A pilot study on the use of the super dimension navigation system for optimal cryobiopsy location in interstitial lung disease diagnostics.

BACKGROUND: Transbronchial cryobiopsies has become increasingly important in the diagnostic workup for interstitial lung diseases. The rate of complications and mortality are low compared to surgical lung biopsies, but the diagnostic yield is not as high. The reason for the lower diagnostic yield could in some cases be explained by biopsies taken too centrally or in less affected areas. In this pilot study we examined the feasibility of using the electromagnetic navigation system, superDimension (SD), when performing cryobiopsies to increase the diagnostic yield. METHODS: Electromagnetic navigation bronchoscopy and cryobiopsies were performed using SD. An electromagnetic board placed on the back of the patient and a position sensor at the tip of the navigational probe created a real-time 3D reconstruction of previously acquired computer tomography images. The procedure was performed with the patients in general anesthesia using a rigid bronchoscope when performed in Florence and with a flexible bronchoscope through an orotracheal tube when performed in Aarhus. RESULTS: In total, 18 patients were included. Five patients were excluded, partly due to technical difficulties. Disposable 1.7 mm cryoprobes were used in Aarhus, and reusable 1.9 mm probes in Florence. Pneumothorax was detected in three (23%), mild hemorrhage was seen in one (8%) and moderate hemorrhage in six (46%). The biopsies contributed to the diagnosis in 11 of the patients (85%). CONCLUSION: Using superDimension electromagnetic navigation system when performing cryobiopsies is feasible. A larger prospective trial is necessary to homogenize the technique between centres and to evaluate diagnostic advantage and complications.

Pulmonary vein stenosis mimicking interstitial lung disease.

Pulmonary vein stenosis (PVS) is a rare condition, often difficult to diagnose and associated with poor prognosis at advanced stages. Lung parenchymal abnormalities are indirect evidence of PVS and can manifest as multifocal opacities, nodular lesions, unilateral effusions, and interstitial septal thickening. These can lead to erroneous diagnoses of airway disease, pneumonia, malignancies or interstitial lung disease. This review summarizes the current literature about the approach to, evaluation and management of these patients. Our case report demonstrates that PVS is an under-recognized complication of cardiovascular surgery and should be considered in all patients presenting with respiratory symptoms after a cardiac procedure.

Endobronchial-ultrasound needle aspiration and endoscopic ultrasound-fine-needle aspiration in thoracic diseases.

EBUS-TBNA and EUS-FNA are minimally invasive techniques rapidly gaining ground in the non-surgical invasive diagnostic approach to thoracic diseases due to their high accuracy and low morbidity and mortality compared to surgical techniques. Moreover, in the diagnosis and staging of lung cancer the combination of the two techniques is superior to either test alone. In this review we focus on the role of EBUS-TBNA and EUS-FNA in both malignant and non-malignant thoracic diseases.

Diffuse Neuroendocrine Hyperplasia with Obliterative Bronchiolitis and Usual Interstitial Pneumonia: An Unusual "Headcheese Pattern" with Nodules.

A 74-year-old non-smoker female presented to our attention with a history of dyspnea and cough. CT scan revealed multiple areas of patchy ground glass attenuation associated to a diffuse mosaic oligoemia. Scattered bilateral subcentimetric pulmonary nodules were also present. Patient underwent a surgical lung biopsy. Specimens showed features of diffuse neuroendocrine hyperplasia, microhoneycombing, fibroblast foci. A final diagnosis of diffuse neuroendocrine hyperplasia with obliterative bronchiolitis and UIP was rendered.

Efficacy of pirfenidone for idiopathic pulmonary fibrosis: An Italian real life study.

BACKGROUND: In this retrospective Italian study, which involved all major national interstitial lung diseases centers, we evaluated the effect of pirfenidone on disease progression in patients with IPF. METHODS: We retrospectively studied 128 patients diagnosed with mild, moderate or severe IPF, and the decline in lung function monitored during the one-year treatment with pirfenidone was compared with the decline measured during the one-year pre-treatment period. RESULTS: At baseline (first pirfenidone prescription), the mean percentage forced vital capacity (FVC) was 75% (35-143%) of predicted, and the mean percentage diffuse lung capacity (DLCO) was 47% (17-120%) of predicted. Forty-eight patients (37.5%) had mild disease (GAP index stage I), 64 patients (50%) had moderate IPF (stage II), and 8 patients (6.3%) had severe disease (stage III). In the whole population, pirfenidone attenuated the decline in FVC (p = 0.065), but did not influence the decline in DLCO (p = 0.355) in comparison to the pre-treatment period. Stratification of patients into mild and severe disease groups based on %FVC level at baseline (>75% and ≤75%) revealed that attenuation of decline in FVC (p = 0.002) was more pronounced in second group of patients. Stratification of patients according to GAP index at baseline (stage I vs. II/III) also revealed that attenuation of decline in lung function was more pronounced in patients with more severe disease. CONCLUSIONS: In this national experience, pirfenidone reduced the rate of annual FVC decline (p = 0.065). Since pirfenidone provided significant treatment benefit for patients with moderate-severe disease, our results suggest that the drug may also be effective in patients with more advanced disease.

Early application of percutaneous vertebroplasty reduces pain without affecting peripheral blood stem cell (PBSC) collection and transplant in newly diagnosed multiple myeloma (MM) patients.

Vertebral fractures occur in over 60% of newly diagnosed multiple myeloma (MM) patients and can cause pain, disability and poor quality of life. Antimyeloma therapy can lead to symptoms improvement, but these effects can take time to be perceived. Application of radiotherapy prior to peripheral blood stem cells (PBSC) mobilisation can impair stem cell collection. Percutaneous vertebroplasty has been proposed as a suitable option to rapidly relieve bone pain from vertebral fractures in MM patients, but, little is known about the effects of this procedure on subsequent PBSC mobilisation, collection and transplant. Eighteen patients (10M/8F, median age 64.5 years) with untreated MM and painful vertebral lesions underwent vertebroplasty prior to proceed to the planned transplant program at our Institution. Forty-one procedures were performed at C2-L5 levels, eight patients were treated at ≥2 levels. Ninety-five per cent of the cases obtained a complete or optimal pain control. All the patients successfully mobilised PBSC (median CD34+ cells = 10.8 × 10(6) /kg) and underwent autologous PBSC transplant; both polymorphonucleates and platelets recovery averaged 11 days. Our data seem to suggest that percutaneous vertebroplasty is useful in newly diagnosed MM patients with painful vertebral fractures as it allows rapid and durable achievement of pain control, without interfering with further treatment.

The effect of anticoagulant therapy for idiopathic pulmonary fibrosis in real life practice.

BACKGROUND: IPF is a common form of interstitial lung disease for which there is no effective therapy and usually results in death. Two previous contradictory studies showed anticoagulant therapy  to be associated with both improved and worsened survival, respectively. OBJECTIVE: The objective of this retrospective cohort study was to evaluate the effect of anticoagulant therapy on the survival and disease progression of patients with idiopathic pulmonary fibrosis (IPF) in real clinical practice. METHODS: We compared the clinical characteristics, time to disease progression, incidence of acute exacerbation, and survival of 25 (20%) IPF patients receiving anticoagulant therapy to the remaining 97 IPF patients not receiving anticoagulant therapy. In addition we conducted a sensitivity analysis using as comparator a group of 25 patients matched by age, sex, functional impairment, cardiac comorbidities and pulmonary hypertension. RESULTS: Patients on anticoagulant therapy had a worse 1- and 3-year survival (84% and 53% versus 89% and 64% in the non-anticoagulant group, respectively), a difference that persisted after adjusting for age and comorbidities (hazard ratio 3.1 - 95% confidence interval, 1.4 to 7.0; p=0.006) and after comparison with the matched group (adjusted HR=4.8, 95% CI: 1.8-12.8; p=0.002). IPF patients on anticoagulant therapy had a shorter interval to disease progression ( 0.7 years versus 1.6 years, adjusted HR 2.2 -95% CI, 0.96 to 5.1; p=0.063) confirmed also in the analysis with matched subgroups (HR=2.7 (95% CI: 1.2-6.5); p=0.023). The incidence of acute exacerbations did not differ in the two groups (22% versus 23%). Two patients (8%) experienced anticoagulant treatment related complications and included an episode of hemorrhagic shock. CONCLUSION: In this retrospective study patients treated with anticoagulants had a worse survival and a shorter interval to disease progression. This support the recent finding that warfarin worsen the respiratory status and survival of IPF patients.

Update on the role of autologous hematopoietic stem cell transplantation in multiple myeloma.

Autologous stem cell transplantation is considered the standard of care for multiple myeloma patients aged < 65 years with no relevant comorbidities. The addition of drugs acting both on bone marrow microenvironment and on neoplastic plasma cells has significantly increased the proportion of patients achieving a complete remission after induction therapy, and these results are mantained after high-dose melphalan, leading to a prolonged disease control. Studies are being carried out in order to evaluate whether short term consolidation or long-term maintenance therapy can result into disease eradication at the molecular level thus increasing also patients survival. The efficacy of these new drugs has raised the issue of deferring the transplant after achiving a second response upon relapse. Another controversial point is the optimal treatment strategy for high-risk patients, that do not benefit from autologous stem cell transplantation and for whom the efficacy of new drugs is still matter of debate.

Diagnostic role of rapid on-site cytologic examination (ROSE) of broncho-alveolar lavage in ALI/ARDS.

BACKGROUND: While bronchoscopy should be considered in patients with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) in which the cause cannot be determined from history or clinical and laboratory data, there are no studies about the utility of rapid on-site examination (ROSE) of broncho-alveolar lavage for identification, as early as possible, of the pathological condition underlying the onset of this condition. The aim of this prospective, observational study was to evaluate the diagnostic role of ROSE of BAL in ALI/ARDS. METHODS: 71 patients with ALI/ARDS underwent bronchoalveolar lavage, and one part of the sample was examined with ROSE. The on-site report was categorized as diagnostic (specific diagnosis), presence of atypical reactive type II pneumocytes with no further comments or not diagnostic. RESULTS: ROSE of bronco-alveolar lavage yielded 29 (41%) specific diagnoses, revealed typical features of diffuse alveolar damage without a specific diagnosis in 28 patients (39%) and did not reveal a specific diagnosis in the remaining 14 cases (20%). CONCLUSIONS: The results of this study show that, in patients with ALI/ARDS, bronchoalveolar lavage with ROSE is diagnostic in 40% of cases: ROSE may therefore spare lung biopsies and improve the prognosis of patients with ARDS (immunocompetent or not) as therapy could be started or modified at a very early phase.

Pulmonary features of Birt-Hogg-Dubé syndrome: cystic lesions and pulmonary histiocytoma.

BACKGROUND: to describe clinical, radiologic and pathologic features of lung lesions in Birt-Hogg-Dubè syndrome (BHDS) (MIM 135150). METHOD: review of 12 patients of BHDS from 3 unrelated Italian families evaluated at GB Morgagni Hospital, Forlì, from 2005 to 2010. RESULTS: mean age (±SD) at diagnosis was 44.6 (±16) years, 8 (66%) were male. All three index cases presented with a history of recurrent pneumothorax and/or cystic lung lesions evaluated by CT scan request by referring pulmonary physicians, none were diagnosed to have BHDS at the time of initial pulmonary evaluation. One of the three cases was a middle-aged female patient with a clinical phenotype indistinguishable from lymphangioleiomyomatosis (LAM), characterized by cystic lung lesions and kidney angiomyolipoma. In one case of BHDS presenting with recurrent pneumothorax and a solitary lung nodule, surgical lung resection revealed a pulmonary histiocytoma. In one case a novel mutation of BHD gene was detected (c.771 del, exon 7). CONCLUSIONS: BHDS is associated with cystic lung disease largely under-recognized by pulmonary physicians and can mimic LAM and may be associated with lung tumor, pulmonary histiocytoma. In one case we found a novel mutation in exon 7, c.771 del (ref.seq. NM_144997.5) never reported before.

Idiopathic nonspecific interstitial pneumonia: an interstitial lung disease associated with autoimmune disorders?

Recent evidence suggests that idiopathic nonspecific interstitial pneumonia (iNSIP) is a distinct clinical entity amongst other idiopathic interstitial pneumonias, and some data seem to suggest a possible pathogenetic role of autoimmunity. The aim of the present study was to assess if iNSIP might represent an early lung manifestation of an autoimmune disease. After initial review of cases found in the medical records database by searching for the term "NSIP" (n = 63), 37 iNSIP cases were identified, and were re-evaluated using a dynamic integrated multidisciplinary approach. 27 cases with iNSIP were selected for the study. Mean ± sd age at first respiratory symptom was 54.2 ± 8 yrs, 70% were females, and 59% were never-smokers. At follow-up (mean ± sd 59.7 ± 29 months, range 12-138 months), autoimmune diseases occurred in 14 (52%) patients, with seven (26%) cases of autoimmune thyroiditis, six (22%) of undifferentiated connective tissue disease and three (11%) of connective tissue disease. Patients developing autoimmune diseases were older and more frequently never-smoking females. In >50% of patients diagnosed with iNSIP, evidence of autoimmune diseases develops within 2 yrs, suggesting a probable link between the clinical entity of iNSIP and autoimmune disorders.

Constitutional FLCN mutations in patients with suspected Birt-Hogg-Dubé syndrome ascertained for non-cutaneous manifestations.

Birt-Hogg-Dubé syndrome (BHDS) is characterized by a clinical triad including cutaneous hamartomas originating from hair follicles, lung cysts/pneumothorax, and kidney tumors. Inactivating mutations of the tumor suppressor gene FLCN are identified in most families with BHDS. Usually, patients are referred for genetic examination by dermatologists because of the presence of typical multiple skin tumors with or without additional symptoms. However, because of phenotypic variability and incomplete penetrance, the clinical presentation of BHDS is not yet fully defined. Criteria for genetic testing and diagnosis that take into account variable manifestations have recently been proposed by the European BHD Consortium. We sequenced the FLCN gene coding region in a series of 19 patients selected for kidney and/or lung manifestations. Overall, FLCN mutations were found in 9 of 19 (47%) families and were detected only in probands who had either >2 components of the clinical triad or a single component (renal or pulmonary) along with a family history of another main BHDS manifestation. Typical cutaneous lesions were present only in 8 of 21 FLCN mutation carriers aged >20 years identified in the mutation-positive families. In addition, we provide clinical and molecular evidence that parotid oncocytoma, so far reported in six BHDS cases, is associated with this condition, based on the observation of a patient with bilateral parotid involvement and marked reduction of the wild-type FLCN allele signal in tumor DNA. Overall, the results obtained in this study contribute to the definition of the phenotypic characteristics that should be considered for BHDS diagnosis and FLCN mutation testing.

The pathologist's role in the diagnosis of idiopathic pulmonary fibrosis.

Diagnosis of idiopathic pulmonary fibrosis (IPF) is challenging, and the cooperation between different specialists including pulmonologists, radiologists and pathologists is highly recommended in order to optimize the diagnostic process, avoiding unnecessary and harmful invasive procedures. The recognition of the usual histological pattern of interstitial pneumonia is not easy in some cases, and immunohistochemical markers can be applied to better visualize subtle microenvironmental changes in lung parenchyma. New data regarding the complex pathogenesis of IPF is helping to understand the severe lung remodeling that characterizes this disease, and may also provide new diagnostic criteria.

Endobronchial ultrasound in Dieulafoy's disease of the bronchus: an additional application of EBUS.

Dieulafoy's disease is a rare vascular malformation represented by an abnormally enlarged submucosal arterial vessel. This malformation is mostly found in gastrointestinal tract causing spontaneous bleeding although a few cases have been described in the bronchial tree. Recognizing Dieulafoy's malformation is crucial for the bronchoscopist in order to avoid biopsy that can lead to a massive hemoptysis, sometimes fatal. In this case report we show the clinical utility of endobronchial ultrasound (EBUS) in the evaluation of bronchial alteration suspicious for Dieulafoy's malformation.

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.