Serum Proteomics and Plasma Fibulin-3 in Differentiation of Mesothelioma From Asbestos-Exposed Controls and Patients With Other Pleural Diseases.

INTRODUCTION: Malignant pleural mesothelioma (MPM) is difficult to diagnose. An accurate blood biomarker could prompt specialist referral or be deployed in future screening. In earlier retrospective studies, SOMAscan proteomics (Somalogic, Boulder, CO) and fibulin-3 seemed highly accurate, but SOMAscan has not been validated prospectively and subsequent fibulin-3 data have been contradictory. METHODS: A multicenter prospective observational study was performed in 22 centers, generating a large intention-to-diagnose cohort. Blood sampling, processing, and diagnostic assessment were standardized, including a 1-year follow-up. Plasma fibulin-3 was measured using two enzyme-linked immunosorbent assays (CloudClone [used in previous studies] and BosterBio, Pleasanton, CA). Serum proteomics was measured using the SOMAscan assay. Diagnostic performance (sensitivity at 95% specificity, area under the curve [AUC]) was benchmarked against serum mesothelin (Mesomark, Fujirebio Diagnostics, Malvern, PA). Biomarkers were correlated against primary tumor volume, inflammatory markers, and asbestos exposure. RESULTS: A total of 638 patients with suspected pleural malignancy (SPM) and 110 asbestos-exposed controls (AECs) were recruited. SOMAscan reliably differentiated MPM from AECs (75% sensitivity, 88.2% specificity, validation cohort AUC 0.855) but was not useful in patients with differentiating non-MPM SPM. Fibulin-3 (by BosterBio after failed CloudClone validation) revealed 7.4% and 11.9% sensitivity at 95% specificity in MPM versus non-MPM SPM and AECs, respectively (associated AUCs 0.611 [0.557-0.664], p = 0.0015) and 0.516 [0.443-0.589], p = 0.671), both inferior to mesothelin. SOMAscan proteins correlated with inflammatory markers but not with asbestos exposure. Neither biomarker correlated with tumor volume. CONCLUSIONS: SOMAscan may prove useful as a future screening test for MPM in asbestos-exposed persons. Neither fibulin-3 nor SOMAscan should be used for diagnosis or pathway stratification.

Cerebrospinal Fluid Cytokines and Neurodegeneration-Associated Proteins in Parkinson's Disease.

INTRODUCTION: Immune markers are altered in Parkinson's disease (PD), but relationships between cerebrospinal fluid (CSF) and plasma cytokines and associations with neurodegeneration-associated proteins remain unclear. METHODS: CSF and plasma samples and demographic/clinical measures were obtained from 35 PD patients. CSF samples were analyzed for cytokines (together with plasma) and for α-synuclein, amyloid ß(1-42) peptide, total tau, and phospho(Thr231)-tau. RESULTS: There were no CSF-plasma cytokine correlations. Interleukin (IL)-8 was higher and interferon-γ, IL-10, and tumor necrosis factor-α were lower in CSF versus plasma. In CSF, total tau correlated positively with IL-8 and IL-1ß, whereas α-synuclein correlated positively with amyloid ß(1-42) and negatively with semantic fluency (a known marker of PD dementia risk). DISCUSSION: CSF and peripheral cytokine profiles in PD are not closely related. Associations between CSF IL-8 and IL-1ß and tau suggest that CSF inflammatory changes may relate to tau pathology within PD. CSF α-synuclein/amyloid ß may reflect the risk of developing PD dementia. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Rapid and sustained airway control in metastatic malignant melanoma: a case report.

Endobronchial metastasis from extrapulmonary malignancies are rare and include malignant melanoma. Cases that are complicated by central airway obstruction should follow a patient-centred approach, guided by patient and tumour characteristics. http://bit.ly/32baZvo.

Esophageal ultrasound (EUS) assessment of T4 status in NSCLC patients.

BACKGROUND: Mediastinal and central large vessels (T4) invasion by lung cancer is often difficult to assess preoperatively due to the limited accuracy of computed tomography (CT) scan of the chest. Esophageal ultrasound (EUS) can visualize the relationship of para-esophageally located lung tumors to surrounding mediastinal structures. AIM: To assess the value of EUS for detecting mediastinal invasion (T4) of centrally located lung tumors. METHODS: Patients who underwent EUS for the diagnosis and staging of lung cancer and in whom the primary tumor was detected by EUS and who subsequently underwent surgical- pathological staging (2000-2016) were retrospectively selected from two university hospitals in The Netherlands. T status of the lung tumor was reviewed based on EUS, CT and thoracotomy findings. Surgical- pathological staging was the reference standard. RESULTS: In 426 patients, a lung malignancy was detected by EUS of which 74 subjects subsequently underwent surgical- pathological staging. 19 patients (26%) were diagnosed with stage T4 based on vascular (n=8, 42%) or mediastinal (n=8, 42%) invasion or both (n=2, 11%), one patient (5%) had vertebral involvement. Sensitivity, specificity, PPV and NPV for assessing T4 status were: for EUS (n=74); 42%, 95%, 73%, 83%, for chest CT (n=66); 76%, 61%, 41%, 88% and the combination of EUS and chest CT (both positive or negative for T4, (n=34); 83%, 100%, 100% 97%. CONCLUSION: EUS has a high specificity and NPV for the T4 assessment of lung tumors located para-esophageally and offers further value to chest CT scan.

Role of electromagnetic navigational bronchoscopy in pulmonary nodule management.

The incidence of pulmonary nodules and lung cancer is rising. Some of this increase in incidence is due to improved pick up by newer imaging modalities. However, the goal is to diagnose these lesion, many of which are located in the periphery, by safe and relatively non-invasive methods. This has led to the emergence of numerous techniques such as electromagnetic navigational bronchoscopy (ENB). Current evidence supports a role for these techniques in the diagnostic pathway. However, numerous factor influence the diagnostic accuracy. Thus despite significant advances, more research needs to be undertaken to further improve the currently available diagnostic technologies.

Anti-collapsin response mediator protein 5 encephalitis masquerading as a low-grade brain tumour.

A 71-year-old woman presented acutely with seizures; her MRI suggested a low-grade glioma of the right temporal lobe. Over the preceding 18 months, she had developed progressive limb chorea and orofacial dyskinesia. Examination showed a predominantly amnestic cognitive profile. Initial investigations were normal, but later she was found to have antibodies to collapsin response mediator protein 5 (also called CV2). Her symptoms and neuroimaging abnormalities gradually improved without treatment. Four months later, surveillance imaging with (18)F-fluorodeoxyglucose-positron-emission tomography revealed a lesion confirmed by biopsy as a TX, N2, M0 small-cell lung cancer. This case is unusual for the strikingly unilateral neuroimaging abnormalities, which led to an initial misdiagnosis, and the spontaneous symptomatic improvement without treatment. In retrospect, the co-occurrence of paraneoplastic chorea, limbic encephalitis and neuropathy in the presence of an occult lung tumour make this almost a 'full house' of symptoms associated with antibodies to collapsin response mediator protein 5. It underlines the importance in clinical reasoning of avoiding the cognitive errors of premature closure and anchoring.

Hiatal hernias are correlated with increased severity of non-cystic fibrosis bronchiectasis.

BACKGROUND AND OBJECTIVE: Hiatal hernias (HH) are associated with gastro-oesophageal reflux and may contribute to lung disease severity. We aimed to evaluate the prevalence of HH among stable non-cystic fibrosis bronchiectasis (NCFB) patients and determine associations with disease severity. METHODS: A retrospective cross-sectional cohort study of 100 consecutive NCFB patients in our institution was performed. Data were collected on baseline variables, microbiology, lung function and radiology, according to the modified Bhalla score. Disease severity was assessed using the Bronchiectasis Severity Index (BSI) and FACED severity scores. RESULTS: Following expert radiological review, 81 patients were deemed suitable for study inclusion (mean age (SD) 62.6 (12.4), females 55 (67.9%), body mass index (BMI) 26.9 (5.7)); 29 (35.8%) were HH positive (HH+). HH+ patients had a trend towards higher BMI (P = 0.07), and a significantly higher proportion had reflux symptoms (HH+ 62.1% vs HH- 28.8%, P < 0.01). The presence of HH+ was associated with cystic bronchiectasis (HH+ 30.1%, HH- 11.5%; P = 0.03), increased number of lobes involved (HH+ 2.62 (1.54), HH- 2.17 (1.42); P = 0.03), increased extent of bronchiectasis, (HH+ 6.2 (4.7), HH- 4.5 (3.1); P = 0.04), decreased parenchymal attenuation (HH+ 1.0 (1.8), HH- 0.2 (0.5); P = 0.03) and reduced per cent predicted forced expiratory volume in 1 s (HH+ 75.4% (24.5), HH- 90.4% (25.5); P = 0.02). There was no lobar predilection. HH+ was associated with increased disease severity scores: BSI (HH+ 4.93 (1.65), HH- 3.25 (2.13); P < 0.001) and FACED (HH+ 2.21 (1.52), HH- 1.35 (1.43); P < 0.01). CONCLUSIONS: HH+ was associated with worse disease severity in NCFB patients, characterized by decreased lung function, increased extent and severity of radiological disease, and increased composite disease severity scores.

A nationwide analysis of successful litigation claims in neurological practice.

OBJECTIVES: Neurological practice has previously been highlighted as a high-risk speciality with regard to malpractice claims. We set out to study the nature of these claims in order to inform physicians about hazardous areas within their speciality and potentially alter clinical practice. DESIGN: Nationwide retrospective analysis of successful neurology and neurosurgery claims over a 17-year period. SETTING: We studied all successful claims occurring between 1995 and 2012 using the NHS Litigation Authority database, which collects data on claims made against clinicians practising in England and Wales. PARTICIPANTS: Four hundred and twenty-three successful claims were identified during the study period. MAIN OUTCOME MEASURES: The errors involved, the patient groups affected, the resulting mortality and the litigation payments. RESULTS: 63.1% of claims were due to negligence in neurosurgical care, whilst 36.9% were due to negligence in neurological care. Litigation payments were significantly higher in neurosurgery compared to neurology cases. Diagnostic error was the most common cause of litigation. The disease categories with the highest numbers of successful litigation claims were spinal pathology, cerebrovascular disease including subarachnoid haemorrhage, intracranial tumours, hydrocephalus and neuropathy/neuromuscular disease. CONCLUSIONS: This is the first study of successful litigation claims against the NHS for negligent neurological or neurosurgical care and provides data to help reduce risk and improve patient safety.

Role of interventional pulmonology in the management of complicated parapneumonic pleural effusions and empyema.

Pleural infection is a major problem that affects 80,000 cases per year in the UK and USA. It is increasing in incidence, and in an ageing population, it presents a complex challenge that requires a combination of medical therapies and may lead to the need for surgery. This article focuses on the role of the interventional pulmonologist in the diagnosis and management of pleural infection. In particular, we examine the role of pleural ultrasound in diagnostics, thoracocentesis and real-time guided procedures, and the current management strategies, including the controversial role of medical thoracoscopy.

Molecular testing and personalized treatment of lung cancer.

Lung malignancy is a leading cause of cancer related morbidity and mortality worldwide. The majority (85%) of cases are histologically proven non-small cell lung carcinomas (NSCLC). More than 55% of lung carcinomas harbor at least one genetic alteration, most of them being histologic subtype specific. This review summarizes the progress in personalized care of lung cancer by reviewing the literature on EGFR, ALK and KRAS molecular alterations, currently used in clinical practice, to direct the decision making process for lung cancer therapy. In addition, we will discuss some recently characterized molecular alterations whose targeting is being tested in clinical trials and holds promise for future therapeutic targeting. The role of minimally invasive procedures in lung cancer diagnosis and staging is also discussed as these techniques now play a central role in lung cancer management by providing the bulk of material for modern molecular diagnostics.

Rigid bronchoscopy.

Complex airway diseases represent a therapeutic challenge and require multidisciplinary input. Surgery remains the definitive modality. Minimally invasive endobronchial techniques have resulted in symptom control and long-term improvements. The rigid bronchoscope remains the method of choice for the treatment of both benign and malignant central airway obstruction. However, it has limited use if lesions are located in the upper lobes or lung periphery, but significant technological advances allow for effective treatments using the flexible bronchoscope. Rigid and flexible bronchoscopes should be seen as complementary procedures and most cases require the use of both modalities.

On-site customization of silicone stents: towards optimal palliation of complex airway conditions.

BACKGROUND: Stents may be indicated as treatment of benign and malignant conditions of the central airways. Occasionally, aberrant and/or distorted airways secondary to therapy or surgery may preclude the use of commercially manufactured stents. The customization of stents is well described for nonpulmonary diseases, but to date there are only limited data in the literature on prosthesis customization for airway disease. OBJECTIVES: To review all the different techniques and indications of on-site silicone stent customizations and their related complications. METHODS: A retrospective study was undertaken to identify all patients who underwent treatment with a silicone stent which was customized on site by the physician. The study included subjects treated during an 8-year period. RESULTS: Forty-nine on-site customizations were performed in 43 patients (34 males, mean age 63 +/- 5.2 years). Stent customization was performed in 5.4% of the cases. Stent customization was performed for malignant and benign disease in 35 (81.3%) and 8 (18.7%) cases, respectively. In all cases, the stent deployed successfully and performed well while in situ. Stent manipulation did not increase complications. CONCLUSIONS: Customization of airway stents by the physician can lead to successful stenting of difficult airway lesions with a good short-term safety profile. Standard commercially available stents may have resulted in suboptimal management of complex airway pathologies. A prospective study is warranted to further investigate the safety profile and complications associated with stent customization.

Tracheal compression in a patient with Marfan's syndrome-associated tracheomegaly treated by an XXL stent: the largest diameter airway stent ever placed in a previously undescribed airway condition.

A 43-year-old man was referred to our institution with severe extrinsic compression of the trachea at the level of the main carina secondary to an aortic aneurysm, causing respiratory distress and requiring mechanical ventilation. The patient had a past history of Marfan's syndrome and tracheomegaly (the estimated tracheal diameter bronchoscopically was 28 mm). Palliation of the compression was successfully achieved by a custom-made, self-expandable, fully covered metallic stent with a diameter of 28 mm and a length of 60 mm. The patient was weaned off ventilation. The stent stayed in place for 2 years without major complications. This case represents the first stent ever inserted in a very rare condition combining tracheomegaly and extrinsic compression in Marfan's syndrome. It is also the first report of successful placement of the largest tracheal stent which was manufactured exclusively for the airway.

Airway stenting for severe endobronchial papillomatosis.

Severe endobronchial papillomatosis is associated with recurrent respiratory infections and airway obstruction. Current management includes treatment with antiviral and cytotoxic agents to slow papilloma growth and endobronchial therapies to excise the lesions. We report 2 cases of severe tracheobronchial papillomatosis which were managed with endobronchial laser and airway stenting. A 32-year-old man and a 55-year-old woman with known history of tracheobronchial papillomatosis were admitted with hemoptysis and dyspnea, respectively. They presented increasing frequencies of respiratory infections in the preceding year despite therapy with interferon alpha-2A, acyclovir, methotrexate and endobronchial treatment. Moreover, the 2nd patient presented 6 months previously to another institution with central airway obstruction which was treated with a covered metallic stent. Both patients underwent rigid bronchoscopy which revealed airway obstruction by papillomatous lesions. In the 2nd case, the metallic stent was broken due to fatigue and was infiltrated by a giant papilloma. Both patients received laser treatment and airway silicone stenting. After stenting, respiratory infection rate was greatly reduced and no further complications related to the papillomas occurred. This paper highlights the serious complications which may arise if endobronchial management of the disease includes insertion of metallic stents. In contrast, airway stenting with a silicone prosthesis may be useful in refractory endobronchial papillomatosis and may offer permanent control of symptoms.

A rare cause of an endobronchial tumour in children: the role of interventional bronchoscopy in the diagnosis and treatment of tumours while preserving anatomy and lung function.

An 11-year-old girl was referred to our institution with complete obstruction of the left main stem bronchus by an endoluminal mass and was successfully treated by a combination of laser and mechanical debulking. Coring of the mass both allowed histological diagnosis (inflammatory myofibroblastic tumour) and definitive treatment with no recurrence after 3 years of follow-up. This case report emphasizes the major role of interventional bronchoscopy in the management of tumoural obstruction in children in whom benign conditions are frequent. Interventional bronchoscopy, which is minimally invasive when compared to surgery, in the vast majority of cases allows a precise diagnosis as it provides large samples of tissue removed during coring; in some cases it can be curative by itself and preserves lung parenchyma and function.

Pharmacogenetic association with adverse drug reactions to azathioprine immunosuppressive therapy following liver transplantation.

Azathioprine (AZA) is a thiopurine prodrug commonly used in triple-immunosuppressive therapy following liver transplantation. Approximately 1 in 10 patients suffers side effects in response to the drug, the most problematic being bone marrow toxicity. There is evidence that polymorphisms in the genes encoding thiopurine methyltransferase (TPMT) and inosine triphosphate pyrophosphatase (ITPase) predict adverse drug reactions to AZA therapy. Furthermore, common genetic polymorphisms in the gene encoding methylenetetrahydrofolate reductase (MTHFR) may have an indirect impact on thiopurine drug methylation by influencing levels of the methyl donor S-adenosylmethionine (SAM). The aim of this study was to determine whether polymorphisms in these candidate pharmacogenetic loci predict adverse drug reactions to AZA immunosuppressive therapy in liver transplant patients. A series of 65 liver transplant recipients were recruited to the study from the Liver Transplant Out-Patient clinic at The Royal Infirmary of Edinburgh. Clinical response to AZA was retrospectively correlated against TPMT activity, TPMT*2, *3A, and *3A genotypes, inosine triphosphatase (ITPA) 94C>A and IVS2+21A>C genotypes, and MTHFR 677C>T and 1298A>C genotypes. Variant TPMT, ITPA, and MTHFR genotypes were not significantly associated with adverse drug reactions to AZA, including bone marrow suppression. However, the 2 patients who suffered nodular regenerative hyperplasia (NRH) were both heterozygous for the TPMT*3A mutation. In conclusion, our findings suggest that TPMT, ITPA, and MTHFR genotypes do not predict adverse drug reactions, including bone marrow suppression, in liver transplant patients. However, the possible association between NRH and a heterozygous TPMT genotype should be investigated further.