Idiopathic pulmonary fibrosis (IPF) is a chronic progressive disease of unknown cause characterized by relentless scarring of the lung parenchyma leading to reduced quality of life and earlier ...mortality. IPF is an age-related disorder, and with the population aging worldwide, the economic burden of IPF is expected to steadily increase in the future. The mechanisms of fibrosis in IPF remain elusive, with favored concepts of disease pathogenesis involving recurrent microinjuries to a genetically predisposed alveolar epithelium, followed by an aberrant reparative response characterized by excessive collagen deposition. Pirfenidone and nintedanib are approved for treatment of IPF based on their ability to slow functional decline and disease progression; however, they do not offer a cure and are associated with tolerability issues. In this review, we critically discuss how cutting-edge research in disease pathogenesis may translate into identification of new therapeutic targets, thus facilitate drug discovery. There is a growing portfolio of treatment options for IPF. However, targeting the multitude of profibrotic cytokines and growth factors involved in disease pathogenesis may require a combination of therapeutic strategies with different mechanisms of action.
This Special Issue of eleven articles, including six original works and five reviews, demonstrates the modern heterogenous approach to lung cancer by means of various methodologies from international ...experts from various countries ....
Surgical lung biopsy is often required for a confident multidisciplinary diagnosis of idiopathic pulmonary fibrosis (IPF). Alternative, less-invasive biopsy methods, such as bronchoscopic lung ...cryobiopsy (BLC), are highly desirable.
To address the impact of BLC on diagnostic confidence in the multidisciplinary diagnosis of IPF.
In this cross-sectional study we selected 117 patients with fibrotic interstitial lung disease without a typical usual interstitial pneumonia pattern on high-resolution computed tomography. All cases underwent lung biopsies: 58 were BLC, and 59 were surgical lung biopsy (SLB). Two clinicians, two radiologists, and two pathologists sequentially reviewed clinical-radiologic findings and biopsy results, recording at each step in the process their diagnostic impressions and confidence levels.
We observed a major increase in diagnostic confidence after the addition of BLC, similar to SLB (from 29 to 63%, P = 0.0003 and from 30 to 65%, P = 0.0016 of high confidence IPF diagnosis, in the BLC group and SLB group, respectively). The overall interobserver agreement in IPF diagnosis was similar for both approaches (BLC overall kappa, 0.96; SLB overall kappa, 0.93). IPF was the most frequent diagnosis (50 and 39% in the BLC and SLB group, respectively; P = 0.23). After the addition of histopathologic information, 17% of cases in the BLC group and 19% of cases in the SLB group, mostly idiopathic nonspecific interstitial pneumonia and hypersensitivity pneumonitis, were reclassified as IPF.
BLC is a new biopsy method that has a meaningful impact on diagnostic confidence in the multidisciplinary diagnosis of interstitial lung disease and may prove useful in the diagnosis of IPF. This study provides a robust rationale for future studies investigating the diagnostic accuracy of BLC compared with SLB.
The distinction between malignant mesothelioma and reactive mesothelial proliferation can be challenging both on histology and cytology. Recently, variants of the BRCA1-associated protein 1 (BAP1) ...gene resulting in nuclear protein loss were reported in hereditary and sporadic mesothelioma. Using immunohistochemistry, we evaluated the utility of BAP1 expression in the differential diagnosis between mesothelioma and other mesothelial proliferations on a large series of biopsies that included 212 mesotheliomas, 12 benign mesothelial tumors, and 42 reactive mesothelial proliferations. BAP1 stain was also performed in 70 cytological samples (45 mesotheliomas and 25 reactive mesothelial proliferations). BAP1 was expressed in all benign mesothelial tumors, whereas 139/212 (66%) mesotheliomas were BAP1 negative, especially in epithelioid/biphasic compared with sarcomatoid/desmoplastic subtypes (69% vs 15%). BAP1 loss was homogeneous in neoplastic cells except for two epithelioid mesotheliomas showing tumor heterogeneity. By fluorescence in situ hybridization, BAP1 protein loss was paralleled by homozygous deletion of the BAP1 locus in the vast majority of BAP1-negative tumors (31/41, 76%), whereas 9/10 BAP1-positive mesotheliomas were normal. In biopsies interpreted as reactive mesothelial proliferation BAP1 loss was 100% predictive of malignancy, as all 6 cases subsequently developed BAP1-negative mesothelioma, whereas only 3/36 (8%) BAP1-positive cases progressed to mesothelioma. On cytology/cell blocks, benign mesothelial cells were invariably positive for BAP1, whereas 64% of mesotheliomas showed loss of protein; all 6 cases showing BAP1 negativity were associated with histological diagnosis of BAP1-negative mesothelioma. BAP1 stain also showed utility in the differential of mesothelioma from most common pleural and peritoneal mimickers, such as lung and ovary carcinomas, with specificity and sensitivity of 99/70% and 100/70%, respectively. Our results show that BAP1 protein is frequently lost in mesothelioma, especially of epithelioid/biphasic subtype and is commonly associated with homozygous BAP1 deletion. BAP1 immunostain represents an excellent biomarker with an unprecedented specificity (100%) in the distinction between benign and malignant mesothelial proliferations. Finding BAP1 loss in mesothelial cells should prompt to immediately reevaluate the patient; moreover, it might be useful in mapping tumor extent and planning surgical resection.
Histologic transformation from NSCLC to SCLC is a mechanism of resistance in EGFR-mutant tumors but is also occasionally observed in nonmutated NSCLC.
We performed a multicenter retrospective ...collection of cases presenting between 2005 and 2017. The objectives were to analyze survival data and to define epidemiologic, clinical, treatment and histomolecular characteristics at both the time of diagnosis of NSCLC and of SCLC.
Forty-eight EGFR-mutant NSCLC and 13 non–EGFR-mutant cases were registered. Most EGFR-mutant tumors retained the same EGFR mutation after transformation. The median time to SCLC transformation was shorter in the EGFR-mutant group than in non-EFGR mutants (16 months versus 26 months (p = 0.01)). Both tumors were responsive to platinum etoposide regimens (45% partial response for the EGFR-mutant group versus 40% for non-EFGR mutants). The median overall survival rates were 28 months in the EGFR-mutant group versus 37 months in the non–EFGR-mutant group, respectively. After transformation, the median overall survival was 9 months in the non–EGFR-mutant group versus 10 months in the EGFR-mutant group.
Transformation into SCLC seems to occur more quickly in EGFR mutated tumors; however, once the tumor is transformed its survival and response to treatment seems comparable to that of classical SCLC.
The term diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) may be used to describe a clinico-pathological syndrome, as well as an incidental finding on histological examination, ...although there are obvious differences between these two scenarios. According to the World Health Organization, the definition of DIPNECH is purely histological. However, DIPNECH encompasses symptomatic patients with airway disease, as well as asymptomatic patients with neuroendocrine cell hyperplasia associated with multiple tumourlets/carcinoid tumours. DIPNECH is also considered a pre-neoplastic lesion in the spectrum of pulmonary neuroendocrine tumours, because it is commonly found in patients with peripheral carcinoid tumours.In this review, we summarise clinical, physiological, radiological and histological features of DIPNECH and critically discuss recently proposed diagnostic criteria. In addition, we propose that the term "DIPNECH syndrome" be used to indicate a sufficiently distinct patient subgroup characterised by respiratory symptoms, airflow obstruction, mosaic attenuation with air trapping on chest imaging and constrictive obliterative bronchiolitis, often with nodular proliferation of neuroendocrine cells with/without tumourlets/carcinoid tumours on histology. Surgical lung biopsy is the diagnostic gold standard. However, in the appropriate clinical and radiological setting, transbronchial lung biopsy may also allow a confident diagnosis of DIPNECH syndrome.
Purpose
To investigate the suitability of the microDiamond detector (mDD) type 60019 (PTW‐Freiburg, Germany) to measure the anisotropy function F(r,θ) of High Dose Rate (HDR) 192Ir brachytherapy ...sources.
Methods
The HDR 192Ir brachytherapy source, model mHDR‐v2r (Elekta AB, Sweden), was placed inside a water tank within a 4F plastic needle. Four mDDs (mDD1, mDD2, mDD3, and mDD4) were investigated. Each mDD was placed laterally with respect to the source, and measurements were performed at radial distances r = 1 cm, 3 and 5 cm, and polar angles θ from 0° to 168°. The Monte Carlo (MC) system EGSnrc was used to simulate the measurements and to calculate phantom effect, energy dependence and volume‐averaging correction factors. F(r,θ) was determined according to TG‐43 formalism from the detector reading corrected with the MC‐based factors and compared to the consensus anisotropy function CONF(r,θ).
Results
At 1 cm, the differences between measurements and MC simulations ranged from −0.8% to +0.8% for θ = 0° and from −2.1% to + 2.3% for θ ≠ 0°. At 3 and 5 cm, the differences ranged from +1.4% to +3.9% for θ = 0°, and from −0.4% to +2.9% for θ ≠ 0°. All differences were within the uncertainties (k = 2). At small angles, the phantom effect correction was up to −1.9%. This effect was mainly caused by the air between source and needle tip. The energy correction was angle‐independent everywhere. For small angles at 1 cm, the volume‐averaging correction was up to −2.9% and became less important for larger angles and distances. The differences of the measured F(r,θ) corrected with the MC‐based factors to CONF(r,θ) ranged from –1.0% to +3.4% for mDD1, –2.2% to +4.2% for mDD2, –2.5% to +4.0% for mDD3, and −2.6% to +3.4% for mDD4. All differences were within the uncertainties (k = 2) except one at (3 cm, 0°). For all the mDDs, F(r,0°) was always higher than CONF(r,0°), with average differences of +3.1% (1 cm), +3.6% (3 cm), and +1.9% (5 cm). The inter‐detector variability was within 2.9% (1 cm), 1.8% (3 cm), and 3.4% (5 cm).
Conclusions
A reproducible method and experimental setup were presented for measuring and validating F(r,θ) of an HDR 192Ir brachytherapy source in a water phantom using the mDD. The phantom effect and the volume‐averaging need to be taken into account, especially for the smaller distances and angles. Good agreement to CONF(r,θ) was obtained. The discrepancies at (1 cm, 0°), accurately predicted by the MC results, may suggest a reconsideration of CONF(r,θ), at least for this position. The slight overestimations at (3 cm,0°) and (5 cm,0°), both in comparison to CONF(r,θ) and MC results, may be due to an underestimation of the air volume between source and needle tip, dark current, intrinsic over‐response of the mDDs, or radiation‐induced charge imbalance in the detector’s components. The results indicate that the mDD is a valuable tool for measurements with HDR 192Ir brachytherapy sources and support its employment for the determination and validation of TG‐43 parameters of such sources.
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