diagnostic process, the current physiopathological knowledge, and the available (non dosimetric) preventive and curative treatments. Radiation-induced lung injury is a diagnosis of exclusion, since clinical, radiological, or biological pathognomonic evidences do not exist. Investigations should necessarily include a thoracic high resolution CT-scan and lung function tests with a diffusing capacity of the lung for carbon monoxide. No treatment ever really showed efficacy to prevent acute radiation-induced lung injury, or to treat radiation-induced lung fibrosis. The most promising drugs in order to prevent radiation-induced lung injury are amifostine, angiotensin-converting-enzyme inhibitors and pentoxifylline. Inhibitors of collagen synthesis are currently tested at a pre-clinical stage to limit the radiation-induced lung fibrosis. Regarding available treatments of radiation-induced pneumonitis, corticoids can be considered the cornerstone. However, no standardized program or guidelines concerning the initial dose and the gradual tapering have been scientifically established. Alternative treatments can be prescribed, based on clinical cases reporting on the efficacy of immunosuppressive drugs. Such data highlight the major role of the lung dosimetric protection in order to efficiently prevent radiation-induced lung injury.

Radiation-Induced Fibrosis: Mechanisms and Opportunities to Mitigate. Report of an NCI Workshop, September 19, 2016.

A workshop entitled "Radiation-Induced Fibrosis: Mechanisms and Opportunities to Mitigate" (held in Rockville, MD, September 19, 2016) was organized by the Radiation Research Program and Radiation Oncology Branch of the Center for Cancer Research (CCR) of the National Cancer Institute (NCI), to identify critical research areas and directions that will advance the understanding of radiation-induced fibrosis (RIF) and accelerate the development of strategies to mitigate or treat it. Experts in radiation biology, radiation oncology and related fields met to identify and prioritize the key areas for future research and clinical translation. The consensus was that several known and newly identified targets can prevent or mitigate RIF in pre-clinical models. Further, basic and translational research and focused clinical trials are needed to identify optimal agents and strategies for therapeutic use. It was felt that optimally designed preclinical models are needed to better study biomarkers that predict for development of RIF, as well as to understand when effective therapies need to be initiated in relationship to manifestation of injury. Integrating appropriate endpoints and defining efficacy in clinical trials testing treatment of RIF were felt to be critical to demonstrating efficacy. The objective of this meeting report is to (a) highlight the significance of RIF in a global context, (b) summarize recent advances in our understanding of mechanisms of RIF,

Prevention and treatment of complications of selective internal radiation therapy: Expert guidance and systematic review.

Selective internal radiation therapy (or radioembolization) by intra-arterial injection of radioactive yttrium-90-loaded microspheres is increasingly used for the treatment of patients with liver metastases or primary liver cancer. The high-dose beta-radiation penetrates an average of only 2.5 mm from the source, thus limiting its effects to the site of delivery. However, the off-target diversion of yttrium-90 microspheres to tissues other than the tumor may lead to complications. The most prominent of these complications include radiation gastritis and gastrointestinal ulcers, cholecystitis, radiation pneumonitis, and radioembolization-induced liver disease, which may occur despite careful pretreatment planning. Thus, selective internal radiation therapy demands an expert multidisciplinary team approach in order to provide comprehensive care for patients. This review provides recommendations to multidisciplinary teams on the optimal medical processes in order to ensure the safe delivery of selective internal radiation therapy. Based on the best available published evidence and expert opinion, we recommend the most appropriate strategies for the prevention, early diagnosis, and management of potential radiation injury to the liver and to other organs. (Hepatology 2017;66:969-982).

Risk Factors Associated With Symptomatic Radiation Pneumonitis After Stereotactic Body Radiation Therapy for Stage I Non-Small Cell Lung Cancer.

Radiation pneumonitis is the most frequent acute pulmonary toxicity following stereotactic body radiation therapy for lung cancer. Here, we investigate clinical and dosimetric factors associated with symptomatic radiation pneumonitis in patients with stage I non-small cell lung cancer treated with stereotactic body radiation therapy. A total of 67 patients with stage I non-small cell lung cancer who received stereotactic body radiation therapy at our institution were enrolled, and their clinicopathological parameters and dosimetric parameters were recorded and analyzed. The median follow-up period was 26.4 months (range: 7-48 months). In univariate analysis, tumor size ( P = .041), mean lung dose ( P = .028), V2.5 ( P = .024), V5 ( P = .014), V10 ( P = .004), V20 ( P = .024), V30 ( P = .020), V40 ( P = .040), and V50 ( P = 0.040) were associated with symptomatic radiation pneumonitis. In multivariable logistic regression analysis, V10 ( P = .049) was significantly associated with symptomatic radiation pneumonitis. In conclusion, this study found that tumor size, mean lung dose, and V2.5 to V50 were risk factors markedly associated with symptomatic radiation pneumonitis. Our data suggested that lung V10 was the most significant factor, and optimizing lung V10 may reduce the risk of symptomatic radiation pneumonitis. For both central and peripheral stage I lung cancer, rate of radiation pneumonitis ≥grade 2 was low after stereotactic body radiation therapy with appropriate fraction dose.

Pulmonary Complications of Childhood Cancer Treatment.

Pulmonary complications of childhood cancer treatment are frequently seen. These can lead to adverse sequelae many years after treatment, with important impact on morbidity, quality of life and mortality in childhood cancer survivors. This review addresses the effects of chemotherapy, radiotherapy, surgery and alloimmunity (in haematopoietic cell transplantation) on the lung in children. It highlights the complexity of lung damage and lung disease in relation to growth and development, infections and other external factors. Screening high risk childhood cancer survivors for treatment related late effects, with therapy based screening protocols, using full medical assessment and pulmonary function tests is important. This will lead to recognition of pulmonary sequelae of cancer treatment, early detection of lung damage in survivors and better treatment and prevention.

Radiation-induced morphea - a literature review.

Radiation-induced morphea (RIM) is a rare and under-recognized skin complication of radiotherapy. It is commonly wrongly diagnosed as other dermatological conditions or malignancy because of similar clinical characteristics. This literature review analyses 66 cases that have been reported in the literature since 1989. The clinical appearance often includes pain and disfiguration of affected area, which may influence the patient's quality of life. There is no clear connection between the radiotherapy dose, the fractionation scheme, the use of a boost, age, the presence of other dermatological conditions or other connective tissue diseases and the occurrence of RIM. Its pathogenesis is still unclear, but several theories are proposed to explain this phenomenon. The available data suggest that the abnormally high secretion of some cytokines (interleukin 4, interleukin 5, transforming growth factor) induced by radiation causes an extensive fibrosis after an activation of fibroblasts. Histological confirmation is crucial in distinguishing RIM from similar-looking diseases, such as chronic radiation dermatitis, cancer recurrence, radiation, recall dermatitis, new carcinoma or cellulitis. There is no clear treatment regimen for this condition. Clinical outcome after therapy is often unsatisfactory. The commonly used methods and agents include: topical and systemic steroids, calcineurin inhibitors, systemic immunosuppressants including methotrexate, tacrolimus, heparin, hyaluronidase, phototherapy (UVA, UVA1, UVB, PUVA), systemic antibiotics, imiquimod, mycophenolate mofetil, photophoresis. The differential diagnosis is challenging and requires a multidisciplinary approach to avoid misdiagnosis and to plan appropriate treatment.

[The effectiveness of magnetic therapy of grade I-II radiation pneumofibrosis].

Radiation therapy of malignant tumours of the chest organs may result in radiation damage of the lungs. To prevent and reduce radiation-induced lung injuries, new types of radiation therapy have been developed, a number of various modifiers investigated, the methods of pharmacotherapy and physiotherapy proposed. The present study involved 37 patients presenting with radiation pneumofibrosis, including 7 ones with lung cancer and 30 patients with breast cancer. Based on the results of clinical, radiographic, and functional investigations, grade 1 and II pneumofibrosis was diagnosed in 20 and 17 patients respectively. After the application of an alternating magnetic field during 15 days, all the patients experience the overall regression of clinical symptoms and disorders of respiratory biomechanics. However, it seems premature to draw a definitive conclusion about the effectiveness of magnetic therapy of grade 1 and II radiation pneumofibrosis before the extensive in-depth investigations are carried out based on a large clinical material including the results of long-term follow-up studies and continuous monitoring.

The interplay between radiation and the immune system in the field of post-radical pneumonitis and fibrosis and why it is important to understand it.

A discussion on the importance and pathogenesis of radiation-induced pneumonitis and fibrosis is provided, with a special focus on the role of the immune system. The need to understand this interaction is highlighted in view of emerging therapeutic potential.

Management of normal tissue toxicity associated with chemoradiation (primary skin, esophagus, and lung).

Nearly one quarter of patients with lung cancer present with locally advanced disease where concurrent chemoradiotherapy is the current standard of care for patients with good performance status. Cisplatin-based concurrent chemoradiotherapy consistently showed an improvement in survival compared with sequential chemoradiotherapy, at the expense of an increase in the toxicity profile. Over the past decades, several encouraging biomarkers such as transforming growth factor-beta and radioprotective agents such as amifostine were studied but without reaching approval for patient care. We reviewed the prevalence and risk factors for different adverse effects associated with the combined chemoradiotherapy modality, especially dermatitis, mucositis, esophagitis, and pneumonitis. These adverse effects can further be divided into acute, subacute, and chronic. Dermatitis is usually rare and responds well to topical steroids and usual skin care. Acute esophagitis occurs in 30% of patients and is treated with proton pump inhibitors, promotility agents, local anesthetic, and dietary changes. Radiation pneumonitis is a subacute complication seen in 15% of patients and is usually managed with steroids. Chronic adverse effects such as radiation fibrosis and esophageal stricture occur approximately 6 months after completion of radiation therapy and are usually permanent. In this review, complications of chemoradiotherapy for patients with locally advanced lung cancer are delineated, and approaches to their management are described. Given that treatment interruption is associated with a worse outcome, patients are aggressively treated with a curative intent. Therefore, planning for treatment adverse effects improves patient tolerance, compliance, and outcome.