Systematic Review and Metanalysis of Oncomarkers in IPF Patients and Serial Changes of Oncomarkers in a Prospective Italian Real-Life Case Series.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a severe progressive interstitial lung disease. At 5-year follow-up, 15% of IPF patients develop lung cancer, which significantly reduces the survival rate. Here we review the literature on the clinical role of oncomarkers in IPF progression, and describe the trend of routine oncomarkers in IPF patients over the longest follow-up yet reported. MATERIALS AND METHODS: A systematic search of the literature in PubMed was performed to find relevant studies published up to 24 September 2020. The most common oncomarkers were chosen to select papers related to pulmonary fibrosis. Then, 24 IPF patients and 25 non-IPF patients, followed at Careggi ILD Referral Centre and Siena Regional Referral Centre for ILD, were enrolled consecutively. RESULTS: A few studies reported an association between serum oncomarkers and severity of IPF. NSE, CEA, Ca19.9, and Ca125 were higher in the IPF, than in the non-IPF, group at every follow-up (p < 0.05). Ca15.3 concentrations were higher in the IPF, than the non-IPF, group at t3 (p = 0.0080) and t4 (p = 0.0168). To improve the specificity and sensitivity of Ca15.3, a panel of biomarkers was analyzed, with the IPF group as dependent variable, and chitotriosidase, Cyfra 21.1, Ca15.3, Ca125, and Ca19.9 as independent variables. CONCLUSIONS: This study focused on the discovery of multiple biomarker signatures, such as combinations of oncomarkers, that are widely and routinely available in biochemistry laboratories. The combination of clinical parameters and biological markers could help achieve more accurate results regarding prognosis and response to treatment in IPF. Our results could pave the way for a more "personalized" medical approach to patients affected by IPF.

Pleural effusion as first extra-medullary clinical presentation of an occult multiple myeloma: The role of medical thoracoscopy.

Multiple myeloma is a malignant neoplasm of plasma cells that usually invades the bone marrow replacing normal bone marrow and producing large amounts of light chains of immunoglobulins (Ig) [1]. Clinical manifestations are related to the accumulation of these proteins in vital organs such as kidney and heart. Pleural effusion may be a sign of chest involvement that occurs in approximately 6% of patients with Known multiple myeloma [2,3]. We present the case of an 80-year- old man with pleural effusion as first extra-medullary clinical presentation of an occult multiple myeloma.

The Relevance of Family History Taking in the Detection and Management of Birt-Hogg-Dubé Syndrome.

BACKGROUND: Birt-Hogg-Dubé syndrome (BHDS) is a rare autosomal-dominant inherited disorder characterized by inactivation of the gene Folliculin (FLCN), pulmonary cysts with recurrent spontaneous pneumothorax, dermatological lesions, and an increased risk of developing renal malignancies. OBJECTIVES: We aimed to investigate the real prevalence of BHDS and its prevalence among patients with a familial history of pneumothorax. METHODS: From July 2014 to December 2016, we consecutively studied all patients with spontaneous pneumothorax and a positive family history for the same condition referring to our Institution. The suspicious cases underwent genetic analysis of the BHDS-causative gene FLCN. FLCN-positive cases were further evaluated with routine blood tests, chest radiography, chest CT, abdominal MRI, and dermatological evaluation. RESULTS: Among 114 patients admitted with spontaneous pneumothorax, 7 patients had a family history of pneumothorax, and 6/7 (85.7%) patients had positive genetic test for FLCN as well as 7/13 family members. Pulmonary cysts were found in all patients with a FLCN-positive genetic test. Most patients (10/13, 76.9%) had tiny pulmonary cysts less than 1 cm in diameter. The vast majority of cysts were intraparenchymal (12/13, 92.3%) and located in lower lobes. Dermatological lesions were found in 7/13 (54%) patients, renal cysts in 4/13 (31%) patients, and renal cancer in 1 (1/13, 7.7%) patient. CONCLUSIONS: Although BHDS is considered a rare disease, BHDS underlies spontaneous pneumothorax more often than usually believed, especially whenever a family history of pneumothorax is present. Diagnosis of BHDS is essential to start monitoring patients for the risk of developing renal malignancies.

The pathogenetic mechanisms of cough in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis is a peripheral subpleural interstitial lung disorder limited to the lung not involving the airways. It has a poor prognosis (survival less than 5 years) and commonly an interstitial pneumonia radiological pattern. Patients complain of a chronic dry cough in 80% of cases. A cough is often the first symptom of this rare disease, preceding dyspnea by years, and is associated with a poor prognosis, high dyspnea scores and low FVC percentages. The pathogenetic mechanisms leading to coughing in IPF are unclear. This review focuses on recent evidence of cough pathophysiology in this disease. Gastroesophageal reflux may promote coughing in IPF patients; bile salts and pepsin may be abundant in BAL of these patients, inducing overproduction of TGF-ß by airway epithelial cells and mesenchymal transition with fibroblast recruitment/activation and extracellular matrix deposition. Patients have an enhanced cough reflex to capsaicin and substance P with respect to control subjects. Moreover, patients with the MUC5B polymorphism show more severe coughing as MUC5B encodes for the dominant mucin in the honeycomb cysts of IPF patients. Comorbidities, including asthma, gastroesophageal reflux, hypersensitivity pneumonitis, bronchiectasis, chronic obstructive pulmonary disease and emphysema, can induce coughing in IPF patients. There is no clear explanation of the causes of coughing in IPF. Further research into the pathophysiology of IPF and the pathogenetic mechanisms of coughing is necessary to improve survival and quality of life.

Airway-Centered Pleuroparenchymal Fibroelastosis Associated with Non-Necrotizing Granulomas: A Rare New Entity.

Pleuroparenchymal fibroelastosis is a rare form of upper-lobe-dominant progressive pulmonary fibrosis characterized histologically by visceral pleural thickening with collagenous fibrosis, subpleural elastosis, and intra-alveolar collagenous fibrosis. It was first described 25 years ago by Amitani et al. This report firstly describes a new variant or rare phenotype of PPFE with airway involvement, minimal pleuroparenchymal connections, and non-necrotizing granulomas.

Unidirectional endobronchial valves for management of persistent air-leaks: results of a multicenter study.

BACKGROUND: To evaluate the efficacy of Endo-Bronchial Valves in the management of persistent air-leaks (PALs) and the procedural cost. METHODS: It was a retrospective multicenter study including consecutive patients with PALs for alveolar pleural fistula (APF) undergoing valve treatment. We assessed the efficacy and the cost of the procedure. RESULTS: Seventy-four patients with persistent air leaks due to various etiologies were included in the analysis. In all cases the air leaks were severe and refractory to standard treatments. Sixty-seven (91%) patients underwent valve treatment obtaining a complete resolution of air-leaks in 59 (88%) patients; a reduction of air-leaks in 6 (9%); and no benefits in 2 (3%). The comparison of data before and after valve treatment showed a significant reduction of air-leak duration (16.2±8.8 versus 5.0±1.7 days; P<0.0001); chest tube removal (16.2±8.8 versus 7.3±2.7 days; P<0.0001); and length of hospital stay (LOS) (16.2±8.8 versus 9.7±2.8 days; P=0.004). Seven patients not undergoing valve treatment underwent pneumo-peritoneum with pleurodesis (n=6) or only pleurodesis (n=1). In only 1 (14%) patient, the chest drainage was removed 23 days later while the remaining 6 (86%) were discharged with a domiciliary chest drainage removed after 157±41 days. No significant difference was found in health cost before and after endobronchial valve (EBV) implant (P=0.3). CONCLUSIONS: Valve treatment for persistent air leaks is an effective procedure. The reduction of hospitalization costs related to early resolution of air-leaks could overcome the procedural cost.

Atypical HRCT manifestations of pulmonary sarcoidosis.

PURPOSE: To present our experience of cases of pulmonary sarcoidosis with atypical HRCT patterns found during 2016 focusing on the differential diagnosis to contribute to the difficult role of the radiologist in the disease identification and to help the clinicians to reach the diagnosis. MATERIALS AND METHODS: The HRCT examinations of 47 patients with sarcoidosis were studied retrospectively. All patients had a histopathological confirm of the disease. 29 (61.7%) show a typical pulmonary pattern and 18 (38.3%) an atypical pattern. The latter were evaluated by three experienced radiologists dedicated to thoracic disease to radiologically define the predominant pattern of presentation. RESULTS: In the 18 patients (38.3%) with atypical sarcoidosis, the following parenchymal patterns were observed: four patients (22.2%) had interstitial fibrotic alterations, three patients (16.6%) with reticular pattern with inter-intralobular septal thickening, two patients (11.1%) with small-airway involvement with mosaic oligoemia, two patients (11.1%) with pleural involvement (pneumothorax and pleural plaques), one patient (5.5%) with fibrocystic changes, 1 (5.5%) with halo-sign, 1 (5.5%) with diffuse bilateral ground-glass opacities, and 1 (5.5%) with isolated lung mass; in addition, three patients (16.6%) with atypical lymph node pattern were also found. CONCLUSIONS AND DISCUSSION: The atypical pulmonary alterations found in CT examination can be confused with other lung diseases and they are always a challenge even for the most experienced radiologist. In our experience, cases with atypical pulmonary sarcoidosis patterns evaluated in the study are consistent with similar cases described in the literature, both in lymph node and atypical parenchymal involvement. All the atypical characteristics of the work should alert the radiologist to consider sarcoidosis among the possible differential diagnoses, always correlating the results of the computed tomography examination with appropriate clinical-laboratory evaluations.

Fibrotic Lung Toxicity Induced by Hydroxycarbamide.

A patient treated for 4 months with hydroxycarbamide (hydroxyurea) for chronic myelomonocytic leukemia was admitted to hospital for recently developed severe dyspnea and acute respiratory failure. The computed tomographic scan of the chest showed diffuse ground glass opacities, some centrilobular low-density nodules (resembling hypersensitivity pneumonitis-like pattern), and minimal interstitial reticulation of the subpleural region. The analysis of bronchoalveolar lavage fluid excluded infection, as did serological examinations. The patient was started on oxygen therapy and with relief of thrombocytopenia and suspected hemolytic anemia, hydroxyurea treatment was discontinued. The patient underwent steroid therapy, with a rapid progressive improvement of clinical and radiological features. As hydroxyurea is increasingly used for a number of systemic disorders, physicians must be aware of its potential lung toxicity, requiring immediate cessation of the treatment and empiric corticosteroid therapy.

A group of patients with Marfan's syndrome, who have finger and toe contractures, displays tendons' alterations upon an ultrasound examination: are these features common among classical Marfan patients?

The involvement of the musculoskeletal system with other mild pleiotropic manifestations represents a clinical criterion, called "systemic features," to d iagnose Marfan's syndrome. We aimed to investigate the features of the hands and feet redressable contractures present in a group of Marfan patients. In 13 patients with previously diagnosed Marfan's syndrome, an accurate clinical examination was performed. In particular the characterization of the musculoskeletal system by visual analogic scale to measure muscle pain (VAS) and muscle strength (MRC system) was carried out; the Beighton scale score was used to evaluate the articular hypermobility. Ultrasound examination (US) was performed to detect deep-superficial flexor tendons and extensor tendons of both hands, and the short and long flexor and extensor tendons of the fingers and toes in static and dynamic positions. The ImageJ program was adopted to measure a profile of tendon echo-intensity. A reduction of the thickness of all tendons was detected by US in our patients; the VAS and Beighton scale scores were in normal ranges. The profile of tendon echo-intensity showed different textural details in all Marfan patients. This study provides evidence for other contractures' localization, and for altered findings of the tendons in patients with Marfan syndrome and finger/toe contractures. These changes may be associated with structural modifications in connective tissue.

Dural ectasia and FBN1 mutation screening of 40 patients with Marfan syndrome and related disorders: role of dural ectasia for the diagnosis.

Marfan syndrome is an autosomal dominant disorder of connective tissue caused by mutations in the gene encoding fibrillin-1 (FBN1), a matrix component of microfibrils. Dural ectasia, i.e. enlargement of the neural canal mainly located in the lower lumbar and sacral region, frequently occurs in Marfan patients. The aim of our study was to investigate the role of dural ectasia in raising the diagnosis of Marfan syndrome and its association with FBN1 mutations. We studied 40 unrelated patients suspected for MFS, who underwent magnetic resonance imaging searching for dural ectasia. In all of them FBN1 gene analysis was also performed. Thirty-seven patients resulted affected by Marfan syndrome according to the '96 Ghent criteria; in 30 of them the diagnosis was confirmed when revaluated by the recently revised criteria (2010). Thirty-six patients resulted positive for dural ectasia. The degree of dural ectasia was grade 1 in 19 patients, grade 2 in 11 patients, and grade 3 in 6 patients. In 7 (24%) patients, the presence of dural ectasia allowed to reach a positive score for systemic feature criterion. Twenty-four patients carried an FBN1 mutation, that were represented by 13 missense (54%), and 11 (46%) mutations generating a premature termination codon (PTC, frameshifts and stop codons). No mutation was detected in the remaining 16 (6 patients with MFS and 10 with related disorders according to revised Ghent criteria). The prevalence of severe (grade 2 and grade 3) involvement of dura mater was higher in patients harbouring premature termination codon (PTC) mutations than those carrying missense-mutations (8/11 vs 2/13, P = 0.0111). Our data emphasizes the importance of dural ectasia screening to reach the diagnosis of Marfan syndrome especially when it is uncertain and indicates an association between PTC mutations and severe dural ectasia in Marfan patients.

Differential responses to Cr(VI)-induced oxidative stress between Cr-tolerant and wild-type strains of Scenedesmus acutus (Chlorophyceae).

A wild-type and a Cr-tolerant strain of the unicellular green alga Scenedesmus acutus were used to investigate if the difference in tolerance to Cr(VI) could depend on a different response to oxidative stress in terms of free cysteine (Cys) and reduced glutathione (GSH), and in preventing membrane lipid peroxidation. The growth of the two strains in standard medium in the presence of Cr(VI) 9.6, 19.2 or 38.4microM was compared, and the content of thiobarbituric acid reactive substances (TBARS) after a 4-day treatment was determined as marker of lipid peroxidation. The Cys and GSH contents were determined in both strains treated with Cr(VI) for 24h in HEPES buffer both enriched and not with sulphate. The treated algae were also subjected to recovery test in standard medium. The growth of wild type was inhibited at all Cr(VI) concentrations, while that of the Cr-tolerant strain only at the highest one. After exposure to 19.2microM Cr(VI), TBARS levels ranging from 0.091 to 0.263micromol/g d.w. were detected in the wild type, while only a slight increase (0.090+/-0.014micromol/g d.w.) was observed in the Cr-tolerant strain. Following treatment with 38.4microM Cr(VI), TBARS levels rose significantly and were similar in the two strains. The Cys content did not vary significantly in the cells exposed to Cr(VI) in either sulphate-lacking or sulphate-enriched buffer, and the differences between the two strains were insignificant. In the wild-type strain, the GSH content showed a significant downward trend with the increase in Cr(VI) concentration in the sulphate-lacking buffer, while it remained as high as the one of control cells in the sulphate-enriched buffer. In the Cr-tolerant strain, the GSH content did not vary significantly when the treatment took place in the sulphate-lacking buffer, while it showed a significant rise with the increase in Cr(VI) concentration in the sulphate-enriched buffer. The growth of both strains during recovery was significantly faster after treatment in the sulphate-enriched than in the sulphate-lacking buffer, the Cr-tolerant strain showing a much higher recovery capacity than the wild type. It appears that the Cr-tolerant strain, when exposed to Cr(VI) in the presence of a sulphur source, can increase GSH pool to levels not achievable by the wild type, and is thus able to recover better. This first report on the role of thiol compounds in Cr tolerance in algae suggests that tolerance to Cr(VI) in S. acutus could depend on a prompt up-regulation of the pathways leading to GSH synthesis.

Cadmium tolerance, cysteine and thiol peptide levels in wild type and chromium-tolerant strains of Scenedesmus acutus (Chlorophyceae).

Two strains of the unicellular green alga Scenedesmus acutus with different sensitivity to hexavalent chromium were compared for their tolerance of cadmium, by means of growth and recovery tests, and determination of cysteine, reduced glutathione and phytochelatin content, after short-term exposure to various cadmium concentrations (from 1.125 to 27 microM). Growth experiments showed that, after 7-day treatments with cadmium, the chromium-tolerant strain reached a significantly higher cell density and, after 24-h exposure to Cd, was able to resume growth significantly better than the wild type. Constitutive level of cysteine was higher in the chromium-tolerant strain, while glutathione levels were similar in the two strains. The higher content of cysteine and the maintenance of both reduced glutathione and phytochelatin high levels in the presence of cadmium, support the higher cadmium co-tolerance of the chromium-tolerant strain in comparison with the wild type one.