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PURPOSE: Radiation pneumonitis remains a major limitation in the radiation therapy treatment of patients with lung cancer. Functional avoidance radiation therapy uses functional imaging to reduce pulmonary toxic effects by designing radiation therapy plans that reduce doses to functional regions of the lung. Lung functional imaging has been developed that uses 4-dimensional computed tomography (4DCT) imaging to calculate 4DCT-based lung ventilation (4DCT-ventilation). A phase 2 multicenter study was initiated to evaluate 4DCT-ventilation functional avoidance radiation therapy. The study hypothesis was that functional avoidance radiation therapy could reduce the rate of grade ≥2 radiation pneumonitis to 12% compared with a 25% historical rate, with the trial being positive if ≤16.4% of patients experienced grade ≥2 pneumonitis. METHODS AND MATERIALS: Lung cancer patients receiving curative-intent radiation therapy (prescription doses of 45–75 Gy) and chemotherapy were accrued. Patient 4DCT scans were used to generate 4DCT-ventilation images. The 4DCT-ventilation images were used to generate functional avoidance plans that reduced doses to functional portions of the lung while delivering the prescribed tumor dose. Pneumonitis was evaluated by a clinician at 3, 6, and 12 months after radiation therapy. RESULTS: Sixty-seven evaluable patients were accrued between April 2015 and December 2019. The median prescription dose was 60 Gy (range, 45–66 Gy) delivered in 30 fractions (range, 15–33 fractions). The average reduction in the functional volume of lung receiving ≥20 Gy with functional avoidance was 3.5% (range, 0%–12.8%). The median follow-up was 312 days. The rate of grade ≥2 radiation pneumonitis was 10 of 67 patients (14.9%; 95% upper CI, 24.0%), meeting the phase 2 criteria. CONCLUSIONS: 4DCT-ventilation offers an imaging modality that is convenient and provides functional imaging without an extra procedure necessary. This first report of a multicenter study of 4DCT-ventilation functional avoidance radiation therapy provided data showing that the trial met phase 2 criteria and that evaluation in a phase 3 study is warranted.

Apalutamide, a competitive inhibitor of the androgen receptor, is being increasingly used for the treatment of prostate cancer. There have been few reports of interstitial lung disease in clinical trials of apalutamide. However, two cases of apalutamide-induced interstitial lung disease with respiratory failure in Japanese males, who were successfully treated with high-dose corticosteroids, are presented here. These cases suggest that clinicians should be alert to the potentially life-threatening risk of pulmonary toxicity associated with apalutamide treatment.

In this report, we aim to present a case of pulmonary toxicity in a patient that received neoadjuvant chemotherapy treatment with doxorubicin and cyclophosphamide for triple-negative breast cancer that was followed with granulocyte colony-stimulating factor (G-CSF) for prevention neutropenia, our patient presented with chest discomfort and dyspnea, with radiologic evidence of radiologic investigations showed acute respiratory distress syndrome, after investigation and follow up we came to the conclusion that it was G-CSF adverse effect.

Background Amiodarone (AMD) is a widely used anti-arrhythmic drug, but its administration could be associated with varying degrees of pulmonary toxicity. In attempting to circumvent this issue, AMD-loaded polymeric nanoparticles (AMD-loaded NPs) had been designed. Materials and Methods AMD was loaded in NPs by the nanoprecipitation method using two stabilizers: bovine serum albumin and Kolliphor® P 188. The physicochemical properties of the AMD-loaded NPs were determined. Among the prepared NPs, two ones were selected for further investigation of spectral and thermal analysis as well as morphological properties. Additionally, in vitro release patterns were studied and kinetically analyzed at different pH values. In vitro cytotoxicity of an optimized formula (NP4) was quantified using A549 and Hep-2 cell lines. In vivo assessment of the pulmonary toxicity on Sprague Dawley rats via histopathological and immunohistochemical evaluations was applied. Results The developed NPs achieved a size not more than 190 nm with an encapsulation efficiency of more than 88%. Satisfactory values of loading capacity and yield were also attained. The spectral and thermal analysis demonstrated homogeneous entrapment of AMD inside the polymeric matrix of NPs. Morphology revealed uniform, core-shell structured, and sphere-shaped particles with a smooth surface. Furthermore, the AMD-loaded NPs exhibited a pH-dependent and diffusion-controlled release over a significant period without an initial burst effect. NP4 demonstrated a superior cytoprotective efficiency by diminishing cell death and significantly increasing the IC50 by more than threefold above the pure AMD. Also, NP4 ameliorated AMD-induced pulmonary damage in rats. Significant downregulation of inflammatory mediators and free radicle production were noticed in the NP4-treated rats. Conclusion The AMD-loaded NPs could ameliorate the pulmonary injury induced by the pure drug moieties. Cytoprotective, anti‐fibrotic, anti-inflammatory, and antioxidant properties were presented by the optimized NPs (NP4). Future studies may be built on these findings for diminishing AMD-induced off-target toxicities., Graphical Abstract

Introduction The CALGB 30610/RTOG 0538 randomized trial was designed to test whether high-dose thoracic radiotherapy (TRT) would improve survival compared with 45 Gy twice-daily (BID) TRT in limited stage small cell lung cancer (LSCLC). Two piloted experimental TRT regimens were of interest to study, 70 Gy daily (QD) and 61.2 Gy concomitant boost (CB). Driven by concerns about adequate patient accrual, a study design was employed that eliminated one experimental TRT arm based on early interim toxicity and tolerability, with the study then continuing as a traditional 2-arm phase III study. Methods Patients with LSCLC were assigned to receive four cycles of cisplatin and etoposide chemotherapy with one of 3 TRT regimens starting with either the first or second cycle of chemotherapy. The interim endpoint was the cumulative highest toxicity calculated from a scoring system based on treatment-related grade 3 and higher toxicity and the ability to complete therapy in the experimental arms. Results The final interim analysis was performed after 70 patients accrued to each experimental cohort, and a difference in treatment related toxicity scoring was not found (p = 0.739). Severe esophageal toxicity was comparable in both cohorts. Pulmonary toxicity was low overall, though 4 patients (5.7 %) on the 61.2 Gy arm developed grade 4 dyspnea, which was not observed in the 70 Gy arm. A protocol mandated decision was made to discontinue the 61.2 Gy arm following review of toxicity with the Data and Safety Monitoring Board. Conclusion A randomized trial design using a planned early interim toxicity analysis to discriminate between experimental treatment arms is feasible in a phase III setting. Refinement of the design could increase the likelihood of detecting clinically meaningful differences in toxicity in future studies.

Purpose of review The current review focuses on serious pulmonary toxicity after inhalation of over the counter available pyrethroid-based insecticides. Pyrethroid is a synthetic product of pyrethrin, which in turn is the active ingredient of pyrethrum, a flower extract. Recent findings On the contrary, a large gap of knowledge exists in the association of interstitial lung disease (ILD) with pyrethroids. So far, two cases of ILD, one associated with pyrethrin and one associated with pyrethrum, were described. Existing literature on both other (pulmo)toxic effects of pyrethroids in human and animals is summarized. Summary We present three cases of severe pulmonary toxicity after inhalation of pyrethroid-based insecticides demanding hospitalization and oxygen therapy. One of these cases died. Although a causal relationship was hard to establish, these cases all demonstrated an obvious history of (repeated) pyrethroid exposure associated with ILD. Moreover, other causes of ILD as well as infections were excluded. Furthermore, studies in mammals as well as aquatic animals confirm (pulmonary) toxicity of pyrethroids. The occurrence of toxicity is dose-dependent but also associated with individual susceptibility. Therefore, we would like to acknowledge that awareness of potential hazards of commercially available insecticides containing pyrethroids to both medical physicians and the public is mandatory.

The last 10 years has seen a steady rise in the use of electronic cigarettes ("e-cigarettes" or ECIGs) or "vape pens." Though initially developed to assist with smoking cessation, use among adolescents has been particularly high. A concomitant rise in ECIG-related injuries disproportionately affecting young patients has been recognized. This unique case series highlights both pulmonary and extra-pulmonary ECIG-induced injuries including vape tip ingestion, maxillofacial fractures after vape pen explosion, myocarditis, and several different manifestations of vaping-associated lung injury. Becoming familiar with expected imaging findings in the wide array of ECIG-induced complications will help radiologists recognize these findings, recommend further imaging as needed, facilitate early diagnosis by help referring clinicians elicit the relevant history from patients, and expedite appropriate treatment.

COVID‐19 is a life‐threatening disease leading to bilateral pneumonia and respiratory failure. The underlying reasons why a smaller percentage of patients present with severe pulmonary symptoms whereas the majority is only mildly affected are to date not well understood. Comparing the immunological phenotype in healthy donors and patients with mild versus severe COVID‐19 shows that in COVID‐19 patients, NK‐/B‐cell activation and proliferation are enhanced independent of severity. As an important precondition for effective antibody responses, T‐follicular helper cells and antibody secreting cells are increased both in patients with mild and severe SARS‐CoV‐2 infection. Beyond this, T cells in COVID‐19 patients exhibit a stronger activation profile with differentiation toward effector cell phenotypes. Importantly, when looking at the rates of pulmonary complications in COVID‐19 patients, the chemokine receptor CCR4 is higher expressed by both CD4 and CD8 T cells of patients with severe COVID‐19. This raises the hypothesis that CCR4 upregulation on T cells in the pathogenesis of COVID‐19 promotes stronger T‐cell attraction to the lungs leading to increased immune activation with presumably higher pulmonary toxicity. Our study contributes significantly to the understanding of the immunological changes during COVID‐19, as new therapeutic agents, preferentially targeting the immune system, are highly warranted., Patients with mild COVID‐19 after SARS‐CoV2 infection exhibit increased T‐cell activation and induction of T‐cell exhaustion. During severe COVID‐19 patients show massive T‐cell activation and upregulation of homing receptors promoting hyperinflammation and increased lung trafficking.

Purpose The aim of the current study was to compare toxicity, cosmesis, and local control between the once daily and the twice daily fractionation schemes for external beam accelerated partial breast irradiation. Methods and Materials From December 2012 to June 2018, we enrolled 113 patients with ductal carcinoma in situ or invasive breast cancer, node negative disease, and tumors less than 3 cm in size to receive accelerated partial breast irradiation (APBI) to a total dose of 38.5 Gy over 10 fractions given either once (oAPBI) or twice daily (tAPBI). Sixty patients were included in the tAPBI arm and 53 patients were included in the oAPBI arm. Results Median follow-up was 74 months (range, 24-105). The median pain score during treatment was 3 out of 10 in the oAPBI and 5 in the tAPBI (P = .001). No differences were observed in GIII early skin toxicity (P = .4) or GI early pulmonary toxicity (P = 1.0) between the 2 treatment arms. GIII late skin toxicity developed in 3.8% and 11.7% of patients in the oAPBI and tAPBI arms, respectively (P = .001). GIII subcutaneous fibrosis developed in 1.9% and 8.3% of patients in the oAPBI and tAPBI, respectively (P = .001). The rate of patients with adverse cosmesis (poor/fair) was 7.5% at 12 months and at 24 months in the oAPBI arm compared with 21.7% and 26.7% in the tAPBI arm (P = .03 and .008, respectively). Conclusions oAPBI is a safe, well-tolerated schedule with more favorable outcomes than the tAPBI schedule with regards to late toxicity and cosmesis.

Introduction Pulmonary toxicity causally related to Imatinib (IM) therapy is uncommon in patients with chronic myeloid leukemia. Case report A 61-year-old patient with chronic myeloid leukemia was treated with IM at 400 mg daily dose. One month within IM, he developed skin lesions and then acute dyspnea and non-productive cough. Chest radiograph and high-resolution lung computed tomography (CT) revealed bilateral reticulonodular infiltration in both lungs. According to Naranjo's algorithm, the causality relationship with the drug is probable with a score of 7. The pharmacovigilance investigation was carried out and implicated IM Management & outcome: IM was discontinued and started steroid therapy (Prednisolone®) at 1 mg/kg daily. Two weeks after, the dyspnea, and abnormal X-ray and CT findings are improved. Discussion The early diagnosis of pulmonary toxicity related to IM therapy is needed to avoid further determinal effects of the drug.

Aims NeoSCOPE is a trial of two different neoadjuvant chemoradiotherapy regimens for resectable oesophageal cancer and was the first multicentre trial in the UK to incorporate four-dimensional computed tomography (4D-CT) into radiotherapy planning. Despite 4D-CT being increasingly accepted as a standard of care for lower third and junctional oesophageal tumours, there is limited evidence of its benefit over standard three-dimensional computed tomography (3D-CT). Materials Using NeoSCOPE 4D-CT cases, we undertook a dosimetric comparison study of 3D-CT versus 4D-CT plans comparing target volume coverage and dose to organs at risk. We used established normal tissue complication probability models to evaluate the potential toxicity reduction of using 4D-CT plans in oesophageal cancer. Results 4D-CT resulted in a smaller median absolute PTV volume and lower dose levels for all reported constraints with comparable target volume coverage. NTCP modelling suggests a significant relative risk reduction of cardiac and pulmonary toxicity endpoints with 4D-CT. Conclusion Our work shows that incorporating 4D-CT into treatment planning may significantly reduce the toxicity burden from this treatment.

Pulmonary function tests (PFT) are sometimes monitored during treatment with known pulmonary toxic drugs to detect asymptomatic drug-induced interstitial lung disease (DILD). We conducted a systematic review to assess the accuracy of PFT, including the diffusing capacity for carbon monoxide (DLCO), for early detection of DILD in a range of drugs. Using a pre-specified, registered review protocol, OvidMEDLINE and EMBASE were searched from 1946 to February 2018. Two reviewers independently screened abstracts and reviewed full-text articles for inclusion. Included studies were assessed for risk of bias using adapted QUADAS-2 domains and primary outcome data were extracted and entered into RevMan5 to estimate sensitivity and specificity with 95% confidence intervals (CI). The search identified 4065 citations and included 42 studies. The most commonly studied drugs were bleomycin and amiodarone. Due to clinical heterogeneity between studies, a pooled analysis was not performed. Sensitivity of monitoring with DLCO varied between 0 and 100%, with the majority of studies finding a sensitivity of

OBJECTIVE: We previously reported that low-dose methotrexate (LD-MTX) was associated with increased risk of pulmonary adverse events (AEs) in a large placebo-controlled randomized trial. Herein, we report details on predictors and severity of pulmonary AEs. METHODS: This was a pre-specified analysis of pulmonary AEs in the Cardiovascular Inflammation Reduction Trial. Adults with known cardiovascular disease and diabetes/metabolic syndrome were randomly allocated to LD-MTX (target dose 15-20 mg/week) or placebo after 6-8 weeks of open-label run-in with LD-MTX. Individuals with systemic inflammatory diseases were excluded. Pulmonary AEs were blindly adjudicated. We described severe pulmonary AEs and examined associations of baseline characteristics with pulmonary AEs of LD-MTX. RESULTS: A total of 2,391 subjects were randomized to LD-MTX and 2,395 to placebo. There were 13 severe pulmonary AEs (0.5%) and seven (0.3%) cases of possible pneumonitis in the LD-MTX group, compared to eight (0.3%) and one (

OBJECTIVE This study aimed to assess the potential benefits and tolerability of an empirical dose of approximately 0.8-1.2 mCi (29.6-44.4 MBq) of Re-4-hexadecyl-1-2,9,9-tetramethyl-4,7-diaza-1,10-decanethiol/lipiodol (Re-HDD/lipiodol) per milliliter of tumor volume, administered after super-selection of the tumor feeding branches of hepatic artery for treatment of inoperable hepatocellular carcinoma (HCC). METHODS Patients with advanced HCC or classified as inoperable, with no demonstrated extrahepatic disease and no significant comorbidities were eligible. The patients selected for this study had a single tumoral lesion, measuring less than 150 cc. The range of total activity administered was between 30 and 100 mCi (1.2-3.7) GBq Re-HDD/lipiodol, administered in the super selected branches of the hepatic artery supplying the tumor in 42 Patients. Whole-body scintigraphies and single-photon emission computed tomography-computed tomography (SPECT-CT) of the liver including tumor were performed at four-time points after injection. Absorbed doses to the various organs were calculated according to the Medical Internal Radiation Dose formalism. Blood and urine samples were collected at multiple time points until 72 h after injection. Hematological, hepatic and pulmonary toxicity was assessed until 12 weeks after administration using the Common Toxicity Criteria for Adverse Events (version 3.0) scale. Responses were evaluated on contrast enhanced computed tomography (CECT) and by alfa-fetoprotein (AFP) level monitoring. RESULTS About 40.6 ± 4.8% of the injected activity was excreted in the urine by 72 h after injection. The mean absorbed dose to the liver, lungs, stomach, kidney and intestine was 14.4 ± 1.8, 4.8 ± 0.6, 5.5 ± 1.1, 5.1 ± 0.7, and 6.5 ± 1.0 Gy (mean ± SD), respectively. Up to 6 days after administration, 26 of 44 patients had adverse events consisting of aggravations of preexisting laboratory changes (24 patients), fatigue (5 patients), vomiting (6 patients), fever (2 patients), right hypochondrial pain (8 patients), and pain at site of femoral catheter insertion (8 patients). Toxicity assessment at weeks 6 and 12 revealed two cases of mild worsening of liver function tests and no lung or hematological toxicity noted. Two patients were lost to follow-up after the 6-week visit. The response was assessed on CECT in all the remaining patients and the classification of results was more standardized when using European Association for the Study of the Liver (EASL) criteria rather than response evaluation criteria in solid tumors (RECIST) criteria. According to EASL criteria, 8 patients had a partial response, 28 patients had a complete response, 4 patients had progressive disease and 4 patients with stable disease were reported. Thirty-six patients had a baseline elevated AFP and on follow-up at 6 weeks, 6 of these patients showed stable AFP, progression in 4 patients and 26 showed a reduction. CONCLUSION After the administration of 1.2-3.7 GBq Re-HDD/lipiodol based on empirical activity calculation of 0.8-1.2 mCi/mL of tumor volume, more than half of the patients in the present study had an objective response on imaging and biochemically. No significant adverse side effects were noted and most of the laboratory markers as well as symptoms returned to normal after 48-72 h post-administration. Selective administration of the radiopharmaceutical into the tumor feeding arteries gives a good anti-tumoral effect with minimal side effects and damage to surrounding normal liver tissue.

Purpose The aim of this study was to evaluate which clinical and treatment-related factors are associated with heart and lung toxicity in oesophageal cancer patients treated with chemoradiation (CRT). The secondary objective was to analyse whether these toxicities are associated with overall survival (OS). Materials and methods The study population consisted of a retrospective cohort of 216 oesophageal cancer patients treated with curative CRT. Clinical and treatment related factors were analysed for OS and new pulmonary and cardiac events by multivariable regression analyses. The effect of these toxicities on OS was assessed by Kaplan Meyer analyses. Results Multivariable analysis revealed that pulmonary toxicity was best predicted by the mean lung dose. Cardiac complications were diverse; the most frequently occurring complication was pericardial effusion. Several cardiac dose parameters correlated with this endpoint. Patients developing radiation pneumonitis had significantly worse OS than patients without radiation pneumonitis, while no difference was observed in OS between patients with and without pericardial effusion. OS was best predicted by the V45 of the lung and tumour stage. None of the cardiac dose parameters predicted OS in multivariable analyses. Conclusion Cardiac dose volume parameters predicted the risk of pericardial effusion and pulmonary dose volume parameters predicted the risk of radiation pneumonitis. However, in this patient cohort, pulmonary DVH parameters (V45) were more important for OS than cardiac DVH parameters. These results suggest that reducing the cardiac dose at the expense of the dose to the lungs might not always be a good strategy in oesophageal cancer patients.

Lung cancer is the leading cause of cancer-related deaths worldwide. As new therapies are developed, it is important to understand the pulmonary toxicities associated with systemic lung cancer therapies. Cytotoxic chemotherapy regimens for NSCLC often include taxanes. Pulmonary toxicity from taxanes presents as an ILD-type reaction characterized by increasing dyspnoea, dry cough, fever and bilateral pulmonary interstitial infiltrates. The incidence of taxane-induced pneumonitis is rare, and many patients respond to steroid therapy; however, fatal cases have been reported. Patients with NSCLC are routinely tested for the presence of tumour oncogenes to determine their candidacy for targeted therapies, such as TKI. EGFR-TKI can cause pneumonitis characterized by progressive dyspnoea and hypoxia. EGFR-TKI-associated ILD rarely presents as an AIP with rapidly progressive respiratory failure and high mortality rates. The most recent development in lung cancer therapy has been the discovery of immune checkpoint inhibitor (ICI). ICI pneumonitis has been increasingly recognized as a common complication of ICI therapy, with reported incidence as high as 19% in some clinical settings. Early-grade ICI pneumonitis may be asymptomatic; however, high-grade ICI pneumonitis can result in progressive dyspnoea, hypoxia and respiratory failure. ICI pneumonitis is unique in that only half of the patients will improve with steroid treatment, and mortality rates are high. As treatment of NSCLC evolves, providers must be able to recognize and respond to the development of drug-induced pulmonary toxicities.

Background Whole lung irradiation (WLI) represents an important part of multimodal therapy in Ewing sarcoma (EwS) patients diagnosed with pulmonary metastases. This review discusses pulmonary toxicity in EwS patients with pulmonary metastases treated with WLI, who received different modes of high-dose chemotheray (HD-Cth). Methods Literature was compiled using the Cochrane Library, PubMed database, and the National Institute of Health (NIH) clinical trials register. Relevant patient information, including nature of HD-Cth, acute and late lung toxicities, and pulmonary function disorders, was selected from the above databases. Results Nine reports with a total of 227 patients, including 57 patients from a single randomized trial were included in this review. No acute or chronic symptomatic pulmonary toxicities were observed in patients that received WLI after HD busulfan-melphalan (HD-Bu/Mel), but 8% of these patients were diagnosed with asymptomatic restrictive lung disease. Grade 1 or 2 acute or chronic lung adverse effects were observed in up to 30% of patients that received WLI after HD treosulfan/Mel (HD-Treo/Mel) or HD etoposide (E)/Mel. Interstitial pneumonitis was present in 9% of patients treated concurrently with E/Mel and total body irradiation (TBI) with 8 Gy. Radiation doses as well as time between HD-Cth and WLI were both identified as significant risk factors for pulmonary function disorders. Conclusion The risk of adverse lung effects after WLI depends on several factors, including cumulative radiation dose and dose per fraction, HD-Cth regimen, and time interval between HD-Cth and WLI. A cumulative radiation dose of up to 15 Gy and a time interval of at least 60 days can potentially lead to a reduced risk of pulmonary toxicities. No evident adverse lung effects were registered in patients that received simultaneous therapy with HD-Cth and TBI. However, pulmonary function testing and lung toxicity reports were lacking for most of these patients.

Introduction The association between e-cigarette use and chronic bronchitis, emphysema, and chronic obstructive pulmonary disease has not been studied thoroughly, particularly in populations defined by concomitant combustible smoking status. Methods Using pooled 2016 and 2017 data from the Behavioral Risk Factor Surveillance System, investigators studied 705,159 participants with complete self-reported information on e-cigarette use, combustible cigarette use, key covariates, and chronic bronchitis, emphysema, or chronic obstructive pulmonary disease. Current e-cigarette use was the main exposure, with current use further classified as daily or occasional use. The main outcome was defined as reported ever having a diagnosis of chronic bronchitis, emphysema, or chronic obstructive pulmonary disease. For all the analyses, multivariable adjusted logistic regression was used, with the study population stratified by combustible cigarette use status (never, former, or current). All the analyses were conducted in 2019. Results Of 705,159 participants, 25,175 (3.6%) were current e-cigarette users, 64,792 (9.2%) current combustible cigarette smokers, 207,905 (29.5%) former combustible cigarette smokers, 432,462 (61.3%) never combustible cigarette smokers, and 14,036 (2.0%) dual users of e-cigarettes and combustible cigarettes. A total of 53,702 (7.6%) participants self-reported chronic bronchitis, emphysema, or chronic obstructive pulmonary disease. Among never combustible cigarette smokers, current e-cigarette use was associated with 75% higher odds of chronic bronchitis, emphysema, or chronic obstructive pulmonary disease compared with never e-cigarette users (OR=1.75, 95% CI=1.25, 2.45), with daily users of e-cigarettes having the highest odds (OR=2.64, 95% CI=1.43, 4.89). Similar associations between e-cigarette use and chronic bronchitis, emphysema, or chronic obstructive pulmonary disease were noted among both former and current combustible cigarette smokers. Conclusions The results suggest possible e-cigarette–related pulmonary toxicity across all the categories of combustible cigarette smoking status, including those who had never smoked combustible cigarettes.

In the past years, several in vitro studies have addressed the pulmonary toxicity of multi-walled carbon nanotubes (MWCNT) and compared it with that caused by asbestos fibers, but their conclusions have been somewhat inconsistent and difficult to extrapolate to in vivo. Since cell coculture models were proposed to better represent the in vivo conditions than conventional monocultures, this work intended to compare the cytotoxicity and genotoxicity of MWCNT-7 (Mitsui-7) and crocidolite using A549 cells grown in a conventional monoculture or in coculture with THP-1 macrophages. Although a decrease in A549 viability was noted following exposure to a concentration range of MWCNT-7 and crocidolite, no viability change occurred in similarly exposed cocultures. Early events indicating epithelial to mesenchymal transition (EMT) were observed which could explain apoptosis resistance. The comet assay results were similar between the two models, being positive and negative for crocidolite and MWCNT-7, respectively. An increase in the micronucleus frequency was detected in the cocultured A549-treated cells with both materials, but not in the monoculture. On the other hand, exposure of A549 monocultures to MWCNT-7 induced a highly significant increase in nucleoplasmic bridges in which those were found embedded. Our overall results demonstrate that (i) both materials are cytotoxic and genotoxic, (ii) the presence of THP-1 macrophages upholds the viability of A549 cells and increases the aneugenic/clastogenic effects of both materials probably through EMT, and (iii) MWCNT-7 induces the formation of nucleoplasmic bridges in A549 cells. This research was supported by the Foundation for Science and Technology, Center for Toxicogenomics and Human Health (ToxOmics) under grant (UID/BIM/00009/2013) and by ToxApp4NanoCELFI (PTDC/SAU-PUB/32587/2017) through national funds (PIDDAC). info:eu-repo/semantics/publishedVersion

Objectives Bleomycin, etoposide, and cisplatin (BEP) is the most common and successful chemotherapy regimen for germ-cell tumor (GCT) patients, accompanied by a bleomycin-induced dose-dependent lung toxicity in certain patients. In an attempt to reduce bleomycin-toxicity, we developed a modified-BEP (mBEP) regimen. Materials and methods Between August 2008 and February 2018, 182 unselected mainly testicular GCT patients (39 with adjuvant purpose and 143 with curative purpose) received a tri-weekly 5-day hospitalization schedule with bleomycin 15 U intravenous (IV) push on day 1 and 10 U IV continuous infusion over 12 hours on days 1 to 3, cisplatin 20 mg/m IV, and etoposide 100 mg/m IV on days 1 to 5. Pulmonary toxicity was assessed through chest computed tomography scan and clinical monitoring. Results Median number of mBEP cycles was 3 (range: 1 to 4). In the curative setting, according to the International Germ Cell Cancer Collaborative Group (IGCCCG) prognostic system, 112, 21, and 9 patients had good-risk, intermediate-risk, and poor-risk class, respectively; 66 (46%) patients had complete response (CR), 67 (47%) had partial response (52 of whom became CR afterwards), 6 (4%) had stable disease (that in 3 became CR afterwards), 3 (2%) progressed, and 1 (1%) died of brain stroke. At a median follow-up of 2.67 years (interquartile range: 1.23-5.00 y), 1 and 5-year overall survival and progression-free survival were 99% and 95%, and 90% and 88%, respectively. In the entire patient population, there was grade 3/4 neutropenia in 92 patients (51%), febrile neutropenia in 11 patients (6%), grade 1/2 nausea in 74 patients (41%), and no death due to pulmonary toxicity. Conclusion In GCT patients, our mBEP-schedule would suggest an effective treatment modality without suffering meaningful pulmonary toxicity.

Item does not contain fulltext BACKGROUND AND PURPOSE: (Chemo)Radiotherapy for locally advanced non-small lung cancer (LA-NSCLC) causes severe dysphagia due to the radiation dose to the mediastinal lymphadenopathy. Reducing the dose to the mediastinum and the margins to the planning target volume (PTV) might reduce severe toxicity rates. The results of both adaptations in LA-NSCLC patients receiving (chemo)radiotherapy were analysed. MATERIALS AND METHODS: 308 LA-NSCLC patients were included in an observational study. Both cohorts received hypofractionated RT (24 × 2.75 Gy) of 70 Gy (EQD2(10)) to the primary tumour. The reference-cohort (N = 170) received the same dose of 70 Gy (EQD2(10)) to the involved lymph nodes, while the reduction-cohort (N = 138) received 24 × 2.42 Gy, biologically equivalent to 60 Gy (EQD2(10)). Furthermore, the patient-specific PTV-margins for both the primary tumour and lymph nodes were reduced by 2-3 mm in the reduction-cohort after implementing a carina based correction strategy. The effects on toxicity, regional failure and overall survival (OS) were assessed. RESULTS: The acute grade 3 (G3) dysphagia and G3 pulmonary toxicity decreased significantly from 12.9% to 3.6% and 4.1% versus 0%, respectively. The regional failures were comparable: 5.9% versus 4.3% (p = 0.546). The median OS was significantly different: 26 months (reference-cohort) versus 35 months (reduction-cohort). After correction for confounders, the association between the reduction-cohort and OS remained significant (HR 0.63 versus HR 0.70). CONCLUSION: A reduction in PTV-margins and dose from 70 Gy to 60 Gy to the involved lymph nodes in LA-NSCLC patients receiving (chemo)radiotherapy did not result in an increase in regional failures. Moreover, significantly lower acute toxicities and an improved OS were observed in the reduction-cohort.

The use of flavoured tobacco products in waterpipe smoking (WPS) has increased its attractiveness and consumption. Nonetheless, the influence of flavourings on pulmonary toxicity caused by WPS remains unclear. Here, the pulmonary toxicity induced by plain (P)-WPS, apple-flavoured (AF)-WPS, and strawberry-flavoured (SF)-WPS (30 minutes/day, 5 days/week for 1 month) was investigated in mice. Control mice were exposed to air. Exposure to P-WPS or AF-WPS or SF-WPS induced a dose-dependent increase of airway hyperreactivity to methacholine. The histological evaluation of the lungs in all the WPS groups revealed the presence focal areas of dilated alveolar spaces and foci of widening of interalveolar spaces with inflammatory cells. In the lung, the activity of neutrophil elastase and myeloperoxidase and the concentrations of tumor necrosis factor-α and glutathione were increased by the exposure to P-WPS, AF-WPS, or SF-WPS. However, the levels of interleukin-6 and catalase were only increased in the AF-WPS and SF-WPS groups, while nitric oxide activity was only increased in the SF-WPS group. DNA injury was increased in all the WPS groups, but the concentration of cleaved caspase-3 was only elevated in the SF-WPS group. The exposure to either P-WPS or AF-WPS or SF-WPS increased the expression of nuclear factor kappa-B (NF-κB) in the lung. In conclusion, the exposure to P-WPS or AF-WPS or SF-WPS induces alterations in lung function and morphology and causes oxidative stress and inflammation via mechanisms that include activation of NF-κB. Overall, the toxicity of flavoured tobacco WPS, in particular SF-WPS, was found to be greater than that of unflavoured WPS.

Because of its physical properties, proton irradiation should be the treatment of choice for loco regional irradiation of breast cancer patients. Conventional irradiation usually with photons has improved in the past decades reducing the dose to the organs at risk like the heart and the lungs. Still due to the properties of photons the organs at risk get unintended dose. Protons are charged particles and are able to deliver the dose to a specified depth where they stop and therefore no exit dose like in photon irradiation. This is the so-called Bragg Peak. Although in recent years there has been a clear increase in the number of proton facilities, the availability remains scarce and the costs high. The increased availability and improvement in delivery techniques have let to more interest in the applicability for breast cancer patients. The most important challenge is how to select patients that most benefit from this new technique. Irradiated breast cancer patients are at increased risk to develop cardiac and pulmonary toxicity and have more chance to develop secondary tumors. The advantages of dose reduction achieved by using proton irradiation or any other technique can be quantified by using data on dose effects relation for the toxicity of interest. Patients that most benefit from proton irradiation can be selected by the model based approach (the Dutch model). This model based approach quantifies the risk reduction based on the difference in dose to the organ of interest between photon and proton irradiation.

Functional lung avoidance during radiotherapy can help reduce pulmonary toxicity. This study assessed the potential impact of four-dimensional computed tomography (4DCT)-ventilation imaging-guided proton radiotherapy (PT) on stereotactic body radiotherapy (SBRT) by comparing it with three-dimensional conformal radiotherapy (3D-CRT) and volumetric modulated arc therapy (VMAT), which employ photon beams. Thirteen lung cancer patients who received SBRT with 3D-CRT were included in the study. 4DCT ventilation was calculated using the patients’ 4DCT data, deformable image registration, and a density-change-based algorithm. Three functional treatment plans sparing the functional lung regions were developed for each patient using 3D-CRT, VMAT, and PT. The prescribed doses and dose constraints were based on the Radiation Therapy Oncology Group 0618 protocol. We evaluated the region of interest (ROI) and functional map-based dose-function metrics for 4DCT ventilation and the irradiated dose. Using 3D-CRT, VMAT, and PT, the percentages of the functional lung regions that received ≥ 5 Gy (fV5) were 26.0%, 21.9%, and 10.7%, respectively; the fV10 were 14.4%, 11.4%, and 9.0%, respectively; and fV20 were 6.5%, 6.4%, and 6.6%, respectively, and the functional mean lung doses (fMLD) were 5.6 Gy, 5.2 Gy, and 3.8 Gy, respectively. These results indicated that PT resulted in a significant reduction in fMLD, fV5, and fV10, but not fV20. The use of PT reduced the radiation to highly functional lung regions compared with those for 3D-CRT and VMAT while meeting all dose constraints.

As many as 6% of reported cinnamon poisonings cause significant clinical effects, however, descriptions of pulmonary toxicity have not yet been reported. Here, we present a pediatric patient's hospital course following powdered cinnamon aspiration. The early presentation with hypercapnia and lower airways obstruction evolved to hypoxemic respiratory failure and severe pediatric acute respiratory distress syndrome requiring a 7-day course of veno-venous extracorporeal membrane oxygenation, 16 ventilator-days, and three diagnostic and therapeutic bronchoscopies with two applications of surfactant therapy. The sum of these modalities contributed to this patient's survival and subsequent return to respiratory baseline 6 months post-hospitalization.

The ubiquitous use of phthalates in various materials and the knowledge about their potential adverse effects is of great concern for human health. Several studies have uncovered their role in carcinogenic events and suggest various phthalate-associated adverse health effects that include pulmonary diseases. However, only limited information on pulmonary toxicity is available considering inhalation of phthalates as the route of exposure. While in vitro studies are often based on submerged exposures, this study aimed to expose A549 alveolar epithelial cells at the air-liquid interface (ALI) to unravel the genotoxic and oxidative stress-inducing potential of dibutyl phthalate (DBP) with concentrations relevant at occupational settings. Within this scope, a computer modelling approach calculating alveolar deposition of DBP particles in the human lung was used to define in vitro ALI exposure conditions comparable to potential occupational DBP exposures. The deposited mass of DBP ranged from 0.03 to 20 ng/cm2 , which was comparable to results of a human lung particle deposition model using an 8 hours workplace threshold limit value (TLV) of 580 μg/m3 proposed by the Scientific Committee on Occupational Exposure Limits (SCOEL) for the European Union. Comet and Micronucleus assay revealed that DBP induced genotoxicity at DNA and chromosome level in sub-cytotoxic conditions. Since genomic instability was accompanied by increased generation of the lipid peroxidation marker malondialdehyde (MDA), oxidative stress might play an important role in phthalate-induced genotoxicity. The results highlight the importance of adapting in vitro studies to exposure scenarios relevant at occupational settings and reconsidering occupational exposure limits for DBP.

BACKGROUND Children with chest wall Ewing sarcoma with malignant pulmonary effusion or pleural stranding require hemithorax radiation, often with plans that exceed lung constraints. We investigated disease control and pneumonitis in children requiring hemithorax radiation. PROCEDURE Eleven children (median age 13 years) received hemithorax radiotherapy. Symptomatic radiation pneumonitis was considered National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) grade 1+ with respiratory symptoms. Mean lung dose (MLD), volume of lung exposed to a dose ≥5 Gy (V5), ≥20 Gy (V20), and ≥35 Gy (V35) were recorded. Adult and pediatric lung constraints were obtained from Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) guidelines and Children's Oncology Group (COG) protocols, respectively. RESULTS Median hemithorax dose was 15 Gy (1.5 Gy/fraction). Median total dose was 51 Gy (1.8 Gy/fraction). Most plans delivered both protons and photons. The ipsilateral MLD, V5, and V20 were 27.2 Gy, 100%, and 48.3%; the bilateral MLD, V20, and V35 were 14.1 Gy, 22.8%, and 14.3%, respectively. One hundred percent, 36%, and 91% of treatments exceeded recommended adult ipsilateral lung constraints of V5

Mitomycin treatment induces pulmonary toxicity, and alveolar epithelial cell senescence is crucial in the pathogenesis of the latter. However, the mechanism by which mitomycin induces alveolar epithelial cell senescence has yet to be elucidated. In this work, different doses (37.5-300 nM) of mitomycin induced the senescence of human alveolar type II-like epithelial cells and enhanced the phosphorylation of GSK3β (S9). The GSK3β (S9A) mutant reversed the senescence of mitomycin-treated alveolar epithelial cells. Pharmacological inhibition and gene deletion of Akt1, a kinase that regulates the phosphorylation of GSK3β (S9), suppressed mitomycin-induced alveolar epithelial cell senescence. The knockdown of p53, a downstream effector of GSK3β and an important regulator of cell senescence, repressed mitomycin-induced alveolar epithelial cell senescence. Treatment with baicalein weakened the phosphorylation of GSK3β (S9) and alleviated the senescence of alveolar epithelial cells brought about by mitomycin treatment. GSK3β (S9) phosphorylation appears to be the first signal involved in the mitomycin-induced senescence of alveolar epithelial cells and may present a potential target for attenuating mitomycin-induced pulmonary toxicity.

Aim Bleomycin, etoposide, and cisplatin (BEP) regimen is the standard treatment for germ-cell tumors (GCTs). Bleomycin-induced pulmonary toxicity (BPT) is fatal and dose-limiting toxicity associated with this regimen. In this study, we aimed to identify the frequency and risk factors of BPT in South Indian GCT patients receiving BEP regimen. Patients and methods The study was carried out in the Department of Medical Oncology, Regional Cancer Centre at a tertiary care hospital in South India. All the patients with GCT (testicular and ovarian) who were receiving BEP regimen from December 2014 to May 2018 were included in the study. BPT was defined as the presence of radiological features and/or clinical symptoms during or post-treatment. Results BPT was observed in 11 (27%) patients of 41 analyzed patients. Five (12%) patients developed BPT during treatment whereas six (15%) patients developed BPT post-treatment. Cumulative bleomycin dose ≥240 mg (relative risk 3.8, confidence interval: 1.2-12.2,P =0.02) was found to increase the risk of BPT. Three-year overall survival in patients with and without toxicity was 82% and 93%, respectively. Conclusions The frequency of BPT in the study population is 27%, and cumulative bleomycin dose ≥240 mg has been found to be associated with increased risk of developing BPT. BPT does not negatively impact survival outcome in GCT patients receiving BEP regimen.

To the Editor: We read with interest the report by Epler and Kelly[1][1] on post-breast cancer radiotherapy bronchiolitis obliterans organizing pneumonia. The authors reported that the post-radiotherapy lung injury usually developed during the 12 months after completion of radiotherapy and was

BackgroundRadiation therapy (RT) plays a key role in curative-intent treatment for locally advanced lung cancer. Radiation induced pulmonary toxicity can be significant for some patients and becomes a limiting factor for radiation dose, suitability for treatment, as well as post treatment quality of life and suitability for the newly introduced adjuvant immunotherapy. Modern RT techniques aim to minimise the radiation dose to the lungs, without accounting for regional distribution of lung function. Many lung cancer patients have significant regional differences in pulmonary function due to smoking and chronic lung co-morbidity. Even though reduction of dose to functional lung has shown to be feasible, the method of preferential functional lung avoidance has not been investigated in a randomised clinical trial.MethodsIn this study, single photon emission computed tomography (SPECT/CT) imaging technique is used for functional lung definition, in conjunction with advanced radiation dose delivery method in randomised, double-blind trial. The study aims to assess the impact of functional lung avoidance technique on pulmonary toxicity and quality of life in patients receiving chemo-RT for lung cancer. Eligibility criteria are biopsy verified lung cancer, scheduled to receive (chemo)-RT with curative intent. Every patient will undergo a pre-treatment perfusion SPECT/CT to identify functional lung. At radiation dose planning, two plans will be produced for all patients on trial. Standard reference plan, without the use of SPECT imaging data, and functional avoidance plan, will be optimised to reduce the dose to functional lung within the predefined constraints. Both plans will be clinically approved. Patients will then be randomised in a 2:1 ratio to be treated according to either the functional avoidance or the standard plan. This study aims to accrue a total of 200 patients within 3 years. The primary endpoint is symptomatic radiation-induced lung toxicity, measured serially 1–12 months after RT. Secondary endpoints include: a quality of life and patient reported lung symptoms assessment, overall survival, progression-free survival, and loco-regional disease control.DiscussionASPECT trial will investigate functional avoidance method of radiation delivery in clinical practice, and will establish toxicity outcomes for patients with lung cancer undergoing curative chemo-RT.Trial registrationClinicaltrials.gov Identifier:NCT04676828. Registered 1 December 2020.

Bleomycins (BLMs) are broad-spectrum antitumor drugs, but the dose-dependent lung toxicity has restricted their therapeutic applications. Many efforts have contributed to develop novel BLM analogues, but mainly focused on single functional domain owing to the structural complexity of BLM. Benefit from the engineered production of two novel analogues 6'-deoxy-BLM Z (6'-DO-BLM Z) and BLM Z, they together with clinical BLM-sulfate comprised a good model with varied sugar or C-terminal domain in any two of them, allowing us to study their structure-activity relationships pairwise. Our investigations suggested the biological activities of BLM or its analogues are mainly depended on the C-terminal amine, while the changed C-terminal amine endowed BLM Z with much higher pulmonary toxicity comparing to BLM-sulfate, whereas the deoxidized gulose unit with same C-terminal amine evidently attenuated the pulmonary toxicity of 6'-DO-BLM Z without effect on antitumor activity. Further mechanistic studies revealed that the alleviation of pulmonary toxicity in 6'-DO-BLM Z by a slight change in the sugar moiety could attribute to the decrease of ROS production and thereby reduce the subsequent caspase-1 activity and resulting inflammatory response. Therefore, the synergistic modifications on C-terminal amine and sugar moiety provide new insights to efficiently develop potential BLM candidate with good clinical performance.

Bilateral lung parenchymal involvement is seen in infective as well as noninfective conditions, appearing as focal or diffuse lung disease. PET/CT with FDG helps in characterization (increased glucose utilization is seen by both inflammatory and neoplastic cells). In this article, we describe the spectrum of patterns of FDG uptake and associated CT changes involving bilateral lung parenchyma. Benign conditions described are aspiration pneumonia; pulmonary toxicity by bleomycin; infections, namely, sarcoidosis, miliary pulmonary tuberculosis, and pulmonary nocardiosis; and inflammatory conditions such as pulmonary Langerhans cell histiocytosis and pulmonary alveolar proteinosis. Neoplastic conditions described are bilateral pulmonary metastases and lymphangitic carcinomatosis.

Introduction: Outcomes of patients with classical Hodgkin lymphoma are excellent, and the intent of frontline therapy for even advanced-stage disease has been curative. This review summarizes the role of brentuximab vedotin in the upfront treatment of advanced stage classical Hodgkin lymphoma in the context of reducing therapy-related toxicity without compromising the high cure rate. Areas covered: Strategies to reduce bleomycin-induced lung toxicity include a response-adapted approach investigated in the RATHL study and a replacement of bleomycin with brentuximab vedotin in frontline chemotherapy regimens. In both studies, omission of bleomycin in the non-standard arms decreased the rate of pulmonary toxicity while maintaining high progression-free survival and overall survival rates. Expert opinion: The approval of A+AVD in North America offers a new bleomycin-free regimen for the treatment of advanced-stage HL, but it must be balanced against a risk-adapted approach. Recently presented subset analyses raise a question about which patients benefit most from this therapy.

Background The use of high fraction of inspired oxygen (FI O2 ) can cause direct pulmonary toxicity and pulmonary complications. The purpose of this study was to evaluate the effect of different FI O2 on development of intraoperative atelectasis in mechanically ventilated children using lung ultrasound. Methods In this randomized controlled, patient- and sonographer-blinded trial, 86 children (≤6 years) undergoing noncardiac surgery were allocated into a low (n = 43) or high (n = 43) FI O2 group. The low FI O2 group consistently received 30% air-oxygen mixture during preoxygenation, ultrasound-guided recruitment maneuver, and mechanical ventilation. The high FI O2 group received 100% oxygen during preoxygenation and ultrasound-guided recruitment maneuver and 60% air-oxygen mixture during mechanical ventilation. Positive end-expiratory pressure of 5 cm H2 O was applied in both groups. Lung ultrasound was performed one minute after the start of mechanical ventilation and at the end of surgery in both groups. Primary outcome was significant atelectasis incidence (consolidation score of ≥2 in any region) on the postoperative lung ultrasound. Secondary outcomes included significant atelectasis incidence on the preoperative lung ultrasound, incidences of intra- and postoperative desaturation, and incidences of postoperative fever and postoperative pulmonary complications. Results Significant atelectasis incidence on the postoperative lung ultrasound was similar between the low and high FI O2 groups (28% vs 37%; Pearson chi-square value = 0.847; P = .357; OR 1.531; 95% CI 0.617-3.800). Significant atelectasis incidence on the preoperative lung ultrasound was also similar between the groups (12% vs 9%; Pearson chi-square value = 0.124; P = .725; OR 0.779; 95% CI 0.194-3.125). There were no statistically significant differences in the other secondary outcomes. Conclusions FI O2 did not affect significant atelectasis formation in mechanically ventilated children who received ultrasound-guided recruitment maneuver and positive end-expiratory pressure.

Introduction Bleomycin pulmonary toxicity (BPT) is a potentially life-threatening consequence of bleomycin usage in patients. An overproduction of epithelium-derived cytokines, habitually linked to allergic inflammation, has been recently revealed in experimental models of BPT. Methods We assessed retrospectively our cohort of patients with Hodgkin Lymphoma treated with bleomycin between 2014 and 2016 for their demographic, clinical features, including BPT development, atopy status and risk factors for BPT. Then they were invited for allergy testing and blood sample collection. The samples were stimulated with different stimuli (Bleomycin, IL-33, TSLP) for 24 h on cell culture. The culture supernatants were analysed for TGF-β, Galectin3, Arginin, Amphiregulin, Eotaxin, IFNγ, TNFα, IL1β, 4, 5, 6, 10, 13, 17, MIP-1α, and bleomycin hydrolase (BLH) levels. Results The cohort consisted of 51 patients showed that atopy was the only significant risk factor for BPT occurrence (OR: 7.2, p = 0.007). Fourteen subjects were included for blood analysis. The analysis of supernatants at the unstimulated condition revealed that BLH and Amphiregulin were significantly lower in patients who had BPT than controls. The BLH cut-off that best identified a history of BPT was 175.31 (Sensitivity: 62.5%, specificity: 100%). Following the stimulation, BLH reduced compared to the unstimulated condition and the difference between groups remained significant (p Conclusion Our study is the first to report that low levels of bleomycin hydrolase in allergic individuals may be predisposing to a possible pathway of fibrosis.

Purpose Thoracic re-irradiation (re-RT) of lung cancer has been challenged by the tolerance doses of normal tissues. We retrospectively analyzed local control, overall survival (OS) and toxicity after thoracic re-RT using highly conformal radiotherapy, such as intensity modulated radiotherapy and stereotactic body radiotherapy. Materials and methods Thirty-one patients who received high-dose thoracic re-RT were analyzed. Doses were recalculated to determine biologically equivalent doses. The median interval to re-RT was 15.1 months (range, 4.4 to 56.3 months), the median initial dose was 79.2 Gy10 (range, 51.75 to 150 Gy10), and the median re-RT dose was 68.8 Gy10 (range, 43.2 to 132 Gy10). Results Eighteen (58.1%) and eleven (35.5%) patients showed loco-regional recurrence and distant metastasis, respectively, after 17.4 months of median follow-up. The 1-year and 2-year local control rates were 60.2% and 43.7%, respectively. The median loco-regional recurrence-free-survival (LRFS) was 15.4 months, and the median OS was 20.4 months. The cumulative and re-RT biologically equivalent dose for α/β=10 (BED10) doses were the most significant prognostic factors. Cumulative BED10 ≥145 Gy10 and re-RT BED10≥68.7 Gy10 were significantly associated with longer OS (p=0.029 and p=0.012, respectively) and LRFS (p=0.003 and p=0.000, respectively). The most frequent acute toxicity was grade 1-2 pulmonary toxicity (41.9%). No acute grade 3 or higher toxicities occurred. Conclusion Our results show that high-dose thoracic re-RT of lung cancer can be safely delivered using highly conformal radiotherapy with favorable survival and acceptable toxicity. An optimal strategy to select patients who would benefit from re-RT is crucial in extending the indications and improving the efficacy with a sufficiently high dose.

Objective To compare the predictive value of pretreatment inflammation-based scoring systems in patients with germ cell tumors receiving first-line bleomycin-based chemotherapy. Methods Retrospectively, we evaluated 57 patients with germ cell tumors. Bleomycin pulmonary toxicity was defined as the presence of asymptomatic decline in pulmonary function tests, pulmonary symptoms or interstitial pneumonia on computed tomography in the absence of infection. The neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, systemic immune-inflammation index, albumin-to-globulin ratio, Prognostic Nutritional Index, Glasgow Prognostic Score and C-reactive protein were measured in all patients. To assess the predictive ability of each scoring system, the area under the receiver operating characteristic curve was calculated, and multivariate analysis was carried out to identify the predictive scores associated with bleomycin pulmonary toxicity. Results Of the 57 patients, 15 patients developed bleomycin pulmonary toxicity. The neutrophil-to-lymphocyte ratio had the highest area under the curve value (0.763) of all inflammation-based scoring systems, followed by the Prognostic Nutritional Index (0.749). In multivariate analysis, the neutrophil-to-lymphocyte ratio (odds ratio 11.5; P = 0.009) and Prognostic Nutritional Index (odds ratio 9.07; P = 0.013) were independently associated with development of bleomycin pulmonary toxicity. As these two independent markers were combined, the area under the curve achieved the highest value (0.822). Conclusions The present study shows that the neutrophil-to-lymphocyte ratio and Prognostic Nutritional Index are independent risk factors for development of bleomycin pulmonary toxicity. The combination of the neutrophil-to-lymphocyte ratio and Prognostic Nutritional Index seems to have superior predictive value compared with other inflammation-based scoring systems.

The wide use of perfluorooctane sulfonate (PFOS) has led to increasing concern about its human health risks over the past decade. In vivo and in vitro studies are important and effective means to ascertain the toxic effects of PFOS on humans and its toxic mechanisms. This article systematically reviews the human health risks of PFOS based on the currently known facts found by in vivo and in vitro studies from 2008 to 2018. Exposure to PFOS has caused hepatotoxicity, neurotoxicity, reproductive toxicity, immunotoxicity, thyroid disruption, cardiovascular toxicity, pulmonary toxicity, and renal toxicity in laboratory animals and many in vitro human systems. These results and related epidemiological studies confirmed the human health risks of PFOS, especially for exposure via food and drinking water. Oxidative stress and physiological process disruption based on fatty acid similarity were widely studied mechanisms of PFOS toxicity. Future research for assessing the human health risks of PFOS is recommended in the chronic toxicity and molecular mechanisms, the application of various omics, and the integration of toxicological and epidemiological data. Keywords: PFOS, Human health risk, In vivo, In vitro

Background This study set out to evaluate the effect of dose rate on normal tissues (the lung, in particular) and the variation in the treatment efficiency as determined by the monitor unit (MU) and energy applied in Linac-based volumetric arc therapy (VMAT) total marrow irradiation (TMI). Methods Linac-based VMAT plans were generated for the TMI for six patients. The planning target volume (PTV) was divided into six sub-volumes, each of which had their own isocenter. To examine the effect of the dose rate and energy, a range of MU rates (40, 60, 80, 100, 300, and 600 MU/min) were selected for 6, 10, and 15 MV. All the plans were verified by portal dosimetry. Results The dosimetric parameters for the target and normal tissue were consistent in terms of the energy and MU rate. The beam-on time was changed from 59.6 to 6 min for 40 and 600 MU/min. When 40 MU/min was set for the lung, the dose rate delivered to the lung was less than 6 cGy/min (that is, 90%), while the beam-on time was approximately 10 min. The percentage volume of the lung receiving 20 cGy/min was 1.47, 3.94, and 6.22% at 6, 10, and 15 MV, respectively. However, for 600 MU/min, the total lung volume received over 6 cGy/min regardless of the energy, and over 20 cGy/min for 10 and 15 MV (i.e., 54.4% for 6 MV). Conclusions In TMI treatment, reducing the dose rate administered to the lung can decrease the incidence of pulmonary toxicity. To reduce the probability of normal tissue complications, the selection of the lowest MU rate is recommended for fields including the lung. To minimize the total treatment time, the maximum MU rate can be applied to other fields. Electronic supplementary material The online version of this article (10.1186/s13014-019-1296-y) contains supplementary material, which is available to authorized users.

The combination of programmed cell death 1/programmed cell death ligand 1 blockade and thoracic radiotherapy has become the new standard of care in the treatment of locally advanced non-small-cell lung cancer. The information regarding the pulmonary safety of such therapy remains limited to mostly retrospective studies and case reports with a small portion of data from prospective clinical trials. By analyzing the underlying mechanisms of interactions between radiation and immunotherapy from preclinical data and summarizing safety data from relevant clinical studies with pulmonary toxicity, we believe that longer and rigorous follow-up is warranted, to determine if the combination of such modalities is appropriate for patients without risking undue toxicity.

To evaluate the role of ultrasonography (USG) in the diagnosis of bleomycin-induced pulmonary toxicity (BT).The study included patients with suspected BT during treatment with bleomycin due to various oncologic diseases between June 2015 and May 2017. The patients initially underwent clinical and high-resolution computed tomography (HRCT) examinations and pulmonary function tests (PFT)-diffusing capacity of the lung for carbon monoxide (DLCO), followed by registration of USG findings-number of comet tail artifact (CTA) images by a different pulmonologist. We compared the findings from USG, HRCT, and PFT-DLCO tests between BT and non-BT groups. With the diagnosis based on clinical-radiologic and PFT-DLCO assessments taken as the gold standard, we determined the sensitivity and specificity of the USG outcomes for diagnosis of BT.The study included a total of 30 patients. Nine patients were diagnosed as having BT according to their clinical and radiologic findings and PFT-DLCO measurements. The mean number of CTA images was 68.7±22 in patients with BT vs 28.2±9.3 in those without BT (P.001). The difference in CTA images between the patients with and without ground glass density was statistically significant (28.3±9.5 and 64.6±24.5, respectively, P.001). In patients with BT, there was a negative correlation between the number of CTAs and DLCO% and FVC% values (P=.004; P=.016). USG had a sensitivity of 100%, and a specificity of 95% diagnosing BT in selected patients.In bleomycin-induced toxicity, USG findings are correlated with HRCT and PFT-DLCO findings, with a remarkably increased number of CTAs in BT. Thoracic USG examination is a diagnostic tool with a high sensitivity and specificity for diagnosing BT.

Introduction We report results from a prospective phase I/II trial for patients with centrally located, early-stage NSCLC receiving stereotactic body radiation therapy. Methods Eligible patients were medically inoperable with biopsy-proven NSCLC within 2 cm of the proximal bronchial tree or 5 mm of the mediastinal pleura or parietal pericardium. Phase I had four dose levels using 5 fractions: 9, 10, 11, and 12 Gy per fraction. The primary phase II objective was to determine if the maximum tolerated dose in phase I achieved local control greater than 80% at 2 years. Results Seventy-four patients were enrolled; 23 to phase I and 51 to phase II. Two phase I patients treated with 10 Gy × 5 fractions developed unrelated acute grade 3 lung toxicities which resolved. The phase II dose level selected was 11 Gy × 5 fractions. The median follow-up for living phase II patients was 27 months (range, 9 to 58 months). Two-year local control using 11 Gy × 5 fractions was 85% (95% confidence interval [CI]: 62%–95%). Two-year overall survival was 43% (95% CI: 28%–57%). Three patients (6%, 95% CI: 1%–17%) experienced acute grade 3 and 4 cardiac or pulmonary toxicities. Of the 41 patients evaluable for late cardiac and pulmonary toxicity, 11 (27%, 95% CI: 14%–43%) developed grade 3, 5 (12%, 95% CI: 4%–26%) developed grade 4, and 1 (4%, 95% CI: 0%–13%) died of grade 5 toxicity. Conclusion Stereotactic body radiation therapy for central NSCLC using 11 Gy × 5 fractions is tolerable and has excellent local control, but is associated severe late toxicity in some patients.

Introduction Bleomycin (BLM) is a chemotherapeutic agent that is used in the management of some human cancers such as lymphomas and squamous cell carcinomas. The major limitation of BLM therapy is pulmonary toxicity. Combining medicinal herbs and chemotherapy drugs are proposed to attenuate this side effect of BLM. Methods We conducted a search of some databases such as PubMed for articles and reviews published between 1998 and 2018, with different keywords including “bleomycin”, “pulmonary fibrosis”, “plant extract”, “bioactive compound”, “herbal preparation”. Results Studies revealed that these natural products have several mechanisms of action to ameliorate pulmonary fibrosis such as inhibitory effects against the elevation of inflammatory markers such as NF-κB and preventing an increase in fibrotic markers like MMP-9 and HYP. Among the plant extracts that were evaluated, Chrysanthemum indicum enhanced the anti-cancer activity of BLM and showed a synergistic effect with BLM besides, substantial potential in improving BLM induced pulmonary fibrosis. Conclusion In conclusion, the present review demonstrates that the herbs and their active ingredients are a promising source of compounds that can play pivotal roles in the alternative adjuvant chemotherapy in reducing the pulmonary fibrosis of BLM.

Pomalidomide, previously used to treat multiple myeloma, has been reported to cause acute pulmonary toxicity that improves with drug discontinuation. We present a case of delayed pneumonitis with persistent fibrosis associated with pomalidomide. A 61-year-old male treated with pomalidomide and corticosteroids presented with acute on chronic dyspnea, profound hypoxemia, and ground glass opacities on computerized tomographic imaging. Corticosteroid taper and discontinuation of pomalidomide resulted in clinical improvement, but with substantial residual pulmonary fibrosis. Given the temporal improvement, but not resolution, following discontinuation of an agent with an established propensity for lung injury, we attribute this presentation to pomalidomide toxicity.

Models of thoracic irradiation have been developed as clinicians and scientists have attempted to decipher the events that led up to the pulmonary toxicity seen in human subjects following radiation treatment. The most common model is that of whole thorax irradiation (WTI), applied in a single dose. Mice, particularly the C57BL/6J strain, has been frequently used in these investigations, and has greatly informed our current understanding of the initiation and progression of radiation induced lung injury (RILI). PURPOSE: In this review, we highlight the sequential progression and dynamic nature of RILI, focusing primarily on the vast array of information that has been gleaned from murine model. Ample evidence indicates a wide array of biological responses that can be seen following irradiation, including DNA damage, oxidative stress, cellular senescence and inflammation, all triggered by the initial exposure to ionizing radiation (IR) and heterogeneously maintained throughout the temporal progression of injury, which manifests as acute pneumonitis and later fibrosis. It appears that the early responses of specific cell types may promote further injury, disrupting the microenvironment and preventing a return to homeostasis, although the exact mechanisms driving these responses remains somewhat unclear. CONCLUSION: Attempts to either prevent or treat RILI in preclinical models have shown some success by targeting these disparate radiobiological processes. As our understanding of the dynamic cellular responses to radiation improves through the use of such models, so does the likelihood of preventing or treating RILI.

Objectives To estimate the relative risk of pulmonary toxicity in patients exposed to a bleomycin-based chemotherapy including filgrastim compared to a similar chemotherapy without filgrastim. Methods We conducted a nested case–control study of patients treated with BEP (bleomycin, etoposide and cisplatin) for germ cell cancer or with ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) for Hodgkin’s lymphoma at the Hôtel-Dieu de Lévis Hospital between 31 October 2000 and 30 June 2016. The relative risk was estimated by an adjusted odds ratio (aOR) using a propensity score-adjusted regression analysis. Results Thirteen cases of pulmonary toxicity, representing 14.7% of the 88 patients included in the study, were matched with 65 controls. A higher proportion of women (31.8%) than men (11.3%) developed pulmonary toxicity although the difference was not statistically significant ( P = 0.08). Within the cohort, two deaths related to lung toxicity were observed among cases where no filgrastim was used. The risk of pulmonary toxicity associated with the addition of filgrastim was not statistically significant (aOR = 2.48 95% CI = 0.50 to 12.19). Conclusion The results add further evidence that the concomitant use of filgrastim might not increase the risk of pulmonary toxicity of bleomycin. It also suggests that female patients might be more likely to develop this adverse effect. A clinical trial would be needed to confirm this result.