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Histological Changes After Radiation Therapy in Patients with Lung Cancer: A Prospective Study.
Abstract
Background:
Radiotherapy for lung cancer may induce pneumonitis. However, histological effects of radiotherapy on normal lung tissue are unknown. Transbronchial biopsy (TBB) is safe and accurate in monitoring parenchymal lesions in lung-transplanted patients. The aim of this prospective study was to evaluate whether histological changes of the healthy lung parenchyma after radiotherapy are present on TBB biopsies.
Patients and methods:
Twelve patients with lung cancer necessitating radiation therapy participated in the study. Serial TBBs were obtained from lung parenchyma contra-lateral to the tumor before, just after radiotherapy, and at six months post-irradiation. Evaluation of each specimen was based on the presence of congestion, inflammation, hemorrhage and fibrosis.
Results:
A significant increase of interstitial fibrosis (thickness) and congestion was observed between the point prior to radiotherapy and after completion of radiotherapy (p=0.047), as well as between the pre-radiotherapy point and at six months after radiotherapy (p=0.014). Six patients (50%) showed intra-alveolar fibroblastic growth after radiotherapy. No patient showed clinical or radiographic findings of radiation pneumonitis.
Conclusion:
Even in the absence of clinical or radiographic findings, the lung parenchyma contra-lateral to the tumor suffers early histological lesions after radiation therapy, as monitored by serial TBBs.
... This is a prospective study conducted at the University Hospital, Medical School Democritus University of Thrace after the approval was obtained from the internal Review Board (IRBN 4360/01/11/2007), according to the Greek regulations for good clinical practice. It is part of a research protocol on lung toxicity from chemotherapy and radiation therapy from which two articles have already been published 10,11 . All patients signed informed consent prior to the study. ...
... Their study showed that the patients suffered from pulmonary toxicity, according to their lung function tests and the lung inflammatory infiltration, studied by BAL 21 . Similarly, we have previously shown that transbronchial biopsies from the healthy lung parenchyma in patients with lung cancer showed early histological changes after chemotherapy and radiation therapy 10 . This was associated with changes in respiratory function tests 11 . ...
Published articles support the effect of chemotherapy in the immune environment of tumors, including lung carcinomas. The role of CD4 + T-cells is crucial for expansion and accumulation of other antigen-specific immune cells, and the participation of CD8 + cells in tumor killing activity has been confirmed by many studies. However, little is known about the effect of chemotherapy on the healthy lung parenchyma from lung cancer patients, and whether there are differences between the different chemotherapy compounds used to treat this patient population. The aim of our study was to explore the effect of chemotherapy on CD4 + and CD8 + cells in the bronchoalveolar lavage fluid (BALF) of the healthy lung in patients treated with standard chemotherapy regimens. Fifteen patients underwent BAL, in the healthy lung before and after six chemotherapy courses. Platinum-based regimens included vinolerbine (VN) in 6 patients, gemcitabine (GEM) in 4 patients and etoposide (EP) in 5 patients. All patients but one were males and smokers (93%). The median age of patients was 56 years (42–75). No significant difference was noted in the patients’ age between the three treated groups. Furthermore, between the three groups, no significant changes in the means of CD4 + and CD8 + cells were noted. However, when we compared the mean CD4 + cells before and after chemotherapy within each group, changes were noted when comparing VN before versus after (p = 0.05), GEM before versus after (p = 0.03), and EP before versus after (p = 0.036). In our pilot study, changes were noted in BALF CD4 + cells for the three most applied regimens at the normal lung parenchyma.
... Additionally, the accuracy was lower compared to that of the palliation group. Radiation therapy induces inflammation or fibrosis and can cause aggressive and irreversible structural changes [24,25]. We believe that these diagnostic values in the radiation group are affected by radiation changes, such as fibrosis, that make an EBUS-TBNA procedure difficult. ...
... Size of target on axial CT images, mm24 Korean Cancer Association This article is protected by copyright. All rights reserved. ...
Purpose:
Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is widely used for the diagnosis and staging of lung cancer. However, evidence of its usefulness for re-biopsy in treated lung cancer, especially according to the previous treatment, is limited. We evaluated the role of EBUS-TBNA for re-biopsy and its diagnostic values in patients with different treatment histories.
Materials and methods:
We reviewed the medical records of patients who underwent EBUS-TBNA for re-biopsy of suspicious recurrent or progressive lesions between January 2006 and December 2016 at the National Cancer Center in South Korea. Patients were categorized into three groups based on the previous treatment modalities: surgery, radiation, and palliation.
Results:
Among the 367 patients (surgery, n=192; radiation, n=40; palliation, n=135) who underwent EBUS-TBNA for re-biopsy, the overall sensitivity, negative predictive value (NPV), and diagnostic accuracy of EBUS-TBNA in detecting malignancy were 95.6%, 82.7%, and 96.3%, respectively. The sensitivity was lower in the radiation group (83.3%) when compared with the surgery (95.7%, p=0.042) and palliation (97.7%, p=0.012) groups. The NPV was lower in the palliation group (50.0%) than in the surgery group (88.5%, p=0.042). The sample adequacy of EBUS-TBNA specimens was lower in the radiation group (80.3%) than in the surgery (95.4%, p < 0.001) or palliation (97.8%, p < 0.001) groups. EGFR mutation analysis was feasible in 94.6% of the 92 cases, in which mutation analysis was requested. There were no major complications. Minor complications were reported in 12 patients (3.3%).
Conclusion:
EBUS-TBNA showed high diagnostic values and high suitability for EGFR mutation analysis with regard to re-biopsy in patients with previously treated lung cancer. The sensitivity was lower in the radiation group and NPV was lower in the palliation group. The complication rate was low.
... The acute stage is observed most frequently from 6 to 12 weeks after RT and symptoms include cough, shortness of breath, fever and changes in pulmonary function (3,4,5,6,7). Its chronic form occurs most often in the span of 6 to 12 months and can last up to 2 years after RT, a process associated with the development of fibrosis (8,9,10,11,12,13,14,15). Frequency and severity depend on a number of parameters, such as age, irradiated area, radiotherapeutic regimen, administered cumulative dose -most often at values above 20 Gray and almost always at doses above 40 Gray, as well as previous or concomitant chemotherapy. ...
... Its chronic form occurs most often in the span of 6 to 12 months and can last up to 2 years after RT, a process associated with the development of fibrosis (8,9,10,11,12,13,14,15). Frequency and severity depend on a number of parameters, such as age, irradiated area, radiotherapeutic regimen, administered cumulative dose -most often at values above 20 Gray and almost always at doses above 40 Gray, as well as previous or concomitant chemotherapy. All of the above mentioned factors may increase drastically the effect of RT (4,11,12,15,16,17,18,19,20). Changes, attributed to RP and visualized by computed tomography (CT), are also divided into early and late ones, respectively, acute inflammatory reactions including matt glass type/ infiltrative parenchymal changes and late or chronic ones (most of the cases) resulting in fibrosis (21,22). ...
Objectives:
Radiation pneumonitis (RP) can be an adverse complication of radiotherapy (RT) and can limit the application of the already planned radiation dose. It is often associated with RT of lung carcinoma and is occasionally caused by radiation therapy of breast carcinoma and lymphomas located in the mediastinum. Positron emission tomography/computed tomography (PET/CT) emerges lately as a prospective modality for early diagnostics of RP. The aim of this study was to summarize the initial data from diagnostic application of PET/CT in patients suspicious of RP and to derive criteria, which can help differentiate RP from early recurrence of the disease and/or residual tumor.
Methods:
The current study included 23 patients who had metabolic (PET) and anatomical (CT) changes consistent with RP. We additionally defined metabolic activity (SUVmax) in the lung parenchyma of 20 patients without RT.
Results:
All patients had increased metabolic activity in the lung parenchyma involved in the irradiated area with a mean SUVmax 3.45 (ranging between 1 and 7.1). The control group had a physiological background metabolic activity-SUVmax 0.61 +/- 0.11.
Conclusion:
Metabolic changes in patients suspicious of RP involved diffusely increased metabolic activity coinciding with the anatomical changes in the irradiated area. Three out of 23 patients had a proven recurrence of the primary neoplastic process in the irradiated area. The metabolic changes in those patients involved an increase in metabolic activity at follow-up or lack of tendency towards normalization after chemotherapy, which implied the existence of viable tumor cells. Our initial experience in the diagnostic application of 18F-FDG PET/CT in patients suspicious of RP allows us to summarize the following: PET/CT is a reliable imaging modality in the diagnostics of RP. Through its sequential use, we can differentiate inflammatory changes related to RP from early recurrence of the primary neoplastic process.
... Radiotherapy (RT) was delivered to the affected lung and mediastinal nodes. All patients were treated with 18-MV photons and three-dimension conformal RT, which spares healthy tissue as previously described (10). Nine fractions of 3.5 Gy were applied, delivering a median biological (for α/ β=4 Gy dose) of 48 Gy to the mediastinum and the tumour mass, followed by five additional fractions of 3.5 Gy that increased the total biological dose to >70 Gy to the gross tumor area. ...
... Radiation results in the damage of endothelial, epithelial (type II pneumocytes) cells, by apoptosis and stimulation of stress response genes progressing to an acute exudative inflammation process, which occurs usually 1-6 months after completion of treatment (4,5). Also, early histological lesions with various grades of interstitial and parenchymal involvement were observed after both chemotherapy and radiation therapy (10). In our study, overall, a progressive decline of FEV1 and FVC was observed after chemoradiation. ...
Background:
Reports point out lung toxicity of chemotherapeutic agents and radiation therapy in cancer patients. The aim of our study was to assess lung function after sequential chemoradiation therapy in patients with lung cancer.
Methods:
Fifteen lung cancer patients participated the study and underwent lung function assessment before and after sequential treatment of chemotherapy with the 3 most applied platinum-based combinations: of vinorelbine (VN) 6 patients, gemcitabine (GEM) 4 patients and etoposide (EP) 5 patients and radiation therapy. Lung function tests were forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), total lung capacity (TLC), diffusing capacity for carbon monoxide (DLCO) and carbon monoxide transfer coefficient (Kco).
Results:
Mean patients' age was 58±9.4 years (42-75 years). Male patients were 14 (93.3%), all smokers. Overall, after chemoradiation treatment significant changes were noted in FEV1 (P=0.012), FVC (P=0.046), TLC (P=0.04) from baseline. The drop from baseline was more significant after chemoradiation therapy in DLCO (P=0.002) and KCO (P=0.008).
Conclusions:
According to our results, sequential chemoradiation causes significant changes in lung function parameters in patients with lung cancer.
... To date, several studies have reported on different biomarker responses and clinical diagnoses 2,11,20,39 . However, most validation efforts have compared functional information between different imaging techniques 40 , and only a few studies have investigated lung pathology post-RT 41,42 . To our knowledge, no study has presented results of imaging biomarkers in conjunction with pathology findings to analyze radiation-induced pulmonary function changes. ...
Imaging biomarkers can assess disease progression or prognoses and are valuable tools to help guide interventions. Particularly in lung imaging, biomarkers present an opportunity to extract regional information that is more robust to the patient’s condition prior to intervention than current gold standard pulmonary function tests (PFTs). This regional aspect has particular use in functional avoidance radiation therapy (RT) in which treatment planning is optimized to avoid regions of high function with the goal of sparing functional lung and improving patient quality of life post-RT. To execute functional avoidance, detailed dose–response models need to be developed to identify regions which should be protected. Previous studies have begun to do this, but for these models to be clinically translated, they need to be validated. This work validates two metrics that encompass the main components of lung function (ventilation and perfusion) through post-mortem histopathology performed in a novel porcine model. With these methods validated, we can use them to study the nuanced radiation-induced changes in lung function and develop more advanced models.
... In critical patients, the thrombogenic biomarker D-dimer may increase a lot, the counts of blood lymphocytes back down persistently, platelet count is reduced and laboratory alterations in biomarkers of multi-organ injury become prominent. Bronchoalveolar lavage (BAL) fluid shows inflammatory cells with activated lymphocytes, while pyrogenic cytokines such as interleukin-6 (IL-6), IL-10 could be also detectable [10]. Clearly swab and BAL are negative for opportunistics or viruses. ...
Coronavirus disease 2019 (COVID-19), is a novel infectious disease responsible for a severe acute respiratory syndrome due to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, which was firstly reported in January 2020 in Wuhan, Hubei Province, China, and then rapidly spread to other countries beyond China with a pandemic proportion in these last two years. In its severe lung expression, disease onset may result in death due to massive alveolar damage and progressive respiratory failure due to acute lung injury (ALI) which predisposes to fatal acute respiratory distress syndrome (ARDS). Autopsies reports describe a diffuse alveolar damage with vascular congestion, inflammatory cell population entrapped, thrombosis with hyaline membrane formation in the alveolar walls allowing to an irreversible lung destruction. Altogether these findings remind the radiation oncologists many similarities with radiation induced lung injury which is a well-known side effect of radiotherapy for lung cancer. A fascinating hypothesis is that a common inflammatory paradoxical response of lung could be underlying the injury whatever the causes may be, virus, drugs or ionizing radiation. In this paper we will review the similarities between these two illnesses just going through the mechanisms of ALI-ARDS and the role of the most important immune cells and cytokines involved.
... 43 Similarly, radiation can cause pneumonitis, often but not always localized near the targeted lesion, and usually occurring weeks after the radiation treatment. 44 We suggest consideration of such entities if the patient has recently received antineoplastic therapy, cardiogenic pulmonary edema is ruled out, a microbiologic workup including bronchoscopy is unrevealing, and there are no other obvious potential etiologies of ARDS. ...
Acute respiratory distress syndrome is a common condition among critically ill patients, but remains under-recognized and undertreated. Under-recognition may result from confusion over the clinical inclusion criteria, as well as a misunderstanding of the complex relationship between the clinical syndrome, the variable histopathologic patterns, and the myriad clinical disorders that cause acute respiratory distress syndrome. The identification of the clinical syndrome and determination of the causal diagnosis are both required to optimize patient outcomes. Here we review the definition, discuss pitfalls in recognizing acute respiratory distress syndrome and consider an approach to ascertain specific etiologies of acute respiratory distress syndrome.
... This picture is also described in Co-19 pneumonia due to a massive lung involvement. 9 Further, similarities can be found in autopsy reporting. ...
... Abnormal proliferation of mesenchymal cells, overproduction/ extensive deposition of ECM, subpleural fibrosis with fibroblastic foci, spatial heterogenity and honeycombing are the histopathological characteristics of a usual interstitial pneumonia pattern [32]. Regarding RILI, an acute exudative phase with inflammatory cell infiltration, alveolar congestion, desquamation of alveolar epithelial cells and/or fibrosis can be seen in the lung tissues, depending on the timing of the histopathological evaluation [33]. ...
Idiopathic pulmonary fibrosis (IPF) is a progressive, fibrotic lung disease with an unknown cause. Uncertainties still remain regarding the pathogenesis of IPF, and the prognosis of this disease is poor despite some recent improvements in treatment. Radiation induced lung injury (RILI) is a common complication and a dose-limiting toxicity of thoracic radiotherapy. Importantly, IPF is a crucial risk factor for pulmonary toxicity after thoracic radiotherapy. Although IPF is not universally accepted as a definite contraindication for thoracic radiotherapy at present, it has been shown that IPF can increase the risk of severe and fatal complications after thoracic radiotherapy. Proton beam therapy has shown promising results in reducing the incidence of thoracic radiotherapy related life-threatening complications in IPF patients, but the current evidence is not sufficient to recommend the standard use of it. Many similarities are noticeable between IPF and RILI in terms of pathogenesis and underlying mechanisms. Better understanding of the mechanisms of IPF and RILI may enable clinicians to provide safer and more effective thoracic radiotherapy treatments in cancer patients with IPF. In this review, we summarize the current knowledge of IPF, present the importance of IPF in radiation oncology practice, and highlight the similarities and relationship between IPF and RILI.
... The surrounding lung parenchyma shows varying degrees of radiation pneumonitis, which can confound radiologic prediction of patient prognosis (44). Findings include interstitial fibrosis, inflammation, organizing pneumonia, hemorrhage, and reactive atypia of the pneumocytes (45). ...
Surgical resection is the standard-of-care approach for early-stage non-small cell lung cancer (NSCLC). Surgery is also considered an acceptable standard infit patients with oligometastatic lesions in the lungs. The COVID-19 pandemic has led to worldwide issues with access to operating room time, with patients and physicians facing uncertainty as to when surgical resection will be available, with likely delays of months. Further compounding this are concerns about increased risks of respiratory complications with lung cancer surgery during active phases of the pandemic. In this setting, many thoracic oncology teams are embracing a paradigm where stereotactic ablative radiotherapy (SABR) is used as a bridge, to provide radical-intent treatment based on a combination of immediate SABR followed by planned surgery in 3–6 months. This pragmatic approach to treatment has been named SABR-BRIDGE (Stereotactic ABlative Radiotherapy Before Resection to avoId Delay for early-stage lunG cancer or oligomEts). This term has also been applied to the pragmatic study of the outcomes of this approach. In this paper, we discuss the standards of care in treatment of early-stage (NSCLC) and pulmonary oligometastases, the impetus for the SABR-BRIDGE approach, and the controversies surrounding assessment of pathological response to neo-adjuvant radiation therapy.
... also induces damage to cells, such as alveolar congestion, inflammation or fibrosis and causes more aggressive and irreversible structural changes [21,22] (Fig. 1C). These changes could occur outside of the radiation field, or even on the contralateral side, thereby affecting the whole lung [23,24]. ...
Purpose:
Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is widely used for the diagnosis and staging of lung cancer. However, evidence of its usefulness for re-biopsy in previously treated lung cancer is limited. We evaluated the role of EBUS-TBNA for re-biopsy and its diagnostic yield in patients with different treatment histories.
Materials and methods:
We reviewed medical records of patients who underwent EBUS-TBNA for re-biopsy of suspected lesions between January 2006 and December 2016 at the National Cancer Center in South Korea. Patients were categorized into three groups based on the previous treatment modality: surgery, radiation, and chemotherapy.
Results:
Among 371 patients (193, 40, and 138 patients in the surgery, radiation and chemotherapy groups, respectively) who underwent EBUS-TBNA, the overall diagnostic yield had sensitivity of 95.6%, negative predictive value (NPV) of 82.5%, and diagnostic accuracy of 96.4%. Sensitivity, accuracy and adequacy were lower in the radiation group (87.8%, 90.7%, and 85.7%, respectively) than in the surgical (95.7%, 96.8%, and 95.4%, respectively) or chemotherapy group (98.3%, 98.3%, and 97.5%, respectively) (P < 0.05 in each comparison). The NPV was lower in the chemotherapy group (60.0%) than in the surgical (88.7%) or radiation group (72.2%) (p < 0.05). Sample adequacy for mutation analysis was 94.6% in 92 cases which were requested for mutation test. There were no major complications requiring admission or intervention. Only minor complications were reported in 12 patients (3.2%).
Conclusion:
For re-biopsy of previously treated lung cancer, EBUS-TBNA showed high diagnostic yield but with relatively low yield in the radiation group. The procedure was safe without any major complications, and the specimens obtained were adequate for mutation analysis.
... [3] The level of genetic damage in peripheral blood lymphocytes can be hypothesized to the amount of damage in the precursor cells that lead to the carcinogenic process in target tissues. [4] Both cohort and nested case-control studies have shown evidence that cytogenetic biomarkers are positively correlated with cancer risk that has been strongly validated showing that chromosome aberrations are a marker of cancer risk reflecting both the genotoxic effects of carcinogens and individual cancer susceptibility. [5] Approximately, 85% and 47% of the lung cancers in men and women are caused by tobacco smoking. ...
... Both lung tissue and peripheral blood T cells isolated from NSCLC patients have low levels of T-bet expression [21,22]. Furthermore, even in the absence of clinical or radiographic findings, the lung parenchyma contralateral to the tumor suffers an early and significant increase in interstitial fibrosis (thickness) and congestion after radiation therapy, as monitored by serial transbronchial biopsy [23]. These observations suggest that NSCLC may be characterized by a Type-2-biased immune phenotype and likely promotes the formation of fibrotic tissue. ...
Lung fibrosis may be associated with Type-2 polarized inflammation. Herein, we aim to investigate whether radiation can initiate a Type-2 immune response and contribute to the progression of pulmonary fibrosis in tumor-bearing animals. We developed a tumor-bearing mouse model with Lewis lung cancer to receive either radiation therapy alone or radiation combined with Th1 immunomodulator unmethylated cytosine-phosphorothioate-guanine containing oligodeoxynucleotide (CpG-ODN). The Type-2 immune phenotype in tumors and the histological grade of lung fibrosis were evaluated in mice sacrificed three weeks after irradiation. Mouse lung tissues were analyzed for hydroxyproline and the expression of Type-1/Type-2 key transcription factors (T-bet/GATA-3). The concentration of Type-1/Type-2 cytokines in serum was measured by cytometric bead array. Lung fibrosis was observed to be more serious in tumor-bearing mice than in normal mice post-irradiation. The fibrosis score in irradiated tumor-bearing mice on Day 21 was 4.33 ± 0.82, which was higher than that of normal mice (2.00 ± 0.63; P < 0.05). Hydroxyproline and GATA-3 expression were increased in the lung tissues of tumor-bearing mice following irradiation. CpG-ODN attenuated fibrosis by markedly decreasing GATA-3 expression. Serum IL-13 and IL-5 were elevated, whereas INF-γ and IL-12 expression were decreased in irradiated tumor-bearing mice. These changes were reversed after CpG-ODN treatment. Thus, Type-2 immunity in tumors appeared to affect the outcome of radiation damage and might be of interest for future studies on developing approaches in which Type-1-related immunotherapy and radiotherapy are used in combination.
... Studying the rotational component could improve highprecision radiation therapy techniques, as for optimizing the collimator position and rotation (Wu et al 2012), in order to prevent healthy structures from radiation (e.g. rectum and bladder for prostate (Rijkhost et al 2009), heart, liver and parenchyma for lung (Karpathiou et al 2014)). Prostate studies (vanHerk et al 1995, Li et al 2009, Tehrani et al 2013, Huang et al 2015 show the presence of a rotational component, which can lead to a dose delivery that is lower than the actual prescription. ...
The quantification of tumor motion in sites affected by respiratory motion is of primary importance to improve treatment accuracy. To account for motion, different studies analyzed the translational component only, without focusing on the rotational component, which was quantified in a few studies on the prostate with implanted markers. The aim of our study was to propose a tool able to quantify lung tumor rotation without the use of internal markers, thus providing accurate motion detection close to critical structures such as the heart or liver. Specifically, we propose the use of an automatic feature extraction method in combination with the acquisition of fast orthogonal cine MRI images of nine lung patients. As a preliminary test, we evaluated the performance of the feature extraction method by applying it on regions of interest around (i) the diaphragm and (ii) the tumor and comparing the estimated motion with that obtained by (i) the extraction of the diaphragm profile and (ii) the segmentation of the tumor, respectively. The results confirmed the capability of the proposed method in quantifying tumor motion. Then, a point-based rigid registration was applied to the extracted tumor features between all frames to account for rotation. The median lung rotation values were -0.6 ± 2.3° and -1.5 ± 2.7° in the sagittal and coronal planes respectively, confirming the need to account for tumor rotation along with translation to improve radiotherapy treatment.
Research and development of medical countermeasures (MCMs) for radiation-induced lung injury relies on the availability of animal models with well-characterized pathophysiology, allowing effective bridging to humans. To develop useful animal models, it is important to understand the clinical condition, advantages and limitations of individual models, and how to properly apply these models to demonstrate MCM efficacy. On March 20, 2019, a meeting sponsored by the Radiation and Nuclear Countermeasures Program (RNCP) within the National Institute of Allergy and Infectious Diseases (NIAID) brought together medical, scientific and regulatory communities, including academic and industry subject matter experts, and government stakeholders from the Food and Drug Administration (FDA) and the Biomedical Advanced Research and Development Authority (BARDA), to identify critical research gaps, discuss current clinical practices for various forms of pulmonary damage, and consider available animal models for radiation-induced lung injury.
Radiation-induced lung injury is a highly complex combination of pathological alterations that develop over time and severity of disease development is dose-dependent. Following exposures to lethal doses of irradiation, morbidity and mortality can occur due to a combination of edema, pneumonitis and fibrosis. Protein glycosylation has essential roles in a plethora of biological and immunological processes. Alterations in glycosylation profiles have been detected in diseases ranging from infection, inflammation and cancer. We utilized mass spectrometry imaging to spatially map N-glycans to distinct pathological alterations during the clinically latent period and at 180 days post-exposure to irradiation. Results identified alterations in a number of high mannose, hybrid and complex N-glycans that were localized to regions of mucus and alveolar-bronchiolar hyperplasia, proliferations of type 2 epithelial cells, accumulations of macrophages, edema and fibrosis. The glycosylation profiles indicate most alterations occur prior to the onset of clinical symptoms as a result of pathological manifestations. Alterations in five N-glycans were identified as a function of time post-exposure. Understanding the functional roles N-glycans play in the development of these pathologies, particularly in the accumulation of macrophages and their phenotype, may lead to new therapeutic avenues for the treatment of radiation-induced lung injury.
To better understand the outcomes of small cell lung cancer (SCLC), we examined the clinical features and prognostic factors of SCLC in this study. A total of 148 patients who were diagnosed as having SCLC between January 2009 and December 2013 in Cancer Center of Union Hospital, Wuhan, China, were enrolled and their clinical features and prognostic factors were retrospectively analyzed. Log-rank test and Cox regression model were employed for analysis of prognostic factors. The 1- and 2-year overall survival (OS) rates were 59.7% and 25.7%, respectively, for limited disease (LD) patients whose median survival time (MST) was 16 months. The 1- and 2-year OS rates were 29.5% and 5.3%, respectively, for extensive disease (ED) patients whose MST was 10 months. The univariate analysis and multivariate analysis revealed that age, tumor stage, serum CEA and Ki-67 antigen were significantly correlated to the outcomes of SCLC, and they were significant prognostic factors for SCLC. © 2016, Huazhong University of Science and Technology and Springer-Verlag Berlin Heidelberg.
Fistulas between the upper intestinal tract and the airway following esophagectomy are a rare and severe complication with significant mortality. Treatment and therapy are difficult and require a multidisciplinary approach. The objective of this retrospective study was to identify risk factors for these fistulas following esophagetcomy, and to assess their impact on the further clinical course and outcome. 211 patients undergoing Ivor-Lewis esophagectomy for esophageal cancer between 2005 and 2012 were included. The preoperative risk factors including the risk score according to Schröder et al. and the O-Physiological and Operative Severity Score (POSSUM) score, operative and postoperative parameters and the outcome were evaluated. 65% of all patients developed postoperative complications, including 12 patients that developed fistulas between the upper intestinal tract and the airway (airway fistulas [AF]; 5.6%). Neither patient related risk factors nor esophagus-specific risk scores correlated with occurrence of AF. Furthermore, surgical treatment and neoadjuvant treatment did not show any effect on development of AF in our patients. However, we could demonstrate that AF significantly impacted on length of hospital stay (AF 52 days vs. No-AF group 16 days, P<0.001), incidence of major pulmonary complications (83.3% vs. 17.1%, P<0.001), 90-day mortality (42% vs. 7.5%, P=0.002) and overall survival (133 days vs. 636 days, P=0.029). With the current study, we could not identify any patient related risk factors, esophagus-specific risk scores or treatment related details that might be useful as predictors of AF after Ivor-Lewis esophagectomy. However, we confirmed that AF significantly impacted on outcomes. This highlights the urgent need for further studies on this rare but devastating complication after esophagectomy.
Reports of bronchiolitis obliterans organizing pneumonia (BOOP) occurring in women after radiation therapy for breast cancer have suggested that radiation to the lung could participate in the develop- ment of BOOP. We now describe the clinical, radiographic, functional, and bronchoalveolar lavage characteristics of this syndrome in a series of 15 patients reported to the Groupe d'Etudes et de Re- cherche sur les Maladies "Orphelines" Pulmonaires (GERM"O"P) in France. All 15 women (60 6 6 yr of age) fulfilled the following inclusion criteria: ( 1 ) radiation therapy to the breast within 12 mo, ( 2 ) general and/or respiratory symptoms lasting for at least 2 wk, ( 3 ) lung infiltrates outside the radia- tion port, and ( 4 ) no specific cause. The patients presented with fever, nonproductive cough, mild dyspnea, and peripheral alveolar opacities on chest radiograph with a characteristic migratory pat- tern. In five patients, BOOP was found at lung pathologic analysis. In all the patients dramatic im- provement was obtained with corticosteroids, but relapses occurred in 12 patients while tapering or after stopping corticosteroids. This report demonstrates that a characteristic BOOP syndrome may occur after radiation therapy to the breast, including tangential radiation to the lung, thus suggest- ing that radiation therapy may prime the development of BOOP. Crestani B, Valeyre D, Roden S, Wallaert B, Dalphin J-C, Cordier J-F, and the Groupe d'Etudes et de Recherche sur les Mala- dies Orphelines Pulmonaires (GERM"O"P). Bronchiolitis obliterans organizing pneumonia syndrome primed by radiation therapy to the breast. AM J RESPIR CRIT CARE MED 1998;158:1929-1935.
Quantitative measurements of the effects of irradiation on normal tissues in humans have been hard to obtain because most tissues are inaccessible and/or direct responses are difficult to quantify in a nondestructive manner. Pneumonitis and fibrotic lung disease are adverse effects seen in varying intensity in patients treated with radiotherapy for carcinomas of the thorax, e.g., breast cancer. In the present study the aim was to evaluate the inflammatory reaction in the underlying parenchyma following postoperative irradiation with bronchoalveolar lavage technique. Twenty-one patients (11 smokers, 10 nonsmokers) with breast cancer stage T1N0M0 received radiotherapy with photons to a target dose of 56 Gy following breast conservative surgery. Nineteen healthy controls were also included. The results showed a clear elevation of neutrophils, mast cells, eosinophils, and lymphocytes in the total irradiated groups, compared to controls. When subclassifying the material according to smoking habit, it was obvious that the smokers displayed a significantly decreased inflammatory reaction, i.e., reduced levels of mast cells and lymphocytes, compared to both nonsmoking controls and patients. Eosinophils were seen in an elevated number in all irradiated patients. Radiological signs of pneumonitis were observed in three patients, all in the nonsmoking group. No correlation was found between the volume of lung irradiated and the inflammatory response. It is concluded that bronchoalveolar lavage is a suitable and sensitive method for investigating radiotherapy-induced reactions in the human lung. Furthermore, ongoing smoking during the treatment depressed the inflammatory response in the lung parenchyma induced by irradiation. The present study as well as earlier observations justify further studies concerning the possibility of interaction of smoking with cancer treatment, both from the view of therapeutic failures and reduced adverse effects.
The priming of bronchiolitis obliterans organising pneumonia by radiation therapy (RT) to the breast is now a well recognised syndrome. This study describes the occurrence of chronic eosinophilic pneumonia following RT after surgery for breast cancer in five female patients, with a mean age of 68 yrs (range 49-77). All patients had a history of asthma and/or allergy. At the onset of eosinophilic pneumonia, all patients were symptomatic. Chest radiograph showed pulmonary infiltrates, unilateral and limited to the irradiated lung in three patients, and bilateral in two. Pulmonary opacities were migratory in one patient. All patients had blood eosinophilia >1.0 10(9) x L(-1) and/or eosinophilia >40% at bronchoalveolar lavage differential cell count. The median time interval between the end of radiation therapy and the onset of eosinophilic pneumonia was 3.5 months (range 1-10). All patients rapidly improved with oral corticosteroids without sequelae. Relapse occurred in two patients after treatment withdrawal. Priming of alveolitis by radiation therapy to the breast might promote either bronchiolitis obliterans organising pneumonia or chronic eosinophilic pneumonia, with the latter depending on genetic or acquired characteristics of patients and/or further stimulation that may trigger a T-helper cell type 2 form of lymphocyte response, especially in patients with asthma or other atopic manifestations.
Bronchiolitis obliterans syndrome (BOS) is a major cause of lung allograft dysfunction. Although previous studies have identified mild to severe rejection (grade>or=A2) as a risk factor for BOS, the role of minimal rejection (grade A1) remains unclear. To determine if A1 rejection by itself is a risk factor for BOS, we performed a retrospective cohort study on 228 adult lung transplant recipients over a 7-year period. Cohorts were defined by their most severe rejection episode (none, A1 only, and >or=A2) and analyzed for the subsequent development and progression of BOS using univariate and multivariate time-dependent Cox regression analysis. In the univariate model, the occurrence of isolated minimal rejection was a risk factor for all stages of BOS. Similarly, multivariate models that included HLA mismatch, cytomegalovirus pneumonitis, community acquired viral infection, underlying disease and type of transplant demonstrated that A1 rejection was a distinct risk factor for BOS. Furthermore, the associated risk with A1 rejection was slightly greater than the risk from >or=A2 and treatment of A1 rejection decreased the risk for subsequent BOS stage 1. We conclude that minimal rejection is associated with an increased risk for BOS development and progression that is comparable to A2 rejection.
The main aim of the present study was to assess the early diagnostic value of bronchoalveolar lavage (BAL) in radiation-induced lung injury in patients with breast carcinoma.Twenty-six females receiving postoperative radiotherapy for breast cancer were evaluated before and 0, 15, 30, 60, and 180 days after radiotherapy. History, physical examination, chest radiographs, and pulmonary function tests were obtained. BAL, including lymphocyte subsets analysis, was limited to the second evaluation after radiotherapy. A group of 21 healthy females were used as control. Findings after radiotherapy in asymptomatic patients were compared with findings in a group of patients with radiation pneumonitis.Irradiated patients showed a significantly (p<0.01) greater percentage (29.5±15.7%) of BAL lymphocytes than controls (6.2±3.3%). No statistical differences existed in BAL findings between the irradiated and unirradiated sides of the chest. Percentages of BAL lymphocytes did not differ significantly between patients who developed subsequent pneumonitis (24.5±13.5%) and those who did not develop pneumonitis (32.8±16.5%). Patients with pneumonitis at the time of BAL had significantly higher (p<0.05) alveolar CD4 subset cells (24.8±10.2%) than asymptomatic patients (15.2±8.9%). Maximal reductions in total lung capacity (p<0.01), and residual volume (p<0.05) occurred 60 days after irradiation.The early lymphocytic alveolitis induced by unilateral thoracic radiotherapy in most patients with breast cancer is always bilateral and does not predict the subsequent development of radiological evidence of pneumonitis.
Clinically mandated transbronchial biopsy is universally regarded as the most efficient tool to establish pathology in the allograft. However, the utility of surveillance transbronchial biopsy to facilitate early detection and treatment of acute pulmonary allograft rejection is a matter of current debate. The purpose of this review is to summarize the evidence for and against the performance of surveillance bronchoscopy postlung transplantation, to discuss the risk/benefit ratio and the application of this procedure in the individual patient.
Detection of silent acute rejection of the pulmonary allograft remains an important benefit of surveillance bronchoscopy although definitive evidence for a positive impact on survival or prevention of development of the bronchiolitis syndrome (BOS) is yet to be demonstrated. Perhaps the wrong target has been the focus as new evidence suggests that high grade lymphocytic bronchiolitis is the important independent risk factor for the development of BOS and death after lung transplantation. Providing effective therapies for lymphocytic bronchiolitis can be developed there is now strong support for performance of surveillance transbronchial biopsy. Most studies attest to a low risk of severe complications.
Surveillance bronchoscopy is useful to detect asymptomatic acute rejection but also to determine the presence and severity of lymphocytic bronchiolitis, which should be the new target of therapeutic endeavours. It is acknowledged that the true risk/benefit ratio of surveillance bronchoscopy may differ between programs so each case deserves individual consideration.
Lung fibrosis is a severe complication after radiotherapy in patients with nonsmall cell lung cancer and is the main undesirable late complication limiting the therapeutic ratio of thoracic radiation treatment. Here we evaluated the lung fibrosis using computed tomography scan mediated assessment of lung tissue density in long-term survivals treated with hypofractionated and accelerated radiotherapy supported with amifostine (HypoARC).
Out of 45 patients with locally advanced nonsmall cell lung cancer treated with conformal HypoARC (3.5 Gy x 15 fractions in 4 weeks) and concurrent chemotherapy, 14 are alive 16 to 47 months (median 20) after radiotherapy. Patients received 500 to 1000 mg of amifostine before each radiotherapy fraction, according to a previously described dose individualization algorithm.
Early pneumonitis was absent in all patients, whereas lung density assessed with computed tomography scan in Hounsfield units (HU), within a median of 20 months after radiotherapy, showed marked increase in 2/6 and 0/8 patients who received 500 to 750 mg and 1000 mg of amifostine, respectively. The HU in these 2 patients increased to values below -550 HU, from initial values of -700 to -800 HU. Only one of these 2 patients had mild exertional dyspnoea.
Given the good tolerance of daily high-dose amifostine administration and the encouraging very low rates of pneumonitis and lung fibrosis noted, despite the aggressiveness of the radio-chemotherapy regimen applied, it is suggested that the value of amifostine in chest radiotherapy should be re-evaluated in properly designed randomized clinical trials.
Radiation pneumonitis is a life-threatening result of therapeutic thoracic irradiation, yet its mechanisms are poorly understood. We studied the effects of unilateral lung irradiation (3,000 rad) in sheep from the immediate response to the later development of radiation pneumonitis. We defined radiation pneumonitis by its diagnostic clinical feature, radiographic infiltration of the irradiated zone with a straight margin corresponding to the radiation port. The immediate response in the few hours after irradiation was characterized by cough, labored respiration, hypoxemia (arterial PO2 decreased 19 Torr), mild pulmonary hypertension (pulmonary arterial pressure increased 20%), and lymphopenia. Hemodynamics and gas exchange returned to normal by day 2 but became abnormal again before or during radiation pneumonitis at 32 +/- 2 days. Respiratory distress, hypoxemia, and pulmonary hypertension recurred during radiation pneumonitis. Bronchoalveolar lavage during radiation pneumonitis contained increased neutrophils (19 +/- 4%, control = 7%), increased protein (0.27 +/- 0.1 g/dl, control = 0.12 +/- 0.03), and severely impaired ability to lower surface tension. Alveolar macrophages from both lungs during unilateral radiation pneumonitis exhibited impaired generation of superoxide after phorbol myristate (only a 30% increase). Normal control alveolar macrophages increased superoxide production after stimulation greater than 400%. We conclude that unilateral lung irradiation in sheep causes a mild immediate response followed by radiation pneumonitis at 1 mo. Unilateral radiation pneumonitis in this model is associated with ipsilateral neutrophilic alveolitis, increased bronchoalveolar lavage protein, and impaired surfactant function, as well as bilateral functional abnormalities of alveolar macrophages.
We report on two women presenting with cough and fever, 4 and 7 months, respectively, after starting breast radiation therapy following surgery for breast carcinoma. Chest roentgenogram and computed tomographic (CT) scan demonstrated alveolar opacities, initially limited to the pulmonary area next to the irradiated breast, but later migrating within both lungs. Intra-alveolar granulation tissue was found in transbronchial lung biopsies. Corticosteroid treatment resulted in dramatic clinical improvement, together with complete clearing of the pulmonary opacities on chest imaging. However, clinical and imaging relapses occurred when corticosteroids were withdrawn too rapidly; with further improvement when they were reintroduced. The reported cases clearly differ from radiation pneumonitis. They were fairly typical of cryptogenic organizing pneumonitis, also called idiopathic bronchiolitis obliterans organizing pneumonia, with the exception of the radiation therapy, partially affecting the lung, which had been performed within the previous months. Since focal radiation therapy involving the lung may induce diffuse bilateral lymphocytic alveolitis, we hypothesize that this may "prime" the lung to further injury, leading to cryptogenic organizing pneumonitis.
To determine if unilateral thoracic irradiation results in a lymphoid alveolitis in both irradiated and unirradiated lung fields.
A prospective, nonrandomized study.
Women receiving postoperative radiotherapy for carcinoma of the breast were evaluated both before and 4 to 6 weeks after radiotherapy. Findings after radiotherapy in 15 asymptomatic patients were compared with findings in a group of patients with clinical radiation pneumonitis.
History, physical examination, chest radiograph, quantitative gallium lung scanning, respiratory function tests, bronchoalveolar lavage, and lavage lymphocyte subset analysis.
After irradiation, lavage lymphocytes increased significantly (34.5% versus 46.8%; P = 0.01) in the 17 patients studied prospectively. There was an associated reduction in vital capacity (102.5% versus 95.5%; P = 0.04). Comparison of results in patients before treatment, after treatment without clinical pneumonitis, and after treatment with clinical pneumonitis showed a dramatic increase in total lymphocytes after irradiation (6.3 versus 9.4 versus 35.2 million, respectively; P = 0.005), particularly in those with clinical pneumonitis. Only in those with clinical pneumonitis was this accompanied by an increase in the gallium index (3.7 versus 3.4 versus 9.0, respectively; P < 0.001). Vital capacity was also progressively reduced (102.5% versus 96.9% versus 76.7%, respectively; P = 0.04), as was diffusing capacity (98.6% versus 91.4% versus 72.6%, respectively; P = 0.003). No statistical differences existed between irradiated and unirradiated sides of the chest in either lavage or gallium lung scan studies.
In most patients, a lymphocytic alveolitis develops in both lung fields after strictly unilateral thoracic irradiation; this is more pronounced in patients developing clinical pneumonitis. These findings suggest that radiotherapy may cause a generalized lymphocyte-mediated hypersensitivity reaction.
Several cancer therapeutic agents have been associated with pulmonary toxicity. Herein, we describe the case of a 73-year-old woman with breast cancer metastatic to the liver, who developed noncardiogenic pulmonary edema (NPE) while on treatment with gemcitabine plus docetaxel combination with granulocyte colony-stimulating factor (G-CSF) support. Gemcitabine, a deoxycytidine analogue, is reported to produce mild self-limiting and only occasionally severe pulmonary toxicity. The microtubule stabilizer docetaxel has been associated with water retention complications. The combination of these two agents has shown promising activity in several solid tumors and is in a phase of clinical development with prophylactic G-CSF in most of the trials due to the high rate of dose-limiting neutropenia observed with this combination. In our case pulmonary toxicity resolved rapidly following the administration of corticosteroids. A possible deleterious synergy of the compounds involved in this case is discussed and the medical literature on NPE related to cancer therapy is shortly reviewed. We conclude that NPE should always be considered in patients with respiratory function deterioration while on therapy with the gemcitabine-docetaxel combination and G-CSF. Corticosteroids can provide maximum benefit if started early upon diagnosis coupled with withdrawal of the causative drugs.
Classical radiation pneumonitis has been described after single dose whole lung irradiation in experimental animals where above a threshold dose of irradiation, there is a sigmoid dose response curve with increasing morbidity and mortality. After clinical fractionated irradiation, however, acute radiation pneumonitis consisting of cough shortness of breath and patchy radiological changes, occurs in <10% of patients, has dyspnoea out of proportion to the volume of lung irradiated and usually resolves completely without long-term effects. There is increasing evidence that this represents a bilateral lymphocytic alveolitis or hypersensitivity pneumonitis and has been termed sporadic pneumonitis. Late radiation toxicity results in pulmonary fibrosis. This is a consequence of repair, which is initiated by tissue injury within the radiation portal. It follows release of chemotactic factors for fibroblasts including transforming growth factor-beta, fibronectin and platelet derived growth factor. Radiation fibrosis is the clinically more significant syndrome for patients. It may result in progressive dyspnoea and mortality in patients. The most predictable change in laboratory lung function tests is a decrease in transfer factor due to damage at the capillary-alveolar level. It also results in decreased lung compliance, which will affect the total lung capacity and the forced vital capacity. The forced expiratory volume in 1 s is less affected, although this seems to depend on the volume of lung irradiated. There is also a decrease in perfusion in the irradiated lung. Radiation fibrosis seems to depend, amongst other factors, on the volume of lung, which is irradiated above a threshold of 20-30 Gy. The morbidity of radiation fibrosis may therefore be minimized by the use of dose volume histogram to minimize the volume of normal lung irradiated in patients at high risk, e.g., patients with who present with poor lung function. The importance of the baseline perfusion in the irradiated areas continues to be studied.
Fiber-optic bronchoscopy with multiple transbronchial lung biopsies (TBB) is the gold standard of evaluation of the pulmonary allograft post-lung transplantation (LT). However, controversy exists regarding the need for surveillance procedures and number of biopsy specimens required for satisfactory yield. The potential morbidity in obtaining multiple TBB specimens remains poorly described. We report the largest series of TBB in LT recipients to date, highlighting the occurrence of acute rejection and infection for surveillance and diagnostic procedures. The safety of TBB is analyzed and a biopsy schedule proposed.
Prospective analysis of 1,235 TBB in 230 LT recipients performed at St Vincent's Hospital from January 1995 to June 2000.
Eight hundred thirty-six (67.7%) TBB were performed as surveillance and 399 (32.3%) for a clinical indication. No significant acute rejection (AR) or infection was disclosed in 53.3% of procedures. The Lung Rejection Study Group requirement of at least five pieces of evaluable lung parenchyma was achieved in 98.2% of procedures. The average number of evaluable fragments per procedure was 6.4, whereas only 3 TBB (0.24%) contained no lung parenchyma and 44 (3.6%) no bronchial wall. Histologic features of AR, lymphocytic bronchiolitis or infection were found in 18.9% of surveillance and 86.4% of clinical TBBs. The yield of surveillance procedures between 4 and 12 months was just 1.1% for cytomegalovirus and 6.1% for AR. The overall complication rate was 6.35% with no deaths recorded.
Taking 10 to 12 TBB specimens has a high diagnostic yield and rarely fails to provide adequate tissue. The role of surveillance procedures post-lung transplantation remains controversial.
These studies were designed to examine radiation-induced in-field and out-of-field DNA damage in rat lung as a function of dose and various volumes of irradiation. They also determined whether superoxide dismutase (SOD) and nitro-L-arginine methyl ester (L-NAME) protected against this damage.
The whole lung, or various volumes of the lower or upper lungs of Sprague-Dawley rats were exposed to doses up to 20 Gy of 60Co gamma rays. Radiation-induced DNA damage was quantified in fibroblasts obtained at 18 h after irradiation from both irradiated and shielded lung regions using a micronucleus assay. The radioprotective role of SOD (CuZnSOD: 10 mg/kg body weight; MnSOD: 50-100mg/kg body weight) and L-NAME (0.2 mg/kg body weight.) in vivo was determined by injecting them into rats 30 min before or immediately after a dose of 10 Gy.
Micronucleus formation was approximately linear with dose up to 15 Gy. When 70% of the lung volume was irradiated with 10 Gy, irradiated lower lung gave similar numbers of micronuclei (MN)/binucleate cell (BN) to that observed following whole lung irradiation (0.91 MN/BN), whereas the irradiated upper lung gave only 0.66 MN/BN. Following lower lung irradiation, the shielded upper lung (30% of lung volume) showed substantial (out-of-field) damage (0.43 MN/BN). When 30% of the lung was given 10 Gy, irradiated upper or lower lung showed similar amounts of in-field damage (0.43 MN/BN) but this was smaller than that seen following irradiation of 70% of the lung volume. For 30% lower lung irradiation, the shielded upper lung showed only a small out-of-field effect (0.1 MN/BN). For both volumes of irradiation there was a similar or smaller effect in the shielded lower lung after upper lung irradiation. Injection of SOD before or L-NAME after 10 Gy to the lower 70% lung volume resulted in a reduction in DNA damage both in-field and out-of-field but the percentage was much greater for out-of-field damage (50-60%) than for in-field damage (10-30%). Following whole lung irradiation (10 Gy) significantly greater DNA damage was observed in fibroblasts from the left lung than from the right lung (0.93 MN/BN vs. 0.82 MN/BN). Following whole lung irradiation there was no significant difference in DNA damage observed in fibroblasts from the lower lung and the upper lung.
With partial lung irradiation the lower lung sustains more in-field DNA damage following irradiation than the upper lung, whereas out-of-field effects are observed primarily in the upper lung (i.e. following lower lung irradiation). Following whole lung irradiation the left lung sustains more damage than the right lung but there is no difference between the upper and lower lung. The protective effects of SOD and L-NAME suggest that inflammatory cytokines induced by the irradiation may be involved in the initiation of a reaction resulting in the production of reactive oxyradicals and nitric oxide that cause indirect DNA damage both in and out of the radiation field.
To assess, in lung cancer patients, the effects of thoracic radiotherapy (RT) on the concentrations of transforming growth factor-beta(1) (TGF-beta(1)) and interleukin-6 (IL-6) in the bronchoalveolar lavage (BAL) fluid.
Eleven patients with lung cancer requiring RT as part of their treatment were studied. BAL was performed bilaterally before, during, and 1, 3, and 6 months after RT. Before each BAL session, the patient's status was assessed clinically using pulmonary function tests and an adapted late effects on normal tissue-subjective, objective, management, analytic (LENT-SOMA) scale, including subjective and objective alterations. The National Cancer Institute Common Toxicity Criteria were used to grade pneumonitis. The TGF-beta(1) and IL-6 levels in the BAL fluid were determined using the Easia kit.
The TGF-beta(1) and IL-6 concentrations in the BAL fluid recovered from the irradiated areas were significantly increased by thoracic RT. The increase in TGF-beta(1) levels tended to be greater in the group of patients who developed severe pneumonitis. In the BAL fluid from the nonirradiated areas, the TGF-beta(1) and IL-6 concentrations remained unchanged.
The observed increase in TGF-beta(1) and IL-6 concentrations in the BAL fluid recovered from the irradiated lung areas demonstrated that these cytokines may contribute to the process leading to a radiation response in human lung tissue.
An ever-increasing number of drugs can reproduce variegated patterns of naturally occurring interstitial lung disease (ILD), including most forms of interstitial pneumonias, alveolar involvement and, rarely, vasculitis. Drugs in one therapeutic class may collectively produce the same pattern of involvement. A few drugs can produce more than one pattern of ILD. The diagnosis of drug-induced ILD (DI-ILD) essentially rests on the temporal association between exposure to the drug and the development of pulmonary infiltrates. The histopathological features of DI-ILD are generally consistent, rather than suggestive or specific to the drug etiology. Thus, the diagnosis of DI-ILD is mainly made by the meticulous exclusion of all other possible causes. Drug dechallenge produces measurable improvement in symptoms and imaging in the majority of patients, whereas corticosteroid therapy is indicated if symptoms are present or drug dechallenge is without an effect. Rechallenge is justified in a minority of patients, and is discouraged for diagnostic purposes only. Pneumotox (www.pneumotox.com) provides updated information on drug-induced respiratory disease.
Radiation pneumonitis and subsequent radiation pulmonary fibrosis are the two main dose-limiting factors when irradiating the thorax that can have severe implications for patients' quality of life. In this article, the current concepts about the pathogenetic mechanisms underlying radiation pneumonitis and fibrosis are presented. The clinical course of fibrosis, a postulated acute inflammatory stage, and a late fibrotic and irreversible stage are discussed. The interplay of cells and the wide variety of molecules orchestrating the immunologic response to radiation, their interactions with specific receptors, and the cascade of events they trigger are elucidated. Finally, the implications of this knowledge with respect to the therapeutic interventions are critically presented.
Radiation-induced lung injury (RILI) is the most common, dose-limiting complication of thoracic radio- and radiochemotherapy. Unfortunately, predicting which patients will suffer from this complication is extremely difficult. Ideally, individual phenotype- and genotype-based risk profiles should be able to identify patients who are resistant to RILI and who could benefit from dose escalation in chemoradiotherapy. This could result in better local control and overall survival. We review the risk predictors that are currently in clinical use--dosimetric parameters of radiotherapy such as normal tissue complication probability, mean lung dose, V20 and V30--as well as biomarkers that might individualize risk profiles. These biomarkers comprise a variety of proinflammatory and profibrotic cytokines and molecules including transforming growth factor beta1 that are implicated in development and persistence of RILI. Dosimetric parameters of radiotherapy show a low negative predictive value of 60% to 80%. Depending on the studied molecule, negative predictive value of biomarkers is approximately 50%. The predictive power of biomarkers might be increased if they are coupled with radiogenomics, e.g., genotyping analysis of single nucleotide polymorphisms in transforming growth factor beta1, transforming growth factor beta1 pathway genes, and other cytokines. Genetic variability and the complexity of RILI and its underlying molecular mechanisms make identification of biological risk predictors challenging. Further investigations are needed to develop more effective risk predictors of RILI.