Resistance to osimertinib in advanced EGFR-mutated NSCLC: a prospective study of molecular genotyping on tissue and liquid biopsies.

BACKGROUND: Resistance to osimertinib in advanced EGFR-mutated non-small cell lung cancer (NSCLC) constitutes a significant challenge for clinicians either in terms of molecular diagnosis and subsequent therapeutic implications. METHODS: This is a prospective single-centre study with the primary objective of characterising resistance mechanisms to osimertinib in advanced EGFR-mutated NSCLC patients treated both in first- and in second-line. Next-Generation Sequencing analysis was conducted on paired tissue biopsies and plasma samples. A concordance analysis between tissue and plasma was performed. RESULTS: Sixty-five advanced EGFR-mutated NSCLC patients treated with osimertinib in first- (n = 56) or in second-line (n = 9) were included. We managed to perform tissue and liquid biopsies in 65.5% and 89.7% of patients who experienced osimertinib progression, respectively. Acquired resistance mechanisms were identified in 80% of 25 patients with post-progression samples, with MET amplification (n = 8), EGFR C797S (n = 3), and SCLC transformation (n = 2) the most frequently identified. The mean concordance rates between tissue and plasma for the EGFR activating mutation and for the molecular resistance mechanisms were 87.5% and 22.7%, respectively. CONCLUSIONS: Resistance to osimertinib demonstrated to be highly heterogeneous, with MET amplification the main mechanism. Plasma genotyping is a relevant complementary tool which might integrate tissue analysis for the study of resistance mechanisms.

Omalizumab and allergen immunotherapy for respiratory allergies: A mini-review from the Allergen-Immunotherapy Committee of the Italian Society of Pediatric Allergy and Immunology (SIAIP)

Although currently approved to treat severe asthma and chronic spontaneous urticaria, omalizumab has also been an effective and safe add-on treatment for other allergic diseases. Namely, omalizumab has been proposed to be used as add-on therapy in patients with allergic rhinitis and asthma and undergoing specific allergen immunotherapy (AIT). AIT is the only treatment that modifies the natural history of IgE-mediated diseases. This brief review summarizes the available evidence and controversies on the efficacy and safety of omalizumab combined with specific AIT (AU)

Pediatric urticaria in the Emergency Department: epidemiological characteristics and predictive factors for its persistence in children.

Summary: Introduction. Acute urticaria (AU) in children is a common clinical manifestation responsible for admission to the emergency department (ED). We aimed to analyze the epidemiological characteristics of AU in children and to identify predictors of both severity and progression. Material and methods. We evaluated 314 children admitted to the ED with a diagnosis of AU. We analyzed information concerning its onset, duration, severity, possible triggering factors, and the persistence of symptoms after 1, 3, and 6 months. Results. The most common etiological factors were infections (43.9%); in up to 32.4% of cases, AU was considered as idiopathic. AU was significantly most common in males and pre-school children. At the 6-month follow-up, 9.5% of children presented a persistence of urticaria, mainly those with contact (44.4%) or idiopathic (30.4%) forms. Conclusions. The AU etiology identified by history in the ED may be a significant predictor of persistence after a first attack of AU.

What can be seen after rotator cuff repair: a brief review of diagnostic imaging findings.

Diagnostic imaging plays an important role in the postoperative evaluation of the rotator cuff, as pain and disability may occur or persist after treatment. Postoperative imaging is therefore of paramount importance for clinicians before planning additional treatments. Multimodality imaging of the postoperative shoulder includes radiography, magnetic resonance (MR) imaging, MR arthrography, computed tomography (CT), CT arthrography, and ultrasound. Correct interpretation of imaging findings of the postoperative shoulder necessitates that the radiologist be familiar with the various treatment strategies, their possible complications and sources of failure, knowledge of normal and abnormal postoperative findings, and awareness of the advantages and weaknesses of the different imaging techniques. Imaging findings, however, should always be correlated with the clinical presentation because postoperative imaging abnormalities do not necessarily correlate with symptoms. This manuscript is a review of some of the most common treatment strategies for rotator cuff pathology, with a focus on expected postoperative imaging findings and postoperative complications.

Imaging of postoperative shoulder instability.

Postoperative imaging in shoulder instability is still a challenge for radiologists due to various postsurgical anatomical findings that could be considered pathologic in treated shoulder. For this reason is very important a deep knowledge about surgical procedures, anatomical changes after surgery and the appropriate diagnostic imaging modalities to work up the symptomatic postoperative shoulder. Postoperative imaging options include use conventional radiography, magnetic resonance imaging (MRI), MRI arthrography, computed tomography (CT) and CT arthrography. The purpose of our review is to explain the different surgical procedures and to describe postoperative changes detected with radiological imaging.

Osteolytic lesions, cytogenetic features and bone marrow levels of cytokines and chemokines in multiple myeloma patients: Role of chemokine (C-C motif) ligand 20.

The relationship between bone marrow (BM) cytokine and chemokine levels, cytogenetic profiles and skeletal involvement in multiple myeloma (MM) patients is not yet defined. This study investigated a cohort of 455 patients including monoclonal gammopathy of uncertain significance (MGUS), smoldering MM and symptomatic MM patients. Skeletal surveys, positron emission tomography (PET)/computerized tomography (CT) and magnetic resonance imaging (MRI) were used to identify myeloma bone disease. Significantly higher median BM levels of both C-C motif Ligand (CCL)3 and CCL20 were found in MM patients with radiographic evidence of osteolytic lesions as compared with those without, and in all MM patients with positive PET/CT scans. BM levels of CCL3, CCL20, Activin-A and Dickkopf-1 (DKK-1) were significantly higher in patients with high bone disease as compared with patients with low bone disease. Moreover, CCL20 BM levels were significant predictors of osteolysis on X-rays by multivariate logistic analysis. On the other hand, DKK-1 levels were related to the presence of MRI lesions independently of the osteolysis at the X-rays. Our data define the relationship between bone disease and the BM cytokine and chemokine patterns highlighting the tight relationship between CCL20 BM levels and osteolysis in MM.

Financial impact of radiological reports on medical-legal evaluation of compensation for meniscal lesions.

To evaluate any discrepancy between radiological reports for clinical purposes and for medicolegal purposes and to quantify its economic impact on repayments made by private insurance companies for meniscal injuries of the knee. The medical records obtained pertaining to 108 knee injury patients (mean age 43.3 years) assessed over a period of 12 months were analysed. Clinical medical reports, aimed at assessing the lesion, and medicolegal reports, drawn up with a view to quantifying compensation, were compared. Unlike reports for clinical purposes in reports for medicolegal purposes, in the evaluation of meniscal lesions, in addition to morphological features of lesions, chronological, topographical, severity and exclusion criteria were applied. To estimate the economic impact resulting from the biological damage, we consulted an actuarial table based on the 9-point minor incapacity classification system. Meniscal lesions not compatible with a traumatic event and therefore not eligible for an insurance payout were found in 56 patients. Of these, 37 failed exclusion criteria, while 19 failed to meet chronological criteria. This difference resulted in a reduction in compensation made by private insurance companies with savings estimated with a saving between euro 203,715.41 and euro 622,315.39. The use of a clinical report for medicolegal purposes can be a source of valuation error, as chronological and/or dynamic information regarding the trauma mechanism may be lacking. Therefore, the use of a full radiological appraisal allows a better damage's assessment and an adequate compensation for injuries.

Magnetic resonance imaging in the complications of kidney transplantation.

Kidney transplantation is currently the treatment of choice in most patients with end-stage chronic renal failure owing to the excellent results in terms of both graft and patient survival. However, surgical complications are still very frequent. Although urological (stricture, urinary fistulas, vesico-ureteral reflux) and lymphatic complications (lymphocoele) have a high incidence, they only rarely lead to graft loss. By contrast, vascular complications (stenosis, arterial and venous thrombosis, arterio-venous fistulas, pseudoaneurysms) are relatively rare, but potentially serious and may affect graft survival. Finally, medical complications such as acute tubular necrosis (ATN), rejection and de novo neoplasms may also arise in kidney transplantation. The purpose of this pictorial review is to illustrate the increasingly significant contribution of magnetic resonance angiography (MRA) in the management of complications of kidney transplantation, and emphasise how this method should now be considered a mandatory step in the diagnostic workup of selected cases. Moreover, the application and role in this setting of new magnetic resonance imaging (MRI) techniques, such as diffusion-weighted and blood oxygen level-dependent (BOLD) MRI, are also discussed.

Relationships between total and regional adiposity and epicardial fat in obese women: how can dual-energy X-ray absorptiometry be associated with echocardiographic epicardial fat measurements?

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Obesity is an increasingly prevalent metabolic disorder and it is associated with a large number of comorbidities, including cardiovascular diseases. Adipose tissue is an active endocrine organ and its ectopic depots and distribution have different metabolic meanings on risks for health; as a matter of fact, epicardial fat seems to play a specific role in cardiovascular diseases. The use of dual-energy X-ray absorptiometry (DXA) to evaluate and follow-up patients affected by obesity is becoming a very important point in the management of the disease. WHAT THIS STUDY ADDS: An investigation of the association between epicardial fat and regional adiposity by DXA in female obese patients. The total amount of central (trunk) fat mass is more strongly correlated than android visceral fat mass to epicardial thickness in obese women. In the interpretation of whole-body DXA data, physician should consider trunk fat mass for good and independent predictivity on epicardial fat depots. Our aim was to analyse in a population of obese women the relationship between the amount of epicardial fat as measured by transthoracic echocardiography (US) and the parameters of regional adiposity by dual-energy X-ray absorptiometry (DXA), with particular reference to a new software for visceral fat assessment and to a new 'heart-suited' regions of interests (ROIs). Sixty patients who satisfied technical inclusion criteria underwent whole-body DXA scan and US on the same day. Total and android fat mass (FM) and FM percentage (FM%) were considered as well as visceral fat (VAT) subcompartment in the android region; moreover, six new ROIs were designed on whole-body DXA images for the investigation of adiposity parameters at heart level. US provided epicardial fat thickness (EPI-thickness) and area (EPI-area), as measured following previously validated methods. Body mass index (BMI), gynoid and lower limbs (FM and FM%) were found not statistically correlated with EPI-thickness. The highest correlation was achieved by trunk FM (and FM%, with r = 0.544 and 0.480 respectively, P < 0.001), followed by ROI-1 FM (ROI-1 was drawn following thoroughly the cardiac profile), and android FM. Multivariate analysis including age, weight, BMI, trunk FM and the new ROIs (added one by one), retained in the final model trunk FM. Correlations of DXA with EPI-area were superimposable. In obese women, VAT or other new-designed ROIs are not better correlated than traditional ROIs (i.e. trunk) with epicardial fat amount.

Computed tomography-histologic correlations in lung cancer.

The multidisciplinary approach is ideal in the management of patients with lung cancer. Multidisciplinary evaluation strengthens the differential diagnosis of aspecific radiological findings, indeed. Notably, the differential diagnosis of early stage lung cancer is a current challenge of CT imaging because the earlier the detection, the lower the accuracy of radiological features. This is particularly true for the most common subtype of lung cancer, adenocarcinoma, because it shows various radiological features. Such variety is also reflected by the 2011 classification of lung cancer, that likely affected the diagnostic agreement between radiologist and clinician. This review discusses the common issues of lung cancer diagnosis by paired radiological-histologic interpretation of CT findings.

Follow-up in pulmonary sarcoidosis: comparison between HRCT and pulmonary function tests.

PURPOSE: The authors assessed the clinical usefulness of high-resolution computed tomography (HRCT) for monitoring sarcoidosis by comparing changes on HRCT with those on pulmonary function test (PFT) results over time. MATERIALS AND METHODS: The baseline and follow-up (after 13 months, range 15-63 months) HRCT scans of 14 consecutive patients with sarcoidosis were reviewed by a single observer. Each follow-up HRCT examination was assessed as stable, improved (when the extent of HRCT findings was reduced compared with baseline) and worsened (when the extent of HRCT findings was increased and/or when HRCT pattern had become fibrotic compared with baseline). Any increase or decrease in forced vital capacity (FVC)≥10% from baseline was considered significant. Changes on HRCT were then compared with those on FVC. RESULTS: During a median follow-up of 33 (range 15-63) months, HRCT findings worsened in 8/14 (58%) cases, improved in 3/14 (21%) and remained stable in 3/14 (21%). Agreement between changes on HRCT and FVC was moderate (κ=0.49). In 9/14 (64%) cases, HRCT changes were in line with those on FVC. In 4/5 discordant cases, the worsened HRCT findings were not mirrored by FVC changes. CONCLUSIONS: Despite the small size of our study population, our results suggest that HRCT may provide clinicians with additional information about the evolution of sarcoidosis.

Direct regulation of microRNA biogenesis and expression by estrogen receptor beta in hormone-responsive breast cancer.

Estrogen effects on mammary epithelial and breast cancer (BC) cells are mediated by the nuclear receptors ERα and ERß, transcription factors that display functional antagonism with each other, with ERß acting as oncosuppressor and interfering with the effects of ERα on cell proliferation, tumor promotion and progression. Indeed, hormone-responsive, ERα+ BC cells often lack ERß, which when present associates with a less aggressive clinical phenotype of the disease. Recent evidences point to a significant role of microRNAs (miRNAs) in BC, where specific miRNA expression profiles associate with distinct clinical and biological phenotypes of the lesion. Considering the possibility that ERß might influence BC cell behavior via miRNAs, we compared miRNome expression in ERß+ vs ERß- hormone-responsive BC cells and found a widespread effect of this ER subtype on the expression pattern of these non-coding RNAs. More importantly, the expression pattern of 67 miRNAs, including 10 regulated by ERß in BC cells, clearly distinguishes ERß+, node-negative, from ERß-, metastatic, mammary tumors. Molecular dissection of miRNA biogenesis revealed multiple mechanisms for direct regulation of this process by ERß+ in BC cell nuclei. In particular, ERß downregulates miR-30a by binding to two specific sites proximal to the gene and thereby inhibiting pri-miR synthesis. On the other hand, the receptor promotes miR-23b, -27b and 24-1 accumulation in the cell by binding in close proximity of the corresponding gene cluster and preventing in situ the inhibitory effects of ERα on pri-miR maturation by the p68/DDX5-Drosha microprocessor complex. These results indicate that cell autonomous regulation of miRNA expression is part of the mechanism of action of ERß in BC cells and could contribute to establishment or maintenance of a less aggressive tumor phenotype mediated by this nuclear receptor.

Increased risk of brain injury in IVF babies.

AIM: The aim of this paper was to assess brain injury occurrence among in vitro fertilization (IVF) babies. METHODS: We examined all babies born in our hospital in the triennium 2004-2006, comparing the presence of brain injuries between IVF babies and the rest of the population. RESULTS: In IVF group (180 babies), brain injury was present in 4 babies, while in the rest of population (n=3602) it was present in 23 babies (P=0.042, RR: 3.18). IVF babies have a higher risk of being born with a birthweight less than 2 500 grams (P<0.0001; RR: 5.133). When we considered only babies born with a birth weight less than 2 500 grams, the difference of brain injury between the two groups was not significant. CONCLUSION: In IVF babies, brain injury occurred more frequently than in the rest of population. This is probably due to a higher rate of premature births and low birth weight in IVF population. Anyway, this data should be disclosed to future parents to make an informed decision.

Subclinical interstitial lung abnormalities in stable renal allograft recipients in the era of modern immunosuppression.

BACKGROUND: Interstitial lung abnormalities have been detected in up to 24% of kidney transplant patients receiving traditional immunosuppressive therapies (eg, cyclosporine, azathioprine); they usually occur early after transplantation and tend to resolve over time. Newer immunosuppressants such as mycophenolic acid and, particularly, mammalian target of rapamycin (mTOR) inhibitors (eg, sirolimus) may cause significant lung toxicity. However, the prevalence and severity of interstitial lung lesions in long-term, stable kidney transplant patients receiving either traditional or newer immunosuppressants is not known. METHODS: We conducted a prospective, cross-sectional study examining high-resolution lung computed tomography (CT) scans in 63 stable kidney transplant recipients whose immunosuppressive therapy had remained unchanged for over 24 months. We compared CT findings of patients taking newer (mycophenolic acid and mTOR inhibitors) and traditional (calcineurin inhibitors and azathioprine) immunosuppressive drugs. RESULTS: Interstitial lung alterations were observed in only 3/63 patients (4.8%); the prevalence was 11.5% (3/26) versus 0% (0/37) among the newer versus traditional immunosuppressive therapy groups, respectively (P = .065). The CT patterns were usual interstitial pneumonia and nonspecific interstitial pneumonia-like. The median time between transplant and CT was 49 months in the three patients with CT alterations and 95 months in the remaining 23 patients on newer immunosuppressants. It was 75 months for all patients on newer immunosuppressive drugs and 133 months for those on traditional therapies (P = .0015). A follow-up CT, performed in 2/3 patients with interstitial abnormalities, showed that the lesions were stable in one, while they had disappeared in the other. CONCLUSIONS: Interstitial lung abnormalities are infrequent and mild in stable kidney transplant patients treated with newer as well as traditional immunosuppressive drugs. As such abnormalities were detected in patients screened earlier after transplantation, the time since transplantation rather than the drug type is probably the major determinant.

Benefits of 3D technique in guiding percutaneous retroperitoneal biopsies.

PURPOSE: This study aimed to assess the usefulness and advantages of multiplanar reformations (MPR) during multidetector-row computed tomography (MDCT)-guided percutaneous fine-needle aspiration biopsy (FNAB) and core biopsy of retroperitoneal lesions that are difficult to access with the guidance of ultrasound and axial CT alone owing to overlying bony structures, large vessels or abdominal organs. MATERIALS AND METHODS: MDCT-guided retroperitoneal FNAB and core biopsy was performed on 14 patients with suspected retroperitoneal neoplasm. We used MPR images (sagittal and coronal) obtained with a six-detector-row MDCT scanner and 20-22 gauge Chiba needles. RESULTS: Using MDCT with 3D MPR allowed biological samples to be obtained in all cases (ten cytological and four histological) and diagnostic samples in 11/14 cases (78.5%). Histological samples were deemed adequate for diagnostic assessment in all cases and cytological samples in 7/10 cases (70%). CONCLUSIONS: MPR images allowed sampling of retroperitoneal lesions until now considered unreachable with the guidance of axial MDCT alone. Compared with the conventional procedure, the use of MPR images does not increase the procedure time.

Critical issues in radiology requests and reports.

PURPOSE: This study evaluated the appropriateness and accuracy of 500 radiology requests and their matched reports in order to identify recurring errors in both areas. MATERIALS AND METHODS: A randomly chosen sample consisting of 167 computed tomography (CT), 166 ultrasonography (US) and 167 radiographic examinations were collected and analysed according to national referral guidelines and to the principles of justification and optimisation (Law no. 187/2000). RESULTS: We identified a high rate of inappropriate requests (27.6%) and requests lacking a clinical question (22%). There was good precision in the anamnestic data (80.6%) and in the formulation of the diagnostic question (76.8%). Almost all requests were handwritten, and 12.5% lacked the referring physician's stamp and/or signature. No report mentioned the clinical information received or the equipment used. The use of contrast medium was always reported. Conclusions were reported in 9.8% of these reports. When further investigation would have been necessary, the radiologist omitted to report this in 60% of cases. CONCLUSIONS: Some important weaknesses emerged, especially regarding requests for radiological examinations (22% lacked the clinical question, 27.6% were inappropriate), potentially limiting the effectiveness of the diagnostic process and leading to negative effects on the correct risk management process. There emerges a need for better collaboration between clinicians and radiologists.

High-resolution computed tomography in the diagnosis and follow-up of idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is the most common interstitial lung disease and is associated with a fatal prognosis. Familiarity with the typical appearances of IPF on high-resolution computed tomography (HRCT) is important, as in the appropriate clinical setting, it is often sufficient for establishing a confident diagnosis of IPF without the need for surgical biopsy. Moreover, HRCT can provide important prognostic information in IPF. This is noteworthy, as the course of IPF is variable, and many patients develop complications leading to respiratory failure and death. The purpose of this paper is to review the progress made towards a better understanding of the HRCT patterns of IPF.

Erdheim-Chester disease: clinical and radiological findings.

PURPOSE: The authors retrospectively reviewed six cases of histologically proven Erdheim-Chester disease (ECD) to evaluate organ involvement and clinical and radiological findings. MATERIALS AND METHODS: Through a search of the pathology databases of four Italian hospitals, we identified six men (mean age, 56 years) with a histological diagnosis of ECD. Histology was performed on retroperitoneal or pulmonary biopsy, depending on disease involvement on imaging. Patients underwent plain radiography of the lower limbs and chest, total-body computed tomography (CT) and bone scintigraphy. Magnetic resonance (MR) imaging was performed in two patients to evaluate the lower limbs and in one patient to study the brain, the chest and the abdomen. RESULTS: Clinical manifestations included dyspnoea (n=2), hydronephrosis (n=2) and bone pain (n=1). Bilateral symmetrical osteosclerosis of the metaphyseal and diaphyseal portions of the lower-limb long bones was present in five patients. Imaging studies revealed extraskeletal manifestations in all patients, including involvement of the retroperitoneal space (n=4), the lung (n=4) and the heart (n=2). CONCLUSIONS: ECD is a multiorgan disease that displays constant involvement of the bones and retroperitoneum; in particular, of the perirenal fat. Although the diagnosis of ECD is histological, imaging can raise suspicion and help to establish a presumptive diagnosis.

Detection of incidental vertebral fractures on routine lateral chest radiographs.

PURPOSE: This study sought to assess the usefulness of routine lateral chest radiographs for detecting unrecognised vertebral compression fractures. MATERIALS AND METHODS: We prospectively selected outpatients without symptoms or risk factors for osteoporosis who underwent chest radiography for different clinical indications. Two independent reviewers with different levels of experience assessed the radiographs for vertebral deformities and graded them as mild, moderate and severe according to the semiquantitative Genant Index. The kappa statistic was used to evaluate interobserver agreement and verify the reproducibility of this method. The prevalence of vertebral fractures observed was compared with that recorded in the official radiology reports. RESULTS: Our study involved 145 patients (73 men, 72 women; age range 50-86 years, mean age 67.5). Clinically relevant vertebral fractures were seen in 18/145 patients (12.4%). These were moderate in 13 patients and severe in five, and single in 12 patients and multiple in six. Interobserver agreement was very high (kappa=0.9). Only 11% of these fractures were recorded in the official reports. CONCLUSIONS: Lateral chest radiographs could be effective for assessing previously unknown vertebral compression fractures in individuals without clinical evidence or risk factors for osteoporosis.