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Coronaviruses are closely related virus causing several types of respiratory tract infections ranging from common cold to more severe diseases such as Middle East Respiratory Syndrome (MERS) and severe acute respiratory syndrome (SARS). There are many other ways in which Covid-19 will impact the existing public health issues. With the rising number of covid19 cases, it has been reported that people with the weaker immune system are at higher risk. We identified the mechanism of action of cyclophosphamide and its impact on the lung. Pulmonary side effects associated with cyclophosphamide are rare and dose-related. They manifest as early-onset pneumonitis, in patients with symptoms especially like cough and dyspnea. Acrolein in cyclophosphamide is the main component linked with the toxic effect. We hypothesize that use of cyclophosphamide, an antineoplastic agent and immunosuppressive agent used in treating many cancers and autoimmune disorders (like rheumatoid arthritis and ANCA vasculitis), induces severe lung toxicity which can be one of the contributing factors for the increased risk of COVID 19 complication. These factors are to be recognized to improve prevention and control of the disease.

Intratracheal instillation is the introduction of a substance directly into the trachea. Intratracheal instillation has been used to investigate the lung toxicity of several chemicals and requires the suspension or dissolution of test material in a vehicle for even dispersal throughout the lung. Importantly, the toxicities of vehicles used in intratracheal instillation studies are generally considered to be insignificant. Hence, evaluating the influence of different vehicles on the lung due to intratracheal instillation is crucial. We examined the toxic effects of pure water, saline, phosphate buffered saline (PBS), 0.5% Kolliphor® P188 (KP188), 0.1% Tween 20 in saline, and 1.0% BSA in PBS. These vehicles were administered to male Crl:CD(SD) rats by a single intratracheal instillation. On day 3, broncho-alveolar lavage fluid (BALF) from the right lung was collected and processed for cell counting and biochemical analysis, while the left lung was used for histopathological examination. Accumulation of alveolar macrophages was observed in all vehicle-treated groups but was minimal in the group administered saline, somewhat higher in the groups administered pure water, PBS, 0.1% Tween 20, and 1% BSA, and notably higher in the group administered 0.5% KP188. The results from BALF analysis indicated that intratracheal instillation of 0.5% KP188 also induced alveolar damage. Additionally, administering pure water did not appear to cause tissue damage. Eosinophil infiltration in the interstitial regions was histopathologically observed. Altogether, the results of this study are helpful for the selection of appropriate vehicles for use in intratracheal instillation studies.

Simple Summary Total body irradiation is an integral part of many conditioning regimens prior to allogeneic stem cell transplantation. It is a large-field technique affecting all organs at risk, of which the lungs are critical for patient survival. However, the precise rates of long-term pulmonary toxicities are unknown. This analysis provides a large patient cohort with long-term follow-up investigating TBI sequelae. Additionally, we present normal tissue complication probability calculations for acute and chronic lung toxicities to enable comparison between biophysical and real-world data. To our knowledge, this is the first adaption of this model to a total-body irradiation patient cohort, which will help to evaluate the feasibility and appropriateness of this approach. Abstract Total body irradiation (TBI) is an essential part of various conditioning regimens prior to allogeneic stem cell transplantation, but is accompanied by relevant (long-term) toxicities. In the lungs, a complex mechanism induces initial inflammation (pneumonitis) followed by chronic fibrosis. The hereby presented analysis investigates the occurrence of pulmonary toxicity in a large patient collective and correlates it with data derived from normal tissue complication probability (NTCP) calculations. The clinical data of 335 hemato-oncological patients undergoing TBI were analyzed with a follow-up of 85 months. Overall, 24.8% of all patients displayed lung toxicities, predominantly pneumonia and pulmonary obstructions (13.4% and 6.0%, respectively). NTCP calculations estimated median risks to be 20.3%, 0.6% and 20.4% for overall pneumonitis (both radiological and clinical), symptomatic pneumonitis and lung fibrosis, respectively. These numbers are consistent with real-world data from the literature and further specify radiological and clinical apparent toxicity rates. Overall, the estimated risk for clinical apparent pneumonitis is very low, corresponding to the probability of non-infectious acute respiratory distress syndrome, although the underlying pathophysiology is not identical. Radiological pneumonitis and lung fibrosis are expected to be more common but require a more precise documentation by the transplantation team, radiologists and radiation oncologists.

Nitrofurantoin is a synthetic derivative of imidazolinedione, used to treat uncomplicated urinary tract infections. It acts by inhibiting bacterial DNA, RNA and cell wall protein synthesis. It is used prophylactically as a urinary anti-infective agent against most gram-positive organism and for long-term suppression of infections. Nitrofurantoin-associated pulmonary injuries occur in 1% of patients, presenting with dyspnoea and dry cough, and it can mimic interstitial lung disease. We present a case of an 81-year-old woman with shortness of breath and cough 3 days after initiation of nitrofurantoin. CT of the chest revealed bilateral pleural effusion and extensive pulmonary interstitial prominence, suggesting pulmonary fibrosis. According to the Naranjo Adverse Drug Reaction Probability Scale score of 6, it was determined that nitrofurantoin was the probable cause, and immediate cessation of the medication showed a marked clinical improvement and resolution after 10 days.

Simple Summary Interstitial lung disease is a group of diseases characterized by chronic lung inflammation that can be related to oncological treatments, such as traditional chemotherapy drugs and the newest targeted therapies and immunotherapies. Awareness about this potentially fatal adverse event is paramount in patient management and to make a conscious therapeutic choice. It represents a differential diagnostic challenge, especially in the context of the COVID-19 pandemic. Our aim is to describe the incidence and characteristics of this adverse event across oncological treatment groups and to promote greater knowledge about this important toxicity. Abstract Interstitial lung disease is recognized as a group of diseases with a different etiopathogenesis characterized by chronic lung inflammation with the accumulation of inflammatory cells, lymphocytes and macrophages, and the consequent release of proinflammatory cytokines. Various degrees of pulmonary fibrosis can be associated with this inflammatory condition. Interstitial lung disease related to oncological drugs is a relevant problem in clinical practice. The etiopathogenetic mechanisms underlying this adverse event are not completely known but can be partly explained by the mechanism of action of the drug involved. Therefore, knowledge of the relevance of this potentially fatal adverse event supported by the reported safety data of pivotal studies becomes fundamental in the management of patients. The prompt diagnosis of drug-related pneumonia and the consequent differential diagnosis with other forms of pneumonia allow a rapid suspension of treatment and the establishment of an immunosuppressive treatment if necessary. In the context of the health emergency related to SARS CoV2 infection and COVID-19-related interstitial lung disease, such knowledge holds decisive relevance in the conscious choice of cancer treatments. Our intent was to describe the oncological drugs most correlated with this adverse event by reporting, where possible, the percentages of insurgency in pivotal studies to provide an overview and therefore promote greater awareness of this important toxicity related to oncological treatment.

Drug-induced interstitial lung disease (DILD) with an estimated incidence of approximately 4.1–12.4 cases/million/year is implicated in ~5% of ILD cases.1 Data vary by country, with DILD more commonly diagnosed in Japan, perhaps due to higher reporting.2 The Common Terminology Criteria for Adverse Events (CTCAE) scale3 (table 1) helps quantify severity and treatment includes cessation of the drug and, in more severe cases, corticosteroid use. At least 350 drugs have been implicated in causing lung toxicity, or pneumonitis, across a spectrum from mild radiological infiltrates to life-threatening respiratory failure.4 This heterogeneity of presentation and lack of diagnostic standards, with rechallenge to confirm toxicity rarely justified, makes DILD difficult to identify, even at individual patient level.4 The result is a heavy reliance on databases such as pneumotox5 that collate evidence from the literature, often case reports or small series, but with no large-scale assessment. View this table: Table 1 Common Terminology Criteria for Adverse Events (CTCAE), V.5.0 Jo et al 6 take a different approach using a large, nationally representative dataset of hospitalised patients in Japan to retrospectively identify patients that had developed DILD, severe enough to warrant corticosteroid therapy, after receiving a ‘risk drug’ from one of 42 categories associated with lung toxicity. We applaud the methodology used in this study which identified 2342 cases of DILD out of ~42 million hospital admissions (0.0056%). For each case the authors selected four controls matched for known DILD risk factors (primary diagnosis, …

Carbon fibers have excellent physicochemical and electrical properties. Vapor-grown carbon fibers are a type of carbon fibers that have a multi-walled carbon tube structure with a high aspect ratio. The representative vapor-grown carbon fiber, VGCFTM-H, is extremely strong and stable and has superior thermal and electrical conductivity. Because some high-aspect-ratio multi-walled carbon nanotubes (MWCNTs) have been reported to have toxic and carcinogenic effects in the lungs of rodents, we performed a 13-week lung toxicity study using VGCFTM-H in comparison with one of MWCNTs, MWNT-7, in rats. Male and female F344 rats were intratracheally administered VGCFTM-H at doses of 0.2, 0.4, and 0.8 mg/kg bw or MWNT-7 at doses of 0.4 and 0.8 mg/kg bw once a week for 8 weeks and then up to week 13 without treatment. The lung burden was equivalent in the VGCFTM-H and MWNT-7 groups; however, the lung weight had increased and the inflammatory and biochemical parameters in the broncho-alveolar lavage fluid and histopathological parameters, including inflammatory cell infiltration, alveolar type II cells proliferation, alveolar fibrosis, pleural fibrosis, lung mesothelium proliferation, and diaphragm fibrosis, were milder in the VGCFTM-H group than in the MWNT-7 group. In addition, the proliferating cell nuclear antigen (PCNA)-positive index in the visceral and pleural mesothelium was significantly higher in the MWNT-7 group than in the controls, but not in the VGCFTM-H group. Thus, the results of this study indicate that the lung and pleural toxicities of VGCFTM-H were less than those of MWNT-7.

Background Diagnosis of amiodarone lung toxicity on computerized tomography (CT) can be challenging especially in the presence of mass-like consolidation. Additional causes of mass-like consolidation including malignancy and pneumonia should be excluded, sometimes requiring tissue sampling. Case Here we present a case of amiodarone lung toxicity, with diagnosis suspected based on patient's history of chronic cardiac disease, amiodarone treatment, and imaging characteristics. Evaluation with dual energy CT demonstrated high iodine content in the mass-like consolidation further supporting the diagnosis. Biopsy of the mass-like consolidation confirmed amiodarone toxicity. Conclusion Dual energy CT has potential utility in differentiating mass-like consolidation from other etiologies such as malignancy or pneumonia.

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.

In view of the growing industrial use of Bacterial cellulose (BC), and taking into account that it might become airborne and be inhaled after industrial processing, assessing its potential pulmonary toxic effects assumes high relevance. In this work, the murine model was used to assess the effects of exposure to respirable BC nanofibrils (nBC), obtained by disintegration of BC produced by Komagataeibacter hansenii. Murine bone marrow-derived macrophages (BMM) were treated with different doses of nBC (0.02 and 0.2 mg/mL, respectively 1 and 10 g of fibrils) in absence or presence of 0.2% Carboxymethyl Cellulose (nBCMC). Furthermore, mice were instilled intratracheally with nBC or nBCMC at different concentrations and at different time-points and analyzed up to 6 months after treatments. Microcrystaline Avicel-plus® CM 2159, a plant-derived cellulose, was used for comparison. Markers of cellular damage (lactate dehydrogenase release and total protein) and oxidative stress (hydrogen peroxidase, reduced glutathione, lipid peroxidation and glutathione peroxidase activity) as well presence of inflammatory cells were evaluated in brochoalveolar lavage (BAL) fluids. Histological analysis of lungs, heart and liver tissues was also performed. BAL analysis showed that exposure to nBCMC or CMC did not induce major alterations in the assessed markers of cell damage, oxidative stress or inflammatory cell numbers in BAL fluid over time, even following cumulative treatments. Avicel-plus® CM 2159 significantly increased LDH release, detected 3 months after 4 weekly administrations. However, histological results revealed a chronic inflammatory response and tissue alterations, being hypertrophy of pulmonary arteries (observed 3 months after nBCMC treatment) of particular concern. These histological alterations remained after 6 months in animals treated with nBC, possibly due to foreign body reaction and the organisms inability to remove the fibers. Overall, despite being a safe and biocompatible biomaterial, BC-derived nanofibrils inhalation may lead to lung pathology and pose significant health risks., The authors acknowledge Embrapa Tropical Agroindustry and Coordination for the Improvement of Higher Education Personnel (CAPES) and the project under the bilateral program FCT/CAPES: Bacterial Cellulose: a platform for the development of bionanoproducts for funding this research. This work was also financially supported by: European Investment Funds by FEDER/COMPETE/POCI - Operational Competitiveness and Internationalization Program, under Project POCI-01-0145-FEDER-006958, National Funds by FCT - Portuguese Foundation for Science and Technology, Project POCI-01-0145-FEDER-006939 (Laboratory for Process Engineering, Environment, Biotechnology and Energy - LEPABE funded by FEDER, funds through COMPETE2020 - Programa Operacional Competitividade e Internacionalização (POCI) - and by national funds through FCT. Rui Gil da Costa is supported by grant nº SFRH/BPD/85462/2012 from FCT, financed by the Portuguese Government and the Social European Fund. This study was supported by the Portuguese Foundation for Science and Technology (FCT) also under the scope of the strategic funding of UID/BIO/04469/2013 unit and COMPETE 2020 (POCI-01-0145-FEDER-006684) and BioTecNorte operation (NORTE-01-0145-FEDER-000004) funded by the European Regional Development Fund under the scope of Norte2020 - Programa Operacional Regional do Norte., info:eu-repo/semantics/publishedVersion

Purpose: To investigate the cardio-pulmonary doses between Deep Inspiration Breath Hold (DIBH) and Free Breathing (FB) technique in left sided breast irradiation. Materials & Methods: DIBH CT and FB CT were acquired for 10 left sided breast patients who underwent whole breast irradiation with or without nodal irradiation. Three fields single isocenter technique were used for patients with node positive patients along with two tangential conformal fields whereas only two tangential fields were used in node negative patients. All the critical structures like lungs, heart, esophagus, thyroid, etc., were delineated in both DIBH and FB scan. Both DIBH and FB scans were fused with the Dicom origin as they were acquired with the same Dicom coordinates. Plans were created in the DIBH scan for a dose range between 50 Gy in 25 fractions. Critical structures doses were recorded from the Dose Volume Histogram for both the DIBH and FB data set for evaluation. Results: The average mean heart dose in DIBH vs FB was 13.18 Gy vs 6.97 Gy, (p = 0.0063) significantly with DIBH as compared to FB technique. The relative reduction in average mean heart dose was 47.12%. The relative V5 reduced by 14.70% (i.e. 34.42% vs 19.72%, p = 0.0080), V10 reduced by 13.83% (i.e. 27.79 % vs 13.96%, p = 0.0073). V20 reduced by 13.19% (i.e. 24.54 % vs 11.35%, p = 0.0069), V30 reduced by 12.38% (i.e. 22.27 % vs 9.89 %, p = 0.0073) significantly with DIBH as compared to FB. The average mean left lung dose reduced marginally by 1.43 Gy (13.73 Gy vs 12.30 Gy, p = 0.4599) but insignificantly with DIBH as compared to FB. Other left lung parameters (V5, V10, V20 and V30) shows marginal decreases in DIBH plans compare to FB plans. Conclusion: DIBH shows a substantial reduction of cardiac doses but slight and insignificant reduction of pulmonary doses as compared with FB technique. Using the simple DIBH technique, we can effectively reduce the cardiac morbidity and at the same time radiation induced lung pneumonitis is unlikely to increase.

Background Bleomycin-induced lung injury, a major complication of chemotherapy for germ cell tumors, occasionally fails to respond to the standard treatment with corticosteroids and develops into severe respiratory insufficiency. Little is known about salvage treatment for refractory cases. Case presentation A 63-year-old man who had been diagnosed with stage I seminoma and undergone a high orchiectomy 1 year previously developed swelling of his left iliac lymph node and was diagnosed with a recurrence of the seminoma. He was administered a standard chemotherapy regimen of cisplatin, etoposide, and bleomycin. At the end of second cycle, he developed a dry cough and fever that was accompanied by newly-identified bilateral infiltrates on chest X-ray. Despite initiation of oral prednisolone, his exertional dyspnea and decline in pulmonary functions continued to be aggravated. High-dose pulse treatment with methylprednisolone was introduced and improved his symptoms and radiologic findings. However, the maintenance dose of oral prednisolone allowed reactivation of the disease with evidence of newly-developed bilateral lung opacities on high-resolution CT scans. Considering his glucose intolerance and cataracts as complications of corticosteroid treatment, administration of pirfenidone was initiated with the patient’s consent. Pirfenidone at 1800 mg/day was well tolerated, and resolved his symptoms and abnormal opacities on a chest CT scan. Subsequently, the dose of prednisolone was gradually tapered without worsening of the disease. At the most recent follow-up, he was still in complete remission of seminoma with a successfully tapered combination dose of prednisolone and pirfenidone. Conclusions Pirfenidone, a novel oral agent with anti-inflammatory and -fibrotic properties, should be considered as a salvage drug for refractory cases of bleomycin-induced lung injury. Electronic supplementary material The online version of this article (doi:10.1186/s12885-017-3521-0) contains supplementary material, which is available to authorized users.

Immune checkpoint inhibitors (ICIs) have been a breakthrough in medical oncology. However, many patients experience a novel type of adverse drug reaction that has a unique clinical presentation, called immune-related adverse events (irAEs). A breakdown of self-tolerance and an exaggerated autoimmune reaction by the host are assumed to be the underlying mechanisms. Therefore, special attention to the optimal diagnosis and management is required. Among the various effects of irAE, pneumonitis has been recognized as an important manifestation because of its high morbidity and mortality. As the application of ICIs is expanding to a wider variety of tumor types, as well as its use with cytotoxic agents and radiation, clinicians are highly likely to encounter this complication. In this review, we will summarize the current understanding of the underlying mechanisms, incidence, risk factors, optimal diagnostic workup, and management of ICI-related pneumonitis (IRP). We will also review fundamental information on drug-induced lung toxicity in the oncology setting. In addition, research perspectives focused on better risk stratification and management to avoid serious complications in the future are presented.

It is reported inflammatory cytokine interleukin-8 (IL-8) could predict radiation-induced lung toxicity (RILT). RILT is believed to be a consequence of a cascade of cytokine production. It is considered that vascular endothelial cell and macrophages are the mainly source of cytokines. This study was investigated the production of IL-8 from cancer cells induced by X-rays may involve in the radiation-induced inflammation.We analyzed IL-8 in human lung cancer cell lines after expose to X-rays, and we also detect IL-8 in HUVEC cells and THP1 cells as endothelial cell and macrophage model to identify the change in normal cells after expose. Furthermore, we added the inhibitors to the culture with or without radiation to identify the role of MAPK and NF-κB pathways on the radiation-induced secretion of IL-8.Radiation could induce IL-8 production both in non-lung cancer cells (HUVECs and THP1 cells) and in lung cancer cells (A549 cells, H446 cells, PC-9 cells). Simultaneously, radiation activated p38/MAPK and NF-X-rays could induce IL-8 production in lung cancer cells, which may be related to the activation of p38/MAPK and NF-κB signaling pathway, providing a new point for elucidating the mechanism of radiation pneumonitis.

Lead (Pb) is recognized as the first heavy metal of the top six toxic air pollutants threatening human health and the second hazardous substance. Pb exposure is associated with lung impairment and high incidences of lung cancer. Nuclear factor kappa B (NF-κB) and aryl hydrocarbon receptor (AhR) signaling pathways are known to be expressed and play an important role in the lung. However, the link between Pb lung toxicity and NF-κB and/or AhR pathways remains unclear. This study was established to explore the role of NF-κB and AhR modulation in Pb-induced lung toxicity in human lung cancer A549 cells. In the current study, treatment of A549 cells with Pb significantly induced cell apoptosis as evidenced by increasing a) the percentage of cells underwent apoptosis determined by flow cytometry and b) p53 mRNA level. Pb treatment induced oxidative stress by a) increasing the formation of reactive oxygen species and b) decreasing GSTA1 mRNA levels. The toxic effects of Pb on the lung was associated with significant increases in NF-κB and AhR levels which was accompanied with increases in downstream targets genes, iNOS and CYP1A1, respectively. Inhibition of NF-κB or AhR either chemically using resveratrol or genetically using small interfering RNA (siRNA) significantly rescued A549 cells from Pb-mediated lung toxicity. The results clearly indicate that Pb-mediated lung toxicities are NF-κB and AhR-dependent mechanism. King Abdulaziz City for Science and Technology KACST Qatar National Library QNL

Millions of workers in the US and worldwide are exposed to complex, metal-rich welding fumes. Although welding is a crucial industrial process, the generated fumes are known to cause acute and chronic health effects when inhaled. The International Agency for Research on Cancer (IARC) classified welding fumes as carcinogenic to humans (Group 1) in 2017, based on sufficient epidemiological evidence and limited evidence in animals, an upgrade from the former Group 2B (possibly carcinogenic to humans) classification. There is human evidence that both iron-abundant mild steel as well as chromium- and nickel-containing stainless steel welding fumes contribute to an increased risk of lung cancer. Recent animal studies show that welding fumes may act as lung tumor promoters, regardless of the presence or absence of potentially carcinogenic metals, such as chromium and nickel. The goal of this manuscript was to examine the pulmonary responses associated with welding fumes by reviewing a series of recent experimental animal studies that assessed the influence of welding fume metal composition (e.g., stainless steel versus mild steel welding fume) on markers of lung toxicity and tumor development. Additional in vivo laboratory studies are needed to further explore the association between welding and lung cancer and to help advance our understanding of a potential mechanistic link.

Nitrofurantoin is an antimicrobial agent commonly used for urinary tract infections. This drug may cause pulmonary toxicities, the manifestations of which range from acute self-limiting reactions to chronic pathologies. Here, we report the case of a 72-year-old male who was admitted with progressive cough and dyspnea for 4 months. On physical examination, his respiratory rate was 26/min and oxygen saturation was 84% at rest while breathing room air. Chest examination revealed bilaterally fine crackles. His thorax computed tomography showed bilateral widespread ground-glass opacities and interlobular and intralobular septal thickening. His blood test revealed antinuclear antibody positivity. He had been using nitrofurantoin for a long time for urinary tract infection. He had a high score on Naranjo Adverse Drug Reaction Probability Scale. When he was a diagnosed, he had a respiratory failure due to lung damage. Patients using nitrofurantoin should be followed up closely for drug toxicity.

Computational modeling together with experimental data are essential to assess the risk for particulate matter mediated lung toxicity and to predict the efficacy, safety and fate of aerosolized drug molecules used in inhalation therapy. In silico models are widely used to understand the deposition, distribution, and clearance of inhaled particles and aerosols in the human lung. Exacerbations of chronic obstructive pulmonary disease (COPD) have been reported due to increased particulate matter related air pollution episodes. Considering the profound functional, anatomical and structural changes occurring in COPD lungs, the relevance of the existing in silico models for mimicking diseased lungs warrants reevaluation. Currently available computational modeling tools were developed for the healthy adult (male) lung. Here, we analyze the major alterations occurring in the airway structure, anatomy and pulmonary function in the COPD lung, as compared to the healthy lung. We also scrutinize the various physiological and particle characteristics that influence particle deposition, distribution and clearance in the lung. The aim of this review is to evaluate the availability of the fundamental knowledge and data required for modeling particle deposition in a COPD lung departing from the existing healthy lung models. The extent to which COPD pathophysiology may affect aerosol deposition depends on the relative contribution of several factors such as altered lung structure and function, bronchoconstriction, emphysema, loss of elastic recoil, altered breathing pattern and altered liquid volumes that warrant consideration while developing physiologically relevant in silico models.

To evaluate acute and late skin/subcutaneous toxicities and radiation-induced lung fibrosis (RILF) in patients treated with adjuvant radiotherapy (RT) for synchronous bilateral breast cancers (SBBC), after conservative surgery. Twenty-five patients were treated with volumetric-modulated arc therapy (VMAT/RapidArc®) on both breasts, and checked clinically for detecting RT toxicities during and after treatment. A high-resolution computed tomography (HRCT) was performed, for detecting RILF during follow-up. We registered acute Grade-1 skin toxicity in 18 patients (72%), while six patients (24%) experienced Grade-2 toxicity. No breath symptoms were reported during and after RT. Late Grade-1 subcutaneous toxicity and late Grade-2 skin toxicity were registered in four patients (16%) and one patient (4%), respectively, at a mean follow-up of 36 months. Grade-1 RILF was detected in six patients (30%). The median volume of fibrosis area was 6.5 cc (range 1.3–21.5 cc). The partial volumes receiving a specified dose (V20, V30, V40, and V50) in patients who developed lung fibrosis were significantly bigger than who did not (p

Bleomycin-induced interstitial lung disease is not a rare complication of treatment and may prove to be fatal if not suspected early in its course. As FDG PET-CT has become an essential clinical tool for interim and end-of-treatment response assessment in oncology, it is important that radiologists/nuclear medicine specialists be aware of the features of this potentially treatable condition so that treatment can be instigated during an early reversible phase before pulmonary damage has occurred. Herein, we report two cases of bleomycin toxicity featuring different patterns on the treatment-response assessment FDG PET-CT scan.

Pulmonary complications of bosutinib therapy and potential cross-intolerance with dasatinibhttp://ow.ly/UKWu303KGhx

Background: The increasing size and frequency of wildland fires are leading to greater potential for cardiopulmonary disease and cancer in exposed populations; however, little is known about how the types of fuel and combustion phases affect these adverse outcomes. Objectives: We evaluated the mutagenicity and lung toxicity of particulate matter (PM) from flaming vs. smoldering phases of five biomass fuels, and compared results by equal mass or emission factors (EFs) derived from amount of fuel consumed. Methods: A quartz-tube furnace coupled to a multistage cryotrap was employed to collect smoke condensate from flaming and smoldering combustion of red oak, peat, pine needles, pine, and eucalyptus. Samples were analyzed chemically and assessed for acute lung toxicity in mice and mutagenicity in Salmonella. Results: The average combustion efficiency was 73 and 98% for the smoldering and flaming phases, respectively. On an equal mass basis, PM from eucalyptus and peat burned under flaming conditions induced significant lung toxicity potencies (neutrophil/mass of PM) compared to smoldering PM, whereas high levels of mutagenicity potencies were observed for flaming pine and peat PM compared to smoldering PM. When effects were adjusted for EF, the smoldering eucalyptus PM had the highest lung toxicity EF (neutrophil/mass of fuel burned), whereas smoldering pine and pine needles had the highest mutagenicity EF. These latter values were approximately 5, 10, and 30 times greater than those reported for open burning of agricultural plastic, woodburning cookstoves, and some municipal waste combustors, respectively. Conclusions: PM from different fuels and combustion phases have appreciable differences in lung toxic and mutagenic potency, and on a mass basis, flaming samples are more active, whereas smoldering samples have greater effect when EFs are taken into account. Knowledge of the differential toxicity of biomass emissions will contribute to more accurate hazard assessment of biomass smoke exposures. https://doi.org/10.1289/EHP2200

Occupational exposure to indium tin oxide (ITO) particles has been associated with the development of severe lung diseases, including pulmonary alveolar proteinosis (PAP). The mechanisms of this lung toxicity remain unknown. Here, we reveal the respective roles of resident alveolar (Siglec-Fhigh AM) and recruited interstitial (Siglec-Flow IM) macrophages contributing in concert to the development of PAP. In mice treated with ITO particles, PAP is specifically associated with IL-1α (not GM-CSF) deficiency and Siglec-Fhigh AM (not Siglec-Flow IM) depletion. Mechanistically, ITO particles are preferentially phagocytosed and dissolved to soluble In3+ by Siglec-Flow IM. In contrast, Siglec-Fhigh AM weakly phagocytose or dissolve ITO particles, but are sensitive to released In3+ through the expression of the transferrin receptor-1 (TfR1). Blocking pulmonary Siglec-Flow IM recruitment in CCR2-deficient mice reduces ITO particle dissolution, In3+ release, Siglec-Fhigh AM depletion, and PAP formation. Restoration of IL-1-related Siglec-Fhigh AM also prevented ITO-induced PAP. We identified a new mechanism of secondary PAP development according to which metal ions released from inhaled particles by phagocytic IM disturb IL-1α-dependent AM self-maintenance and, in turn, alveolar clearance.

Purpose: To assess the association between dosimetric factors of the lung and incidence of intra- and postoperative mortality among esophageal cancer (EC) patients treated with neoadjuvant radiochemotherapy (N-RCT) followed by surgery (S). Methods and Materials: Inclusion criteria were: age < 85 years, no distant metastases at the time of diagnosis, no induction chemotherapy, conformal radiotherapy, total dose ≤ 50.4 Gy, and available dose volume histogram (DVH) data. One-hundred thirty-five patients met our inclusion criteria. Median age was 62 years. N-RCT consisted of 36 - 50.4 Gy (median 45 Gy), 1.8 - 2 Gy per fraction. Concomitant chemotherapy consisted of 5-Fluoruracil (5-FU) and cisplatin in 113 patients and cisplatin and taxan-derivates in 15 patients. Seven patients received a single cytotoxic agent. In 130 patients an abdominothoracal and in 5 patients a transhiatal resection was performed. The following dosimetric parameters were generated from the total lung DVH: mean dose, V5, V10, V15, V20, V30, V40, V45 and V50. The primary endpoint was the rate of intra- and postoperative mortality (from the start of N-RCT to 60 days after surgical resection). Results: A total of ten postoperative deaths (7%) were observed: 3 within 30 days (2%) and 7 between 30 and 60 days after surgical intervention (5%); no patient died during the operation. In the univariate analysis, weight loss (≥10% in 6 months prior to diagnosis, risk ratio: 1.60, 95%CI: 0.856-2.992, p=0.043), Eastern Cooperative Oncology Group-performance status (ECOG 2 vs. 1, risk ratio: 1.931, 95%CI: 0.898-4.150, p=0.018) and postoperative pulmonary plus non-pulmonary complications (risk ratio: 2.533, 95%CI: 0.978-6.563, p=0.004) were significantly associated with postoperative mortality. There was no significant association between postoperative mortality and irradiated lung volumes. Lung V45 was the only variable which was significantly associated with higher incidence of postoperative pulmonary plus non-pulmonary complications (Exp(B): 1.285, 95%CI 1.029-1.606, p=0.027), but not with the postoperative pulmonary complications (Exp(B): 1.249, 95%CI 0.999-1.561, p=0.051). Conclusions: Irradiated lung volumes did not show relevant associations with intra- and postoperative mortality of patients treated with moderate dose (36 - 50.4 Gy) conventionally fractionated conformal radiotherapy combined with widely used radiosensitizers. Postoperative mortality was significantly associated with greater weight loss, poor performance status and development of postoperative complications, but not with treatment-related factors. Limiting the volume of lung receiving higher radiation doses appears prudent because of the observed association with risk of postoperative complications.

PURPOSE: The aim of this study was to define the dose and dose-volume relationship of radiation induced pulmonary toxicities occurring in and out-of-field in mouse models of early inflammatory and late fibrotic response.MATERIALS AND METHODS: Early radiation induced inflammation and fibrosis were investigated in C3H/NeJ and C57BL/6J mice respectively. Animals were irradiated with 20 Gy delivered to the upper region of the right lung as a single fraction or as three consecutive fractions using the Small Animal Radiation Research Platform (SARRP, Xstrahl Inc., Camberley, UK). Cone Beam Computed Tomography (CBCT) was performed for image guidance prior to irradiation and to monitor late toxicity. Histological sections were examined for neutrophil and macrophage infiltration as markers of early inflammatory response, type I collagen staining as a marker of late occurring fibrosis. Correlation was evaluated with the Dose Volume Histogram (DVH) parameters calculated for individual mice and changes in the observed CBCT values.RESULTS: Mean Lung Dose (MLD) and the volume receiving over 10 Gy (V10) showed significant correlation with late responses for single and fractionated exposures in directly targeted volumes. Responses observed outside the target volume were attributed to non-targeted effects and showed no dependence on either MLD or V10.CONCLUSIONS: Quantitative assessment of normal tissue response closely correlates early and late pulmonary response with clinical parameters demonstrating this approach as a potential tool to facilitate clinical translation of preclinical studies. Out-of-field effects were observed but did not correlate with dosimetric parameters suggesting non-targeted effects may have a role in driving toxicities outside the treatment field.

Radiation-induced acute and chronic lung toxicity is one of the important adverse events that has a negative influence on quality of life. It is widely accepted today that there are important factors such as personal sensibility and genetic differences between patients which effect both treatment response and treatment toxicity. In this study, the influence of gender differences on acute lung toxicity due to radiotherapy is investigated. Accordingly, it is examined if there is a relation between gender and histopathologically proven vasculitis and pneumonia in the lung tissues of male and female rats that are sacrificed 6 weeks after radiotherapy. It is concluded that the gender differences in rats have no effect on lung toxicity.

Purpose Although the relationship between pulmonary emphysema (PE) and pneumonitis after radiotherapy has been investigated in recent years, it remain controversial [1] , [2] . The aim of this study was to retrospectively examine the role of PE on radiation-induced lung toxicity (RILT). The feasibility of a “functional treatment plan (FTP)”, designed to spare the functional volumes of the lungs (FLV), was also investigated. Methods 34 patients with NSCLC who underwent radiotherapy has been selected for this study. An expert radiologist analysed the first CT after-treatment and subdivided patients in two categories: RILT-1, 13 patients with no/low RILT; RILT-2, 21 patients with high RILT. Thresholds were applied on planning CT (before-treatment) to define PE (below −900 U) and FLV (between −899 and −500 HU). Through the Mann-Whitney test, RILT-1 and RILT-2 were compared in terms of PE volumes and of dosimetric parameters V5Gy and V20Gy of both total (DPTL) and functional lungs (DPFL). For patients who had considerable PE volumes, FTPs were developed based on VMAT technique. To selectively spare the FLV, arc sectors that involved parts of FLV were avoided and high-weight constraints for FLV were applied in the VMAT Optimizer. Results PE volume was significantly higher in RILT-1 than in RILT-2 (p Conclusions This study suggested that patients with emphysema were less subject to RILT. In addition, RILT was better associated with FLV exposure than total lung exposure. Therefore, a FTP would be desirable, but it’s limited to a small number of cases depending on PE amount and distribution.

We report a single institution experience with total lung irradiation in 53 metastatic bone sarcoma patients in the context of two young female patients who died from treatment-induced pulmonary toxicity. A radiation dose of 19.5Gy in 1.5Gy daily fractions was given as two opposing fields with a conventional technique. Both patients succumbed within 3 months following radiotherapy. One patient had osteosarcoma whereas the other advanced Ewing's sarcoma; both with widespread metastases to the lungs at primary diagnosis. In retrospect, most likely high dose methotrexate lung toxicity observed in the osteosarcoma patient, and the GI-toxicity following pelvic radiotherapy in Ewing's case, both observed during the initial phase of their multimodal treatment, might indicate an increased individual radiosensitivity.In view of this, a review of our experience in 53 bone sarcoma patients (19 with Ewing's sarcoma and 34 with osteosarcoma) treated at our institution was conducted. We have not previously experienced significant toxicity following total lung irradiation. Among these, 42% (8/19) with Ewing's sarcoma and 9% (3/34) with osteosarcoma are long-term survivors and without clinically significant lung toxicity.

Sirolimus-associated pneumonitis, a rare but serious drug-induced lung injury, has become a great concern clinically, because of the increasing use of sirolimus (rapamycin) in patients who have been subjected to solid organ transplantation. We report sirolimus-associated pneumonitis in two women who underwent renal transplantation. At variance with previous reports, the radiological findings shown on chest radiographs and computed tomography scans of the chest in these two cases were consolidation lesions mainly with minimal interstitial abnormalities. Our reported cases highlight that awareness of various radiological findings of sirolimus-associated pneumonitis is pivotal for physicians to make early diagnosis of the disorder in patients who have undergone solid organ transplantation.

Zinc oxide (ZnO) is known to induce lung toxicity, including terminal bronchiolar epithelial hyperplasia, which gives rise to concerns that nanosized ZnO (nZnO) might lead to lung carcinogenesis. We studied the tumor promoting activity of nZnO by an initiation–promotion protocol using human c-Ha-ras proto-oncogene transgenic rats (Hras128 rats). The rats were given 0.2 % N-nitrosobis(2-hydroxypropyl)amine (DHPN) in the drinking water for 2 weeks and then treated with 0.5 ml of 250 or 500 μg/ml nZnO suspension by intra-pulmonary spraying once every 2 weeks for a total of 7 times. Treatment with nZnO particles did not promote DHPN-induced lung carcinogenesis. However, nZnO dose-dependently caused epithelial hyperplasia of terminal bronchioles (EHTB) and fibrosis-associated interstitial pneumonitis (FAIP) that were independent of DHPN treatment. Tracing the fate of EHTB lesions in wild-type rats indicated that the hyperplastic lesions almost completely disappeared within 12 weeks after the last nZnO treatment. Since nZnO particles were not found in the lung and ZnCl2 solution induced similar lung lesions and gene expression profiles, the observed lesions were most likely caused by dissolved Zn2+. In summary, nZnO did not promote carcinogenesis in the lung and induced EHTB and FAIP lesions that regressed rapidly, probably due to clearance of surplus Zn2+ from the lung. Electronic supplementary material The online version of this article (doi:10.1007/s00204-013-1086-5) contains supplementary material, which is available to authorized users.

A patient treated for 4 months with hydroxy­carbamide (hydroxyurea) for chronic myelomonocytic leukemia was admitted to hospital for recently developed severe dyspnea and acute respiratory failure. The computed tomographic scan of the chest showed diffuse ground glass opacities, some centrilobular low-density nodules (resembling hypersensitivity pneumonitis-like pattern), and minimal interstitial reticulation of the subpleural region. The analysis of bronchoalveolar lavage fluid excluded infection, as did serological examinations. The patient was started on oxygen therapy and with relief of thrombocytopenia and suspected hemolytic anemia, hydroxyurea treatment was discontinued. The patient underwent steroid therapy, with a rapid progressive improvement of clinical and radiological features. As hydroxyurea is increasingly used for a number of systemic disorders, physicians must be aware of its potential lung toxicity, requiring immediate cessation of the treatment and empiric corticosteroid therapy.

Summary Background: Amiodarone, class III anti-arrhythmic was originally introduced to treat angina pectoris, was later approved by FDA in 1985 for the treatment of ventricular arrhythmias. Despite its anti-arrhythmic properties, amiodarone is associated with side effects such as thyroid dysfunction, corneal deposits, bluish skin discoloration, neuropathy and pulmonary toxicity. Amiodarone induced pulmonary toxicity (AIPT) is one of the most serious side effect thus limiting its use. Case Report: We encountered a 66 year old male with early onset AIPT who presented with dyspnea and chest imaging revealed extensive ground-glass opacities throughout lung parenchyma with rapid resolution of these opacities in a week following treatment with corticosteroids. Conclusions: There have been few case reports of AIPT with complete resolution of ground glass opacities on treatment with corticosteroids, but none demonstrated a rapid response to corticosteroids. Heath care providers should withdraw amiodarone at the earliest suspicion (as illustrated in our case); any delay can potentially be fatal. This case highlights the fact that AIPT is a reversible phenomenon, provided its early recognition and treatment before fibrosis sets in This case also highlights the need to include AIPT in the differential diagnosis in any patient on amiodarone who presents with shortness of breath.

Pulmonary symptoms from advanced-stage lung cancer often require palliative treatments for compassionate patient care. Although many of these symptoms can result from complications of advanced lung cancer treatment regimens (ie, radiation/chemotherapy-induced lung toxicity) or the patient's underlying comorbid conditions and poor constitution, a significant number of patients have symptoms that originate from the primary tumor itself or from locoregional metastases within the thoracic cavity. These complications from advanced-stage lung cancer can be a serious threat to life and require appropriate intervention.

Introduction Nitrofurantoin is a frequently used antibiotic for treatment and prophylaxis against urinary tract infections. It is a relatively safe medication with rare side effects, however, cases of severe pulmonary injury secondary to its use have been reported. 1 We report a patient with pulmonary infiltrates with eosinophilia, pleural effusion, and interstitial lung disease induced by the chronic use of nitrofurantoin. The association of severe eosinophilic bronchopneumopathy with interstitial fibrosis makes this case rare and shows the possible deleterious effect of chronic nitrofurantoin use.

The use of novel radiotherapy techniques is widely increasing, allowing clinicians to treat diseases that were previously difficult to treat with radiation therapy. Malignant pleural mesothelioma is a clear example of this clinical challenge. We describe our first experience with intensity-modulated radiotherapy technique which was used to treat a 73-year-old patient with multiple relapsing malignant pleural mesothelioma. Intensity-modulated radiation therapy has allowed to respect the QUANTEC (quantitative analyses of normal tissue effects in the clinic) dose constraints, patient has experienced a 14 months progression-free time, without relevant subacute or late lung toxicity.

Depleted uranium (DU) is a radioactive heavy metal coming from the nuclear industry and used in numerous military applications. Uranium inhalation can lead to the development of fibrosis and neoplasia in the lungs. As little is known concerning the molecular processes leading to these pathological effects, some of the events in terms of genotoxicity and inflammation were investigated in rats exposed to DU by inhalation. Our results show that exposure to DU by inhalation resulted in DNA strand breaks in broncho-alveolar lavage (BAL) cells and in increase of inflammatory cytokine expression and production of hydroperoxides in lung tissue suggesting that the DNA damage was in part a consequence of the inflammatory processes and oxidative stress. The effects seemed to be linked to the doses, were independent of the solubility of uranium compounds and correlating with the type of inhalation. Repeated inhalations seemed to induce an effect of potentiation in BAL cells and also in kidney cells. Comet assay in neutral conditions revealed that DNA damage in BAL cells was composed partly by double strands breaks suggesting that radiation could contribute to DU genotoxic effects in vivo. All these in vivo results contribute to a better understanding of the pathological effect of DU inhalation. © The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved.

Radiation therapy (RT) for thoracic-region tumors often causes lung injury. The incidence of lung toxicity depends on the method of assessment (eg, radiographs, patient's symptoms, or functional endpoints such as pulmonary function tests). Three-dimensional (3D) treatment planning tools provide dosimetric predictors for the risk of symptomatic RT-induced lung injury and allow for beams to be selected to minimize these risks. A variety of cytokines have been implicated as indicators/mediators of lung injury. Recent work suggests that injury-associated tissue hypoxia perpetuates further injury. Sophisticated planning/delivery methods, such as intensity modulation, plus radioprotectors such as amifostine, hold promise to reduce the incidence of RT-induced lung injury.

To investigate whether a normal resident microbiological flora of conventional rats influences the lethality of chemical-induced lung damage, the pneumotoxin O,S,S-trimethyl phosphorodithioate (OSSMe, 75 or 100 mg/kg, s.c.) was administered to age-matched conventional and germ-free male F344 rats. Microbiological and serological examinations confirmed the germ-free state of the germ-free rats and showed that no specific lung pathogens were present in the conventional rats. As in conventional rats, clinical symptoms and death of OSSMe-treated germ-free rats resulted from respiratory failure. The germ-free rats were not more resistant, but rather more susceptible to OSSMe than conventional rats. Increases in lung weight and histological examination of lung tissue 3 days after dosing with OSSMe (75 mg/kg, s.c.) showed no differences between germ-free and conventional rats. Despite alterations in their nasopharyngeal flora, death in the conventional rats was probably not caused by bacterial superinfection. The higher susceptibility of germ-free rats to OSSMe can be partly attributed to pharmacokinetic differences, since plasma levels of OSSMe decreased more slowly in germ-free than in conventional rats. It is concluded that germ-free rats are not protected from the lethal consequences of acute chemical-induced lung damage.