Pre-existing Pulmonary Fibrosis Research Articles

Pharmacotherapy and pulmonary fibrosis risk after SARS-CoV-2 infection: a prospective nationwide cohort study in the United States

Pulmonary fibrosis is characterized by lung parenchymal destruction and can increase morbidity and mortality. Pulmonary fibrosis commonly occurs following hospitalization for SARS-CoV-2 infection. As there are medications that modify pulmonary fibrosis risk, we investigated whether distinct pharmacotherapies (amiodarone, cancer chemotherapy, corticosteroids, and rituximab) are associated with differences in post-COVID-19 pulmonary fibrosis incidence. We used the National COVID-19 Cohort Collaboration (N3C) Data Enclave, which aggregates and harmonizes COVID-19 data across the United States, to assess pulmonary fibrosis incidence documented at least 60 days after COVID-19 diagnosis among adults hospitalized between January 1st, 2020 and July 6th, 2022 without pre-existing pulmonary fibrosis. We used propensity scores to match pre-COVID-19 drug-exposed and unexposed cohorts (1:1) based on covariates with known influence on pulmonary fibrosis incidence, and estimated the association of drug exposure with risk for post-COVID-19 pulmonary fibrosis. Sensitivity analyses considered pulmonary fibrosis incidence documented at least 30- or 90-days post-hospitalization and pulmonary fibrosis incidence in the COVID-19-negative N3C population. Among 5,923,394 patients with COVID-19, we analyzed 452,951 hospitalized adults, among whom pulmonary fibrosis incidence was 1.1 per 100-person-years. 277,984 hospitalized adults with COVID-19 were included in our primary analysis, among whom all drug exposed cohorts were well-matched to unexposed cohorts (standardized mean differences <0.1). The post-COVID-19 pulmonary fibrosis incidence rate ratio (IRR) was 2.5 (95% CI 1.2-5.1, P=0.01) for rituximab, 1.6 (95% CI 1.3-2.0, P<0.0001) for chemotherapy, and 1.2 (95% CI 1.0-1.3, P=0.02) for corticosteroids. Amiodarone exposure had no significant association with post-COVID-19 pulmonary fibrosis (IRR=0.8, 95% CI 0.6-1.1, P=0.24). In sensitivity analyses, pre-COVID-19 corticosteroid use was not consistently associated with post-COVID-19 pulmonary fibrosis. In the COVID-19 negative hospitalized population (n=1,240,461), pulmonary fibrosis incidence was lower overall (0.6 per 100-person-years) and for patients exposed to all four drugs. Recent rituximab or cancer chemotherapy before COVID-19 infection in hospitalized patients is associated with increased risk for post-COVID-19 pulmonary fibrosis. The analyses described in this publication were conducted with data or tools accessed through the NCATS N3C Data Enclave https://covid.cd2h.org and N3C Attribution & Publication Policy v1.2-2020-08-25b supported by NIHK23HL146942, NIHK08HL150291, NIHK23HL148387, NIHUL1TR002389, NCATSU24 TR002306, and a SECURED grant from the Walder Foundation/Center for Healthcare Delivery Science and Innovation, University of Chicago. WFP received a grant from the Greenwall Foundation. This research was possible because of the patients whose information is included within the data and the organizations (https://ncats.nih.gov/n3c/resources/data-contribution/data-transfer-agreement-signatories) and scientists who have contributed to the on-going development of this community resource (https://doi.org/10.1093/jamia/ocaa196).

A CRITICALLY APPRAISED TOPIC:ISTHEREANEFFECTIVEPOST-COVID PULMONARYFIBROSISTREATMENT?

Background: the COVID-19 infection induces interstitial lung remodeling after the development of restrictive respiratory distress syndrome, which endures the affected individuals a higher risk for hospitalization and intensive care unit admission from the developed pulmonary fibrosis. Thus, we reviewed the literature for an effective post-covid pulmonary fibrosis treatment. Methods: PubMed, MEDLINE, and ClinicalKey databases were searched using Medical Subject Headings [MeSH] from November 2019 to Jun 2022 to include human-only studies on confirmed COVID-19 patients via PCR with radiological evidence of interstitial fibrosis. We excluded studies that have pre-existing pulmonary fibrosis patients. Results: We identified a total of 137 studies. Continuing the title and abstract screening later, we included eight papers for analysis in our review. We found efficacious medication for post-covid pulmonary fibrosis, such as Anakinra, Nintedanib, and human embryonic stem cell-derived immunity- and matrix-regulatory cells (hESC- IMRCs). Moreover, it was tested on a small sample of participants, and the results are promising and safe that can be tested on more extensive randomized trials. Recommendation: interventional pre-and-post randomized controlled trials shall be conducted to inform further action to reduce morbidity and mortality for such a population.

Diesel exhaust PM2.5 greatly deteriorates fibrosis process in pre-existing pulmonary fibrosis via ferroptosis

Fine particulate matter (PM2.5) has been widely reported to contribute to the pathogenesis of pulmonary diseases. The direct hazardous effect of PM2.5 on the respiratory system at high concentrations in vitro and in vivo have been well identified. However, its effect on the pre-existing respiratory diseases of patients at environment-related concentrations remains unclear. Diesel exhaust PM2.5 as a primary representative of ambient PM2.5 fine particles were used to investigated the effect of PM2.5 on the fibrosis progression of existing pulmonary fibrosis disease models. This study reported that PM2.5 could result in the enhanced sensitivity to fibrotic response, which may be ascribed to ferroptosis induced by PM2.5 in damaged lung areas. Proteomic analysis revealed that the upregulation of HO-1 as a key mechanism in the ferroptosis and exacerbation of pulmonary fibrosis induced by PM2.5. As a result, HO-1 degraded heme-containing protein and released iron in fibrotic cells, leading to generation of mitochondrial ROS and impaired mitochondrial function. Transmission electron microscopic assay verified that PM2.5 entered the mitochondria of fibrotic cells and was accompanied by significant mitochondrial morphological changes characterized by increased mitochondrial membrane density and reduced mitochondrial size. The HO-1 inhibitor zinc protoporphyrin and mitochondrion-targeted antioxidant Mito-TEMPO significantly attenuated PM2.5-induced ferroptosis and exacerbation of fibrosis. In addition, AMPK-ULK1 axis-triggered autophagy activation and NCOA4-mediated degradation of ferritin by autophagy were found to be related to the PM2.5-induced ferroptosis of fibrotic cells. As evidenced by the inhibition of autophagy with 3-methyladenine or AMPK inhibitor, NCOA4 knockdown decreased intracellular iron accumulation and lipid peroxidation, thereby relieving PM2.5-induced epithelial–mesenchymal transition and cell death in fibrotic cells. Overall, this study provided experimental support for the idea that PM2.5 greatly deteriorates fibrosis process in pre-existing pulmonary fibrosis, and HO-1-mediated mitochondrial dysfunction and NCOA4-mediated ferritinophagy are jointly required for the PM2.5-induced ferroptosis and enhanced fibrosis effects.

Clinical outcomes and risk factor of immune checkpoint inhibitors-related pneumonitis in non-small cell lung cancer patients with chronic obstructive pulmonary disease

Objectives:Chronic obstructive pulmonary disease (COPD) is the most common co-morbidity associated with non-small cell lung cancer (NSCLC) patients. Immune checkpoint inhibitors related pneumonitis (CIP) is a common immune-related adverse event that can be life-threatening. The study aims to evaluate the association of COPD with the incidence and outcome of CIP in NSCLC patients receiving immune checkpoint inhibitors (ICIs).Materials and methods:We retrospectively collected data from 122 patients diagnosed with NSCLC and treated with ICIs in our department. Baseline pulmonary function was performed in the whole cohort. The incidence, risk factors, treatment and outcome of CIP patients were evaluated. Furthermore, the efficacy of ICIs in patients with COPD was analyzed.Results:Nineteen patients (15.5%, 19/122) developed CIP during ICIs treatment, most patients with CIP were grade 1–2, and the incidence of CIP was comparable in patients with COPD and those without COPD (18.0% vs. 13.1%, P = 0.618). In addition, an increasing trend in the incidence of CIP among patients with pulmonary fibrosis on baseline chest CT scans (27.3% vs. 13.0%, P = 0.093). There is a longer progression-free survival in COPD patients than the non-COPD patients.Conclusion:Coexisting COPD did not predict the higher risk of CIP in NSCLC treated with ICIs therapy. Nevertheless, pre-existing pulmonary fibrosis on CT scan may increase the risk of CIP, close monitoring is advised in these patients during ICIs.

Pre-existing pulmonary fibrosis is associated with adverse outcomes after lung resection

IntroductionPulmonary fibrosis is a risk factor for the development of lung cancer. However, the low incidence of the pathology means that it is not well represented in thoracic surgery risk scoring systems. We aimed to assess whether short and long-term outcomes after lung resection for primary lung cancer were worse in patients with pre-existing pulmonary fibrosis. MethodsA total of 5029 consecutive patients undergoing lung resection for primary lung cancer between 2012 and 2018 in two UK centres were included. Primary outcomes were 90-day & 1-year mortality, post-operative complications and overall survival. Univariable analyses were used to compare outcomes between patients with and without pre-existing pulmonary fibrosis. ResultsIn total, 0.7% (n = 33) of patients had a pre-existing diagnosis of pulmonary fibrosis (idiopathic pulmonary fibrosis 48.5%, non-specific interstitial pneumonia 6.1%, unknown 45.5%). Overall, 90-day and 1-year mortality were all significantly higher amongst patients with fibrosis (90-day: 18.2% vs 3.6%, p < 0.001; 1-year: 36.4% vs 10.7%, p < 0.001). The rate of reintubation was significantly higher for patients with fibrosis (9.1% vs 2.9%, p = 0.038) yet there was no difference in post-operative length of stay between groups (fibrosis: 6 days [IQR 4–9 days] vs non-fibrosis: 5 days [IQR 4–8 days], p = 0.675). Overall survival was also significantly reduced for patients with pulmonary fibrosis (log-rank analysis, p < 0.001). ConclusionsDespite its small size, this study suggests that short and long-term outcomes after lung resection are worse for patients with pre-existing pulmonary fibrosis. Segmental resections could be considered in these patients where oncologically appropriate to minimise peri-operative risk.

Atypical characteristics of COVID-19 infection on CT imaging with preexisting combined pulmonary fibrosis and emphysema: A case report

Abstract Introduction: Combined pulmonary fibrosis and emphysema (CPFE) complicating Coronavirus Disease 2019 (COVID-19) is a challenging clinical scenario. Patient concerns: We report the case of a 44-year-old Chinese man with a medical history of CPFE showing atypical characteristics of COVID-19 infection on computed tomography (CT) imaging. Diagnoses: The patient was reported to have had close contact with a COVID-19 patient, with 4 real-time reverse transcriptase-polymerase chain reaction tests for COVID-19 - all positive. CT imaging showed scattered mixed ground-glass nodules and small ground-glass lesions in the lower and posterior parts of the posterior segment of the left upper lobes. Intervention: The patient received antiviral therapy (ritonavir tablets twice-daily, Xiyanping injection, and oral delivery of Keke capsules). Outcomes: On follow-up, nodules near the hilar side of the lung showed shrinkage at 7th day and nearly disappeared after 15 days. Conclusion: Clinicians should be alert to the results of lung CT examination and atypical lesions should be diagnosed in time. Precise clinical evaluation, well-directed monitoring, and intervention can effectively improve prognosis.

Patients with idiopathic pulmonary fibrosis have poor clinical outcomes with COVID-19 disease: a propensity matched multicentre research network analysis

IntroductionOutcomes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in patients with pre-existing idiopathic pulmonary fibrosis (IPF) remain understudied, and it is unknown if IPF is an independent predictor...

Surgical treatment of recalcitrant gastroesophageal reflux disease in patients with systemic sclerosis: a systematic review

IntroductionGastroesophageal reflux disease (GERD) is frequently seen in patients with systemic sclerosis (SSc). Long-standing GERD may cause esophagitis, long-segment strictures, and Barrett’s esophagus and may worsen pre-existing pulmonary fibrosis with an increased risk of end-stage lung disease. Surgical treatment of recalcitrant GERD remains controversial. The purpose of this systematic review was to summarize the current data on surgical treatment of recalcitrant GERD in SSc patients.Materials and methodsA systematic literature review according to PRISMA and MOOSE guidelines. PubMed, EMBASE, and Web of Science databases were consulted.ResultsA total of 101 patients were included from 7 studies. The age ranged from 34 to 61 years and the majority were females (73.5%). Commonly reported symptoms were heartburn (92%), regurgitation (77%), and dysphagia (74%). Concurrent pulmonary disease was diagnosed in 58% of patients. Overall, 63 patients (62.4%) underwent open fundoplication, 17 (16.8%) laparoscopic fundoplication, 15 (14.9%) Roux en-Y gastric bypass (RYGB), and 6 (5.9%) esophagectomy. The postoperative follow-up ranged from 12 to 65 months. Recurrent symptoms were described in up to 70% and 30% of patients undergoing fundoplication and RYGB, respectively. Various symptoms were reported postoperatively depending on the type of surgical procedures, anatomy of the valve, need for esophageal lengthening, and follow-up.ConclusionsThe treatment of recalcitrant GERD in SSc patients is challenging. Esophagectomy should be reserved to selected patients. Minimally invasive RYGB appears feasible and safe with promising preliminary short-term results. Current evidence is scarce while a definitive indication about the most appropriate surgical treatment is lacking.

Primary total hip replacement using Burch-Schneider cages for acetabular fractures.

Osteoporotic acetabular fractures are common and pose a difficult technical challenge for the trauma surgeon. Acute total hip arthroplasty (THA) using a Burch-Schneider antiprotrusio cage with immediate postoperative weight-bearing is a method to approach these injuries. This case series reports our outcomes of acute THA using Burch-Schneider cages for acetabular fractures from a UK major trauma centre based on length of stay, radiological outcome, complications and outcome scores. Data were collected from all patients who underwent acute THA with a Burch-Schneider cage for acetabular fractures between June 2006 and August 2015. Patients were followed up clinically, radiologically, and using Oxford Hip Scores (OHS). 20 patients with a median age of 73 (range 60-90 years) were identified. All patients were independent walkers at follow-up, and had achieved radiological union. There were no dislocations, subsidence, revision or deep infections. Significant complications include 1 perioperative death as a result of complications arising from pre-existing pulmonary fibrosis; 1 deep vein thrombosis; 1 intraoperative arterial injury to the superior gluteal artery; and 1 leg-length discrepancy. Mean length of stay was 10 days. The mean OHS was 37/48 at a mean follow-up of 26 months. This case series further validates the use of Burch-Schneider cages with primary THA in acute acetabular fractures.

P1.01-62 Association of Baseline Pulmonary Fibrosis with the Outcome of PD-1 Inhibitor in Patients with Advanced Non-Small Cell Lung Cancer

PD-1/PD-L1 inhibitors have become standard care for previously treated advanced non-small cell lung cancer (NSCLC). However, not all patients are suitable for the immunotherapy. This study aimed to investigate the efficacy and safety of PD-1/PD-L1 inhibitors in patients with advanced NSCLC and pre-existing pulmonary fibrosis (PF). Patients who had a NSCLC diagnosis, received anti-PD-1/PD-L1 monotherapy and had baseline chest HRCT screen at Shanghai Pulmonary Hospital, Tongji University were retrospectively collected from January 2016 to February 2019. The pre-existence of PF was identified by reviewing baseline chest imaging. Baseline clinicopathologic characteristics, treatment outcomes and immune-related pneumonitis were collected. 116 patients were included with 61 age < 65. Among them, 97 (83.6%) were male, 76 (65.5%) were smoker, 51 (44%) were squamous, 61 (52.6%) received anti-PD-1 monotherapy (Pembolizumab n=62, Nivolumab n=28) as 2nd line setting, 28 (24.1%) had PF prior to PD-1 inhibitors. Baseline characteristics such as age, gender, ECOG PS, smoking history, pathology are similar between patients with or without PF. Patients with PF had a comparable response (ORR: 25% vs 15.9%, p=0.277, figure A), disease control (DCR: 60.7% vs 48.9%, p=0.274, figure B) and PFS (median 2.5 vs 2.8 months, p=0.950). The incidence of immune-related pneumonitis in the entire cohort was 9.2%, which was numerally higher in PF group (17.9% vs 6.8%, p=0.172, figure C). No death from immune-related pneumonitis occurred. NSCLC patients with pre-existing PF showed comparable response to PD-1 inhibitors but a higher incidence to immune-related pneumonitis.

IBRUTINIB-INDUCED INTERSTITIAL LUNG DISEASE IN A PATIENT WITH CHRONIC LYMPHOCYTIC LEUKEMIA

SESSION TITLE: Wednesday Medical Student/Resident Case Report Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: 10/23/2019 09:45 AM - 10:45 AM INTRODUCTION: Chronic Lymphocytic Leukemia (CLL) is a neoplasm of dysfunctional lymphocytes. Ibrutinib, a Bruton’s tyrosine kinase inhibitor, has been a favored treatment for CLL because of its great efficacy in inducing a rapid decrease in lymph node size with a relatively minimal side effect profile, which includes fatigue, diarrhea, and thrombocytopenia. In this case, we present a patient found to have acute respiratory failure secondary to interstitial lung disease (ILD) shortly after initiating therapy with Ibrutinib. CASE PRESENTATION: A 93-year-old female with CLL who presented to the emergency department with a 3-day history of progressively worsening dyspnea and productive cough with green sputum appreciated 1-week after starting Ibrutinib. She was in acute hypoxemic respiratory failure, saturating at 81% on ambient air. A Computed Tomography Angiography (CTA) of the chest was performed. It revealed diffuse bilateral ILD with honeycombing in the right upper lung and a large left sided pleural effusion. These findings were new compared to a CT of the lung done four months prior. Analysis of the effusion fluid revealed a malignant etiology. A chest tube was placed. She was treated with steroids as well as empiric antibiotics for pneumonia. She had subsequent improvement of her respiratory failure and was ultimately discharged in stable condition. Ibrutinib was not restarted due to patient’s frailty. A follow up CT done four months after discharge showed resolution of ILD. DISCUSSION: Pulmonary complications of Ibrutinib, while rare, have been previously reported. Most of these complications have been limited to pneumonia and pulmonary infiltrates, seen in 2% of patients in one study [1], and dyspnea seen in patients with pre-existing chronic obstructive pulmonary disease, pulmonary fibrosis, and malignant pleural effusions [2]. To the best of our knowledge, there has only been one reported case [3] of a patient with healthy lungs who experienced acute respiratory failure secondary to ILD that occurred one week after the initiation of Ibrutinib for mantle cell lymphoma. While acknowledging the limitation of evidence provided by two case reports, ILD is a consideration in patients receiving Ibrutinib who present with respiratory complaints. CONCLUSIONS: We present a 93-year-old patient who, after recently starting Ibrutinib for CLL, experienced acute hypoxemic respiratory failure with radiographic findings consistent with ILD. Ibrutinib was discontinued and the patient made a successful recovery after being treated with steroids, antibiotics, and chest tube placement. Based on this case and another one that reports similar findings, we recommend monitoring patients receiving Ibrutinib for respiratory adverse events. Reference #1: Ibrutinib for previously untreated and relapsed or refractory chronic lymphocytic leukaemia with TP53 aberrations: a phase 2, single-arm trial. Farooqui MZ, Valdez J, Martyr S, Aue G, Saba N, Niemann CU, Herman SE, Tian X, Marti G, Soto S, Hughes TE, Jones J, Lipsky A, Pittaluga S, Stetler-Stevenson M, Yuan C, Lee YS, Pedersen LB, Geisler CH, Calvo KR, Arthur DC, Maric I, Childs R, Young NS, Wiestner A Lancet Oncol. 2015 Feb; 16(2):169-76. Reference #2: Long-term follow-up of MCL patients treated with single-agent ibrutinib: updated safety and efficacy results. Wang ML, Blum KA, Martin P, Goy A, Auer R, Kahl BS, Jurczak W, Advani RH, Romaguera JE, Williams ME, Barrientos JC, Chmielowska E, Radford J, Stilgenbauer S, Dreyling M, Jedrzejczak WW, Johnson P, Spurgeon SE, Zhang L, Baher L, Cheng M, Lee D, Beaupre DM, Rule S. Blood. 2015 Aug 6; 126(6):739-45. Reference #3: Jungmann S, Ludwig WD, Schönfeld N, et al. A Patient with Non-Hodgkin Lymphoma and Nonspecific Interstitial Pneumonia during Ibrutinib Therapy. Case Rep Oncol Med. 2017;2017:5640186. DISCLOSURES: No relevant relationships by Phillip Berges, source=Web Response No relevant relationships by Najia Hussain, source=Web Response No relevant relationships by Kashif Hussain, source=Web Response No relevant relationships by Samer Ibrahim, source=Web Response No relevant relationships by Nandini Seshan, source=Web Response No relevant relationships by Deepali Sharma, source=Admin input

Pre-existing pulmonary fibrosis is a risk factor for anti-PD-1-related pneumonitis in patients with non-small cell lung cancer: A retrospective analysis

ObjectivesPneumonitis related to the use of anti-programmed death 1 (PD-1) antibodies is a common immune-related adverse event that can be life-threatening. However, the relationship between pulmonary fibrosis/emphysema and the incidence of anti-PD-1-related pneumonitis is unclear. Materials and methodsWe retrospectively reviewed data from 123 patients who were diagnosed with non-small-cell lung cancer and treated with anti-PD-1 antibodies (nivolumab or pembrolizumab) at the Aichi Cancer Center Hospital, Japan, between December 17, 2015, and November 30, 2017. Patients who previously received thoracic radiotherapy to the primary lesion, mediastinum, spinal, or rib metastases were excluded from the analysis. Fibrosis score (0–5) and emphysema score (0–4) on baseline chest computed tomography (CT) were determined by two diagnostic radiologists. ResultsEighteen patients (14.6%) experienced anti-PD-1-related pneumonitis, of which four (3.3%) were grade ≥3. The median onset time of pneumonitis after starting anti-PD-1 therapy was 60 days (range, 6–634 days). According to the analysis of fibrosis score, pneumonitis occurred in 13 (35.1%) of the 37 patients with a fibrosis score ≥1 and in 5 (5.8%) of 86 patients with a fibrosis score of 0. Univariate and multivariate logistic regression analysis revealed that fibrosis score ≥1 was the only risk factor for anti-PD-1-related pneumonitis (p = 0.0008). ConclusionOur results indicate that pre-existing pulmonary fibrosis significantly increases the risk of anti-PD-1-related pneumonitis. Further studies are needed to identify predictive factors of anti-PD-1-related pneumonitis in patients with fibrotic changes on CT findings.

DART-bid for loco-regionally advanced NSCLC

BackgroundTo report acute and late toxicity with long-term follow-up, and to describe our experiences with pulmonary dose constraints.MethodsBetween 2002 and 2009, 150 patients with 155 histologically/cytologically proven non-small cell lung cancer (NSCLC; tumor stages II, IIIA, IIIB in 6, 55 and 39%, respectively) received the following median doses: primary tumors 79.2 Gy (range 72.0–90.0 Gy), lymph node metastases 59.4 Gy (54.0–73.8 Gy), nodes electively 45 Gy; with fractional doses of 1.8 Gy twice daily (bid). In all, 86% of patients received 2 cycles of chemotherapy previously.ResultsFive treatment-related deaths occurred: pneumonitis, n = 1; progressive pulmonary fibrosis in patients with pre-existing pulmonary fibrosis, n = 2; haemorrhage, n = 2. In all, 8% of patients experienced grade 3 and 1.3% grade 4 pneumonitis; 11% showed late fibrotic alterations grade 2 in lung parenchyma. Clinically relevant acute esophagitis (grade 2 and 3) was seen in 33.3% of patients, 2 patients developed late esophageal stenosis (G3). Patients with upper lobe, middle lobe and central lower lobe tumours (n = 130) were treated with V20 (total lung) up to 50% and patients with peripheral lower lobe tumours (n = 14, basal lateral tumours excluded) up to 42%, without observing acute or late pulmonary toxicity >grade 3. Only patients with basal lateral lower lobe tumours (n = 5) experienced grade 4/5 pulmonary toxicity; V20 for this latter group ranged between 30 and 53%. The mean lung dose was below the QUANTEC recommendation of 20–23 Gy in all patients. The median follow-up time of all patients is 26.3 months (range 2.9–149.4) and of patients alive 80.2 months (range 63.9–149.4.). The median overall survival time of all patients is 26.3 months; the 2-, 5- and 8‑year survival rates of 54, 21 and 15%, respectively. The local tumour control rate at 2 and 5 years is 70 and 64%, the regional control rate 90 and 88%, respectively.Discussion and conclusionGrade 4 or 5 toxicity occurred in 7/150 patients (4.7%), which can be partially avoided in the future (e.g. by excluding patients with pre-existing pulmonary fibrosis). Tolerance and oncologic outcome compare favourably to concomitant chemoradiation also in long-term follow-up.

Tyrosine Kinase Inhibitor-Induced Interstitial Lung Disease: Clinical Features, Diagnostic Challenges, and Therapeutic Dilemmas.

Since the approval of the first molecularly targeted tyrosine kinase inhibitor (TKI), imatinib, in 2001, TKIs have heralded a new era in the treatment of many cancers. Among their innumerable adverse effects, interstitial lung disease (ILD) is one of the most serious, presenting most frequently with dyspnea, cough, fever, and hypoxemia, and often treated with steroids. Of the 28 currently approved TKIs, 16 (57 %) are reported to induce ILD with varying frequency and/or severity. The interval from drug administration to onset of ILD varies between patients and between TKIs, with no predictable time course. Its incidence is variously reported to be approximately 1.6-4.3 % in Japanese populations and 0.3-1.0 % in non-Japanese populations. The mortality rate is in the range of 20-50 %. Available evidence (primarily following the use of erlotinib and gefitinib in Japan because of the unique susceptibility of that population) has identified a number of susceptibility and prognostic risk factors (male sex, a history of smoking, and pre-existing pulmonary fibrosis being the main ones). Although the precise mechanism is not understood, collective evidence suggests that immune factors may be involved. If TKI-induced ILD is confirmed by thorough evaluation of the patient and exclusion of other causes, management is supportive, and includes discontinuation of the culprit TKI and administration of steroids. Discontinuing the culprit TKI presents a clinical dilemma because the diagnosis of TKI-induced ILD in a patient with pre-existing pulmonary fibrosis can be challenging, the patient may have TKI-responsive cancer with no suitable alternative, and switching to an alternative agent, even if available, carries the risk of the patient experiencing other toxic effects. Preliminary evidence suggests that therapy with the culprit TKI may be continued under steroid cover and/or at a reduced dose. However, this approach requires careful individualized risk-benefit analysis and further clinical experience.

Interstitial lung disease associated with amrubicin chemotherapy in patients with lung cancer: a single institutional study.

Amrubicin, which is used as a chemotherapeutic agent for lung cancer, can induce interstitial lung disease. There is insufficient evidence on the incidence of amrubicin-associated interstitial lung disease under practical use settings. We therefore investigated the occurrence of interstitial lung disease in the patients with lung cancerwho received amrubicin in our institution. We reviewed the data of all patients with lung cancerwho received amrubicin at the Nippon Medical School Hospital from March 2002 to April 2015. Interstitial lung disease was diagnosed based on clinical symptoms, radiographic findings and the exclusion of other diseases. We reviewed 92 consecutive patients with lung cancer. Amrubicin-associated interstitial lung disease occurred in 3 of the 92 patients (3.3%): 2 were definite interstitial lung disease and 1 was possible interstitial lung disease. The severity of interstitial lung disease was mild to moderate, and interstitial lung disease improved with or without corticosteroid therapy in all cases. The findings in a computed tomography image analysis showed preexisting pulmonary fibrosis (n=13), including interstitial pneumonitis (n=10) and radiation fibrosis (n=3). No patients showed the presence of honeycomb lung. Among the 13 patients, 1 (7.7%) developed interstitial lung disease after amrubicin chemotherapy. Interstitial lung disease occurred in 3.3% of the patients in our study; this appeared to be less frequent than the rates in previous reports. Preexisting pulmonary fibrosis may be a risk factor for interstitial lung disease; however, no fatal cases were found among the patients with asymptomatic pulmonary fibrosis without honeycomb lung. It is thus considered to be necessary to carefully assess the possibility of preexisting pulmonary fibrosis and clarify the presence or absence of honeycomb lung before starting amrubicin chemotherapy.

The anti-fibrotic effect of TGFβ/ALK5 inhibition in experimental pulmonary fibrosis is attenuated in the presence of concurrent γherpesvirus infection

ABSTRACTTGFβ-ALK5 pro-fibrotic signalling and herpesvirus infections have been implicated in the pathogenesis and exacerbation of pulmonary fibrosis. In this study we addressed the role of TGFβ-ALK5 signalling during the progression of fibrosis in a two-hit mouse model of murine γ-herpesvirus 68 (MHV-68) infection on the background of pre-existing bleomycin-induced pulmonary fibrosis. Assessment of total lung collagen levels in combination with ex vivo micro-computed tomography (µCT) analysis of whole lungs demonstrated that MHV-68 infection did not enhance lung collagen deposition in this two-hit model but led to a persistent and exacerbated inflammatory response. Moreover, µCT reconstruction and analysis of the two-hit model revealed distinguishing features of diffuse ground-glass opacities and consolidation superimposed on pre-existing fibrosis that were reminiscent of those observed in acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF). Virally-infected murine fibrotic lungs further displayed evidence of extensive inflammatory cell infiltration and increased levels of CCL2, TNFα, IL-1β and IL-10. Blockade of TGFβ-ALK5 signalling attenuated lung collagen accumulation in bleomycin-alone injured mice, but this anti-fibrotic effect was reduced in the presence of concomitant viral infection. In contrast, inhibition of TGFβ-ALK5 signalling in virally-infected fibrotic lungs was associated with reduced inflammatory cell aggregates and increased levels of the antiviral cytokine IFNγ. These data reveal newly identified intricacies for the TGFβ-ALK5 signalling axis in experimental lung fibrosis, with different outcomes in response to ALK5 inhibition depending on the presence of viral infection. These findings raise important considerations for the targeting of TGFβ signalling responses in the context of pulmonary fibrosis.

Lung, CNS and musculo-skeletal targeted therapy-induced toxicity: imaging features

By focusing on molecular and cellular changes that are up regulated in cancer, targeted agents may have less severe side effects compared with conventional chemotherapy. However, many of these signaling pathways also exist in healthy cells and targeted therapies can therefore result in specific complications [1-3]. The spectrum of toxicity encountered with the targeted agents includes fatigue, skin rash and mucositis, eye, cardiac and muscle toxicity, drug-induced interstitial lung disease (DILD), posterior reversible encephalopathy syndrome (PRES) and a wide spectrum of gastro-intestinal complications. Nephrotoxic effects such as proteinuria, nephrotic syndrome or hypertension are also seen with agents such as VEGFR or mTOR inhibitors. The DILD imaging appearances encompass a range of patterns including nonspecific ground-glass opacity with and without interlobular septal thickening, multifocal consolidations with or without traction bronchiectasis, flitting subcentimetre nodules with or without ground glass halo, bronchiolitis and pulmonary fibrosis or pleural effusions [4]. Acute respiratory distress syndrome (ARDS) has also been described. The EGFR inhibitors related DILD is an important challenge for their use in lung carcinoma especially in patients with preexisting pulmonary fibrosis. Up to one-sixth of patients taking mammalian target of rapamycin (mTOR) inhibitors get a reversible interstitial pneumonitis [5]. Posterior reversible encephalopathy syndrome (PRES) is an uncommon complication (incidence < 0.1%) of VEGF/VEGFR pathway therapy. Most patients recover fully with discontinuation of the causative agent and supportive management of hypertension and seizures [6]. Intra-cerebral bleeding has also been described with anti-VEGF agents, especially in tumours with a strong hemorrhagic tendency, such as renal-cell carcinoma. On imaging, there is usually symmetrical vasogenic oedema in the occipital and parietal regions. However, PRES can be found in a non-posterior distribution, occurring at watershed areas of vascular territories, including the frontal, inferior temporal, cerebellar and brainstem areas. Increases of creatine kinase (CK) are amongst the most common grade 3-4 toxicity treatment-related adverse events of the Mitogen-activated protein kinase (MEK) inhibitors, although most patients are asymptomatic. Symptoms of CK increase include muscle weakness and myalgia. The true significance especially of asymptomatic CK increases is still unknown. An association between CK elevation and skin rash of novel targeted agents in phase I trials, possibly due to increased CK-BB (brain and skin) expression of keratinocytes was reported by Moreno Garcia et al [7]. With the continuous increase in the use of anti-cancer targeted therapies, it is important for the radiologist to be familiar with the clinical and treatment history and associated complications that may occur, in order to accurately identify drug-related complications and differentiate them from disease progression.

DART-BID (Differentiated Accelerated Radiation Therapy–1.8 Gy Twice Daily) for Locoregionally Advanced NSCLC: Mature Results of a Novel Therapeutic Approach

DART-BID (Differentiated Accelerated Radiation Therapy–1.8 Gy Twice Daily) for Locoregionally Advanced NSCLC: Mature Results of a Novel Therapeutic Approach

DART-bid (Dose-differentiated accelerated radiation therapy, 1.8 Gy twice daily)–a novel approach for non-resected NSCLC: final results of a prospective study, correlating radiation dose to tumor volume

BackgroundSequential chemo-radiotherapies with intensive radiation components deliver promising results in non-resected non-small cell lung cancer (NSCLC). In general, radiation doses are determined by dose constraints for normal tissues, not by features relevant for tumor control. DART-bid targets directly the doses required for tumor control, correlating doses to tumor volume in a differentiated mode.Materials/MethodsRadiation doses to primary tumors were aligned along increasing tumor size within 4 groups (<2.5 cm/2.5–4.5 cm/4.5–6.0 cm/>6.0 cm; mean number of three perpendicular diameters). ICRU-doses of 73.8 Gy/79.2 Gy/84.6 Gy/90.0 Gy, respectively, were applied. Macroscopically involved nodes were treated with a median dose of 59.4 Gy, nodal sites about 6 cm cranial to involved nodes electively with 45 Gy. Fractional doses were 1.8 Gy twice daily (bid).2 cycles chemotherapy were given before radiotherapy.Between 2004 and 2009, 160 not selected patients with 164 histologically/cytologically proven NSCLC were enrolled; Stage I: 38 patients; II: 6 pts.; IIIA: 69 pts.; IIIB: 47 pts. Weight loss >5%/3 months: 38 patients (24%).Primary endpoints are local and regional tumor control rates at 2 years (as >90% of locoregional failures occur within 2 years). Secondary endpoints are survival and toxicity. With a minimum follow-up time of 2 years for patients alive, the final results are presented.Results32 local and 10 regional recurrences occurred. The local and regional tumor control rates at 2 years are 77% and 93%, respectively.The median overall survival (OS) time is 28.0 months, the 2- and 5-year OS rates are 57% and 19%, respectively. For stage III patients, median OS amounts to 24.3 months, 2- /5-year OS rates to 51% and 18%, respectively.2 treatment-related deaths (progressive pulmonary fibrosis) occurred in patients with pre-existing pulmonary fibrosis. Further acute and late toxicity was mild.ConclusionsThis novel approach yields a high level of locoregional tumor control and survival times. In general it is well tolerated. In all outcome parameters it seems to compare favourably with simultaneous chemo-radiotherapies, at present considered ‘state of the art’; and is additionally amenable for an unselected patient population.

Change in serum KL-6 level from baseline is useful for predicting life-threatening EGFR-TKIs induced interstitial lung disease

BackgroundA high incidence of interstitial lung disease (ILD) has been reported in patients with advanced non-small cell lung cancer (NSCLC) treated with epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), particularly in Japanese populations. A previous report from our laboratory demonstrated that KL-6 was a useful serum biomarker to assess the severity of drug-induced pneumonitis. Based on these observations, this study was conducted to evaluate the risk factors of EGFR-TKIs induced ILD and the usefulness of monitoring serum KL-6 levels in patients who developed EGFR-TKIs induced ILD in a large multi-institutional setting.MethodsWe retrospectively reviewed clinical records and radiographies of 341 patients with advanced NSCLCs who were treated with EGFR-TKIs, and analyzed risk factors for the development of EGFR-TKIs induced ILD. Changes of circulating levels of KL-6 were also evaluated in the patients who developed EGFR-TKIs induced ILD.ResultsAmong the 341 patients included in this study, 20 (5.9%) developed EGFR-TKIs induced ILD, and 9 (2.6%) died from ILD. Univariate analyses revealed that only preexisting pulmonary fibrosis was a significant risk factor for the development of EGFR-TKIs induced ILD (p = 0.003). Absolute levels of circulating KL-6 at neither baseline nor the onset of ILD could discriminate between life-threatening and non-life threatening EGFR-TKIs induced ILDs. However, we found that the ratios of serum KL-6 levels just after the onset of EGFR-TKIs induced ILD to those at baseline could quite precisely distinguish survivors from non-survivors (p = 0.006) as well as acute interstitial pneumonia (AIP) pattern from non-AIP pattern (p = 0.005).ConclusionsThe results of this study strongly support the potential of KL-6 as a diagnostic biomarker for life-threatening EGFR-TKIs induced ILD. Monitoring of KL-6 is also useful to evaluate the progression and severity of EGFR-TKIs induced ILD.