The role of imaging in malignant pleural mesothelioma: an update after the 2018 BTS guidelines.

Malignant pleural mesothelioma (MPM) is a primary malignancy of the pleura and is associated with a poor outcome. The symptoms and signs of malignant mesothelioma present late in the natural history of the disease and are non-specific, making the diagnosis challenging and imaging key. In 2018, the British Thoracic Society (BTS) updated the guideline on diagnosis, staging, and follow-up of patients with MPM. These recommendations are discussed in this review of the current literature on imaging of MPM. It is estimated MPM will continue to cause serious morbidity and mortality in the UK late into the 21st century, and internationally, people continue to be exposed to asbestos. We aim to update the reader on current and future imaging strategies, which could aid early diagnosis of pleural malignancy and provide an update on staging and assessment of tumour response.

Non-invasive methods for estimating mPAP in COPD using cardiovascular magnetic resonance imaging.

PURPOSE: Pulmonary hypertension (PH) is associated with a poor outcome in chronic obstructive pulmonary disease (COPD) and is diagnosed invasively. We aimed to assess the diagnostic accuracy and prognostic value of non-invasive cardiovascular magnetic resonance (CMR) models. METHODS: Patients with COPD and suspected PH, who underwent CMR and right heart catheter (RHC) were identified. Three candidate models were assessed: 1, CMR-RV model, based on right ventricular (RV) mass and interventricular septal angle; 2, CMR PA/RV includes RV mass, septal angle and pulmonary artery (PA) measurements; 3, the Alpha index, based on RV ejection fraction and PA size. RESULTS: Of 102 COPD patients, 87 had PH. The CMR-PA/RV model had the strongest diagnostic accuracy (sensitivity 92%, specificity 80%, positive predictive value 96% and negative predictive value 63%, AUC 0.93, p<0.0001). Splitting RHC-mPAP, CMR-RV and CMR-PA/RV models by 35mmHg gave a significant difference in survival, with log-rank chi-squared 5.03, 5.47 and 7.10. RV mass and PA relative area change were the independent predictors of mortality at multivariate Cox regression (p=0.002 and 0.030). CONCLUSION: CMR provides diagnostic and prognostic information in PH-COPD. The CMR-PA/RV model is useful for diagnosis, the RV mass index and PA relative area change are useful to assess prognosis. KEY POINTS: • Pulmonary hypertension is a marker of poor outcome in COPD. • MRI can predict invasively measured mean pulmonary artery pressure. • Cardiac MRI allows for estimation of survival in COPD. • Cardiac MRI may be useful for follow up or future trials. • MRI is potentially useful to assess pulmonary hypertension in patients with COPD.

CT features of pulmonary arterial hypertension and its major subtypes: a systematic CT evaluation of 292 patients from the ASPIRE Registry.

We evaluated the prevalence and prognostic value of CT-pulmonary angiographic (CTPA) measures in 292 treatment naive patients with pulmonary arterial hypertension (PAH). Pulmonary artery calcification (13%) and thrombus (10%) were exclusively seen in PAH-congenital heart disease. Oesophageal dilation (46%) was most frequent in PAH-systemic sclerosis. Ground glass opacification (GGO) (41%), pericardial effusion (38%), lymphadenopathy (19%) and pleural effusion (11%) were common. On multivariate analysis, inferior vena caval area, the presence of pleural effusion and septal lines predicted outcome. In PAH, CTPA provides diagnostic and prognostic information. In addition, the presence of GGO on a CT performed for unexplained breathlessness should alert the physician to the possibility of PAH.

MRI model-based non-invasive differential diagnosis in pulmonary hypertension.

Pulmonary hypertension(PH) is a disorder characterised by increased mean pulmonary arterial pressure. Currently, the diagnosis of PH relies upon measurements taken during invasive right heart catheterisation (RHC). This paper describes a process to derive diagnostic parameters using only non-invasive methods based upon MRI imaging alone. Simultaneous measurements of main pulmonary artery (MPA) anatomy and flow are interpreted by 0D and 1D mathematical models, in order to infer the physiological status of the pulmonary circulation. Results are reported for 35 subjects, 27 of whom were patients clinically investigated for PH and eight of whom were healthy volunteers. The patients were divided into 3 sub-groups according to the severity of the disease state, one of which represented a negative diagnosis (NoPH), depending on the results of the clinical investigation, which included RHC and complementary MR imaging. Diagnostic indices are derived from two independent mathematical models, one based on the 1D wave equation and one based on an RCR Windkessel model. Using the first model it is shown that there is an increase in the ratio of the power in the reflected wave to that in the incident wave (Wpb/Wptotal) according to the classification of the disease state. Similarly, the second model shows an increase in the distal resistance with the disease status. The results of this pilot study demonstrate that there are statistically significant differences in the parameters derived from the proposed models depending on disease status, and thus suggest the potential for development of a non-invasive, image-based diagnostic test for pulmonary hypertension.

Single centre prospective study of the efficacy of percutaneous cement augmentation in the treatment of vertebral compression fractures.

INTRODUCTION: Despite controversial outcomes of recent published trials, percutaneous cement augmentation remains widely used in managing painful vertebral compression fractures. We prospectively assessed patients with such fractures using an eleven-point visual analogue scale for pain and the Qualeffo 41 questionnaire for quality of life. METHODS: Consecutive patients undergoing percutaneous cement augmentation for painful vertebral compression fractures were recruited. Patients were assessed pre-procedure by completing a visual analogue scale for pain, on a scale of 0 to 10. A Qualeffo 41 questionnaire was also completed. Patients were followed up at 1 week and 3 months. RESULTS: Fifty six patients were prospectively recruited (111 vertebroplasty and 5 kyphoplasty). Visual analogue scores dropped from 6.4 ± 2.3 pre-procedure to 4.0 ± 2.7 at 1 week (p < 0.0001) and 4.3 ± 2.7 (p < 0.0001) at 3 months. Three subgroups were identified; osteoporotic patients (n = 28), a second non-osteoporotic group (n = 20) who had acute fracture following fall and a third group with compression fractures secondary to metastatic disease (n = 8). At 3-month follow-up, patients with osteoporotic fractures had reduction in pain score from 6.3 ± 2.1 to 4.8 ± 2.7 (p = 0.02). Patients who had traumatic fractures experienced more significant pain relief, 6.4 ± 2.6 to 3.8 ± 2.7 (p = 0.0009) but patients with malignant fracture had most benefit, 6.0 ± 3.0 to 1.8 ± 0.8 (p = 0.01). Total Qualeffo scores improved from 63 ± 15 to 49 ± 22 (p < 0.0001). Within the domains of the Qualeffo questionnaire, most improvement was seen in pain and physical function. Median in-patient stay post procedure was one day. CONCLUSION: In our experience percutaneous cement augmentation is safe and efficacious in the management of painful VCF related to osteoporosis, trauma and cancer, achieving rapid and significant pain reduction and improvement in physical function as measured with a visual analogue scale and the Qualeffo 41 questionnaire.

A role for coding functional variants in HNF4A in type 2 diabetes susceptibility.

AIMS/HYPOTHESIS: Rare mutations in the gene HNF4A, encoding the transcription factor hepatocyte nuclear factor 4α (HNF-4A), account for ~5% of cases of MODY and more frequent variants in this gene may be involved in multifactorial forms of diabetes. Two low-frequency, non-synonymous variants in HNF4A (V255M, minor allele frequency [MAF] ~0.1%; T130I, MAF ~3.0%)-known to influence downstream HNF-4A target gene expression-are of interest, but previous type 2 diabetes association reports were inconclusive. We aimed to evaluate the contribution of these variants to type 2 diabetes susceptibility through large-scale association analysis. METHODS: We genotyped both variants in at least 5,745 cases and 14,756 population controls from the UK and Denmark. We also undertook an expanded association analysis that included previously reported and novel genotype data obtained in Danish, Finnish, Canadian and Swedish samples. A meta-analysis incorporating all published association studies of the T130I variant was subsequently carried out in a maximum sample size of 14,279 cases and 26,835 controls. RESULTS: We found no association between V255M and type 2 diabetes in either the initial (p = 0.28) or the expanded analysis (p = 0.44). However, T130I demonstrated a modest association with type 2 diabetes in the UK and Danish samples (additive per allele OR 1.17 [95% CI 1.08-1.28]; p = 1.5 × 10⁻4), which was strengthened in the meta-analysis (OR 1.20 [95% CI 1.10-1.30]; p = 2.1 × 10⁻5). CONCLUSIONS/INTERPRETATION: Our data are consistent with T130I as a low-frequency variant influencing type 2 diabetes risk, but are not conclusive when judged against stringent standards for genome-wide significance. This study exemplifies the difficulties encountered in association testing of low-frequency variants.

Safety and immunogenicity of heptavalent pneumococcal vaccine conjugated to CRM(197) among infants with sickle cell disease. Pneumococcal Conjugate Vaccine Study Group.

OBJECTIVES: To determine the immunogenicity and safety of heptavalent pneumococcal polysaccharide vaccine (serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F) conjugated to CRM(197) (7-valent conjugate pneumococcal vaccine [7VPnC]) among infants with sickle cell disease (SCD) and a comparison group of infants without SCD (non-SCD). DESIGN: Two cohorts of infants were enrolled and received open-label doses of 7VPnC vaccine; infants enrolled before 2 months of age received 7VPnC vaccine at 2, 4, and 6 months of age followed by 23-valent pneumococcal polysaccharide vaccine (PS-23) at 24 months of age for those infants with SCD (schedule A), and infants enrolled between 2 and 12 months of age received 7VPnC at 12 months of age followed by PS-23 at 24 months of age for infants with SCD (schedule B). Safety data were collected for 3 days after each dose of vaccine. Antibody concentrations were measured to each of the 7VPnC serotypes by enzyme-linked immunosorbent assay before each vaccine dose and 1 month after the last 7VPnC dose and the PS-23 vaccine dose. RESULTS: Forty-five infants (34 SCD and 11 non-SCD) were vaccinated according to schedule A and 16 infants (13 SCD and 3 non-SCD) according to schedule B. The 7VPnC vaccine was highly immunogenic for all serotypes among infants with and without SCD who received 3 doses of vaccine according to schedule A: depending on serotype, 89% to 100% achieved antibody concentrations above.15 microg/mL and 56% to 100% achieved antibody concentrations above 1.0 microg/mL. Among infants immunized according to schedule B, a single dose of 7VPnC vaccine resulted in antibody concentrations above.15 microg/mL in 53% to 92% by serotype and above 1.0 microg/mL in 31% to 71% by serotype. A single dose of PS-23 resulted in dramatic increases in the antibody concentrations to all serotypes regardless of 1- or 3-dose priming. There was no difference in the reactogenicity of the 7VPnC vaccine between those with and without SCD. There were no serious reactions to the 7VPnC or PS-23 vaccines, even among those with high antibody concentrations before immunization. CONCLUSIONS: Infants with SCD respond to 7VPnC vaccine with antibody concentrations that are at least as high as infants without SCD. Infants immunized with 7VPnC vaccine at 2, 4, and 6 months of age developed antibody concentrations in the same range as those achieved among infants without SCD enrolled in a large trial that demonstrated vaccine efficacy against invasive disease. Significant rises were seen in antibody concentrations to all 7VPnC serotypes after the PS-23 booster in children receiving schedule A or B.

Serum opsonic activity in infants with sickle-cell disease immunized with pneumococcal polysaccharide protein conjugate vaccine. The Pneumococcal Conjugate Vaccine Study Group.

Pneumococcal infections are an important cause of morbidity and mortality in children with sickle-cell disease (SCD). Pneumococcal conjugate vaccines (PCVs) are immunogenic in healthy infants <2 years of age but have not been evaluated in young children with SCD. Infants with SCD were immunized with a 7-valent PCV (Wyeth-Lederle Vaccines & Pediatrics) at 2, 4, and 6 months of age. A booster dose of 23-valent pneumococcal polysaccharide vaccine (PPV; Pnu-Immune) was administered at 24 months of age. Antipneumococcal type 6B and 14 serum opsonic activity was measured to assess the biologic function of the antibody. Following the administration of three doses of PCV, opsonic activity against serotype 6B increased from 4. 8% at 2 months to 33.5% at 7 months, with a subsequent decline to 8.1% at 12 months and 7.5% at 24 months and with an increase to 30.7% at 25 months after administration of a booster dose of PPV. Similar trends were seen with serotype 14 (opsonic activities were 9.4% at 2 months, 24.9% at 7 months, 16.5% at 12 months, and 12.6% at 24 months, and the opsonic activity was 27.3% 1 month after the administration of PPV). Serum opsonic activity correlated with antibody levels for both serotypes. PCV induces serum opsonic activity in infants with SCD. Antipneumococcal serum opsonic activity correlates with antibody levels.

Surface analysis of biomedical devices.

Modern surface analysis methods are highly effective tools in the development and manufacture of biomedical devices. Improvements in the performance of surface analysis techniques and sample handling are shown to have extended their value throughout device development. The application of these techniques and key improvements in their capabilities are discussed in the light of possible future regulatory requirements, which could include auditing of the surface chemistry of devices during manufacture, packaging, and storage.

Soluble human complement receptor type 1 inhibits complement-mediated host defense.

Soluble complement receptor type 1 (sCR1) is a powerful inhibitor of complement activation. Because of this ability, sCR1 may prove to be an important therapeutic agent that can be used to block the immunopathologic effects of uncontrolled complement activation in a variety of clinically significant disorders. Although several previous studies have examined the ability of sCR1 to inhibit complemented-mediated immunopathologic damage, there is no information on its ability to interfere with the host's defense against infection. In the current experiments sCR1 exerted a concentration-dependent inhibitory effect on the phagocytosis of Streptococcus pneumoniae by human polymorphonuclear leukocytes in vitro. Not only di sCR1 inhibit complement-dependent opsonization of the pneumococcus but at higher concentrations it also inhibited the ingestion of bacteria which had been previously opsonized. Furthermore, when rats were injected with sCR1, it inhibited both their serum hemolytic activity and serum opsonic activity in a dose-dependent fashion. Finally, for rats treated with sCR1, the 50% lethal dose was S. pneumoniae and Pseudomonas aeruginosa. These data demonstrate that sCR1 significantly inhibits complement-mediated host against bacterial infection.

The binding of Pneumococcal lipoteichoic acid to human erythrocytes.

Previous studies have evaluated the binding characteristics of lipoteichoic acids (LTA) composed of polyglycerol phosphate to mammalian cell membranes. This present study was performed to evaluate the binding characteristics of Pneumococcal LTA, a polyribitol phosphate containing LTA, to human erythrocytes. Binding was found to be specific, reversible, and dependent on temperature and time. Maximum binding was achieved within 2 h at 37 degrees C. Scatchard plot analysis of the binding revealed a biphasic plot which suggests two receptor sites with different affinities. Competitive inhibition studies with LTA composed of polyglycerol phosphate and isolated from Streptococcus pyogenes and Lactobacillus fermentum revealed significant inhibition of Pneumococcal LTA-binding to the erythrocyte membrane by these heterologous LTAs. These results demonstrate that Pneumococcal LTA binds specifically to human erythrocytes and that the receptor site is similar for other structurally different LTAs.

Membranoproliferative glomerulonephritis in dogs with a genetically determined deficiency of the third component of complement.

Renal disease is a common clinical manifestation of genetically determined deficiencies of the complement system in man. Like their human counterparts, dogs with a genetically determined complete deficiency of C3 also develop renal disease. Five of 20 C3-deficient dogs developed clinical evidence of renal failure. However, 14 of the 15 remaining dogs had histological evidence of type I membranoproliferative glomerulonephritis. The lesions were characterized by mesangial cell proliferation, an increase in the mesangial matrix, thickening of the glomerular capillary wall, electron-dense deposits in the mesangium and subendothelial space, and the presence of IgG and IgM. In order to determine the effect of treatment with C3 on the renal disease of C3-deficient dogs, two C3-deficient dogs were infused with normal canine plasma twice weekly for 3 weeks. Their urinary protein excretion rose progressively from less than 200 mg/24 hr to greater than 1000 mg/24 hr; renal function remained normal. Renal biopsies performed 1 week after the last infusion revealed more severe glomerulonephritis and the presence of C3. As controls, a C3-deficient dog was given C3-deficient canine plasma and a normal dog was given normal canine plasma; neither control animal developed proteinuria or changes in their renal biopsy. These observations suggest that renal disease may be more common in humans with complement deficiencies than would be suspected based on clinical assessment. Furthermore, these results suggest that treatment with complement-containing blood products may worsen preexisting renal disease in complement-deficient individuals.

Complement-mediated serum activities against genetically defined capsular transformants of Haemophilus influenzae.

Although there are six different capsular serotypes of Haemophilus influenzae (a-f), only type b strains commonly cause systemic infections in man. The present study was performed to determine whether the propensity of the type b organism to cause invasive infections is due to a unique ability to evade complement-mediated host defenses. The ability of genetically defined capsular transformants (a-f) of an unencapsulated H. influenzae to resist the bactericidal and opsonic activities of serum was examined. The unencapsulated organism and the type f transformants were relatively susceptible to serum bactericidal activity in both adult and infant serum pools, the type a and e transformants were relatively resistant, and the types b, c and d transformants were intermediate. With respect to serum opsonic activity in both adult and infant serum pools, the unencapsulated organism and the type f transformant were relatively susceptible, the type a, b and e transformants were relatively resistant and the type c and d transformants were intermediate. Thus, although the type b capsule endows the organism with the ability to resist the bactericidal and opsonic effects of complement, this property is not unique to type b.

The ability to sensitize host cells for destruction by autologous complement is a general property of lipoteichoic acid.

Previous studies have demonstrated that lipoteichoic acid (LTA) from Streptococcus pneumoniae binds to erythrocytes and renders them susceptible to lysis by autologous complement. The present study was performed to determine whether LTA from two other gram-positive bacterial species had the ability to render mammalian cells susceptible to lysis by autologous complement. Human erythrocytes were sensitized with LTA from S. pneumoniae, Streptococcus pyogenes, or Lactobacillus fermentum. Under incubation in normal autologous serum, lysis was observed with each of the LTA-sensitized erythrocyte preparations. When erythrocytes from a C2-deficient patient were sensitized with the LTA preparations and then incubated in autologous, C2-deficient serum, the erythrocytes sensitized with S. pyogenes or L. fermentum LTA demonstrated relatively little lysis, whereas the erythrocytes sensitized with S. pneumoniae LTA yielded near-total lysis. After reconstitution of the C2-deficient serum with purified human C2, lysis was observed with all three LTA preparations. When erythrocytes from an agammaglobulinemic patient were sensitized with either the S. pyogenes or the L. fermentum LTA, they were not lysed in the presence of autologous agammaglobulinemic serum, whereas the erythrocytes sensitized with S. pneumoniae LTA were completely lysed. Serum obtained from the agammaglobulinemic patient after reconstitution with intravenous pooled gamma globulin was able to lyse autologous erythrocytes sensitized with each of the three LTA preparations. These results demonstrate that the ability to render host cells susceptible to lysis by autologous complement is a general property of LTA. Whether activation of the autologous complement occurs by the classical or alternative pathways and whether it is antibody dependent depends on the nature of the bacterial LTA.

Activation of the alternative complement pathway by pneumococcal lipoteichoic acid.

Cell wall teichoic acids of some gram-positive bacteria are potent activators of the alternative pathway of complement. It is unclear, however, whether the other form of teichoic acid, cell membrane lipoteichoic acid (LTA), can also activate the alternative pathway. In the present study, radiolabelled pneumococcal LTA was found to bind spontaneously to sheep erythrocytes in a temperature- and time-dependent fashion. In addition, the presence of pneumococcal LTA on the erythrocyte surface was verified by the fact that they could be agglutinated by a myeloma protein (TEPC-15) specific for choline, a constituent of pneumococcal LTA. Pneumococcal LTA when fixed to the surface of erythrocytes was able to activate the alternative pathway of complement in both guinea pig serum deficient in the fourth component of complement and human serum deficient in the second component of complement, resulting in lysis of the sensitized erythrocytes. The sensitizing principle of the LTA preparation was removed before erythrocyte sensitization by immunoabsorption, using the choline-specific TEPC-15 myeloma protein. These data demonstrate that purified pneumococcal LTA will bind to sheep erythrocytes and endow them with the ability to activate the alternative pathway.

Defective activation of the third component of complement in the sera of newborn infants.

The activation of the terminal complement components, C3--9, plays an important role in the host's defense against infection. In the present study, the ability of bacteria to activate the third component of complement (C3) in newborn serum was examined. A variety of bacteria were incubated in test sera at 37 degrees C for 30 min and the percent of available C3 that was activated was measured. Using one strain of Escherchia coli (no. 3), 32% (mean) of the available C3 was activated in sera from 18 newborns, as compared to 85% in sera from their mothers and 79% in sera from 13 normal adults (P less than 0.005). In contrast, using another strain of E. coli (N70), the percent of C3 activated in newborn sera (83%) was the same as in sera from their mothers (81%) or in sera from normal adults (73%). The defective activation of C3 in newborn sera by E. coli was not related to the presence of the K1 antigen. Newborn sera were also challenged with other bacterial species and the activation of C3 was deficient when tested with klebsiellae, but not with staphylococci or streptococci. The defect in newborn sera appeared to be due to a deficiency of a serum factor rather than to the presence of an inhibitor.