Lung cancer screening and the impact of lung parenchyma on pulmonary nodule volumetry

Lung Cancer Screening (LCS) reduces lung cancer mortality, allowing for the early identification of pulmonary nodules using low-dose computed tomography (LDCT). Appropriate measurement and management of pulmonary nodules are essential in LCS programs. Guidelines recommend nodule volumetry analysis as the preferred method for nodule size measurement. However, artificial intelligence (AI) tools for volumetric analysis still present limiting factors, some of the most common being the nodule's location, size, shape and density. The study investigated whether changes in the attenuation of the lung parenchyma adjacent to a nodule affect the performance of nodule segmentation using computed tomography (CT) studies and volumetric tools. Two radiologists retrospectively applied two commercially available volumetric tools to assess lung nodules with diameters of 5– 8 mm detected by low-dose chest CT during a lung cancer screening program. The radiologists recorded the following parameters: • segmentation success and adequacy; • volume, longest and shortest diameters of the nodule; • mean attenuation value of the adjacent lung parenchyma; • presence of interstitial changes, emphysema, pleural plaques, or atelectasis. Predictors of appropriate volumetric segmentation of the nodule were assessed by regression analysis. Intraclass correlation coefficient assessed the interobserver agreement, and software-dependent appropriateness of nodule segmentation. In total, data on 1265 nodules (mean patient age, 68.3 ± 5.1 years; 70.2% male) were included in the study. The regression model revealed that the attenuation of the adjacent lung parenchyma effect in the size of the nodules was highly significant (odds ratio 0.987, p < 0.001). Interobserver and inter software agreement on appropriate segmentation were good. It was also observed that a software package performed better and that the measurements differed consistently between software packages. The conclusion from the main study showed that the likelihood of good segmentation of lung nodules with diameters of 5–8 mm declines with increasing attenuation of the adjacent parenchyma. These results support the hypothesis that lung nodule volume may not be assessed without critical analysis of the adjacent parenchyma. Numerous incidental findings were detected during the review of the cases for this study. Lack of uniformity in the approach to the incidental findings observed during the study justified the need for a separate publication proposing a more uniform approach to incidental findings on LCS studies, providing recommendations for the reporting and management, including the description and analysis of changes that increase the attenuation of the lung parenchyma. In my studies during this research, I observed that lung cancer with cystic characteristics could be misdiagnosed or overlooked and that they are not well detected or segmented by the current AI systems. I, therefore, felt appropriate to prepare an additional publication to alert the medical community regarding types of lung cancer associated with cystic airspaces. In summary, the central hypothesis that the volumetry of nodules detected on LCS can be affected by the attenuation values of the lung parenchyma surrounding the nodule was confirmed. These results have been published to alert that critical analysis of the parenchyma surrounding the nodule is needed before blindly accepting the numeric values from nodule volumetry to define stability or growth. Observation of inconsistencies in the approach to incidental findings and cystic lung cancer types led to the decision to publish the two additional papers related to this research.O rastreio do cancro do pulmão (RCP) reduz a mortalidade do cancro do pulmão, permitindo a identificação precoce de nódulos pulmonares usando tomografia computorizada de baixa dose (TC-BD). A medição e orientação adequadas dos nódulos pulmonares são essenciais nos programas de RCP. As diretrizes recomendam a análise da volumetria dos nódulos como o método preferido para a medição do tamanho dos nódulos. Contudo, as ferramentas de inteligência artificial (IA) para análise volumétrica ainda apresentam fatores limitantes, sendo alguns dos mais comuns a localização, tamanho, forma e densidade do nódulo. O estudo investigou se as alterações na atenuação do parênquima pulmonar adjacente a um nódulo afetam o desempenho da segmentação dos nódulos pulmonares identificados em exames de tomografia computorizada (TC) e ferramentas volumétricas. Dois radiologistas aplicaram retrospetivamente duas ferramentas volumétricas disponíveis comercialmente para avaliar nódulos pulmonares com diâmetros entre 5 e 8 mm detetados por TC-BD de baixa dose durante um programa de rastreio do cancro do pulmão. Os radiologistas registaram os seguintes parâmetros: • sucesso e adequação da segmentação; • volume, diâmetros mais longos e mais curtos do nódulo; • valor médio da atenuação do parênquima pulmonar adjacente; • presença de alterações intersticiais, enfisema, placas pleurais, ou atelectasia. Os preditores da segmentação volumétrica adequada do nódulo foram avaliados por análise de regressão. O coeficiente de correlação intra-classe avaliou a concordância inter-observador, e a qualidade da segmentação do nódulo, a qual depende do software. No total, foram incluídos no estudo dados sobre 1265 nódulos (idade média do doente, 68,3 ± 5,1 anos; 70,2% do sexo masculino). O modelo de regressão revelou que a atenuação do efeito parênquima pulmonar adjacente no tamanho dos nódulos era altamente significativa (‘odds ratio’ (OR) 0,987, p < 0,001). O acordo inter-observador e inter-software sobre a segmentação adequada foram bons. Observou-se também que um pacote de software tinha um melhor desempenho e que as medidas diferiam consistentemente entre pacotes de software. A conclusão do estudo principal mostrou que a probabilidade de uma boa segmentação dos nódulos pulmonares com diâmetros de 5-8 mm diminui com a atenuação crescente do parênquima adjacente. Estes resultados apoiam a hipótese de que o volume dos nódulos pulmonares não pode ser avaliado sem uma análise crítica do parênquima adjacente. Numerosos achados incidentais foram detetados durante a revisão dos casos para este estudo. A falta de uniformidade na abordagem dos achados incidentais observados durante o estudo justificou a necessidade de uma publicação separada propondo uma abordagem mais uniforme dos achados incidentais nos estudos de RCP, fornecendo recomendações para a elaboração de relatórios e orientação, incluindo a descrição e análise de alterações que aumentam a atenuação do parênquima pulmonar. Nos meus estudos durante esta investigação, observei que o cancro do pulmão com características císticas poderia ser mal diagnosticado ou ignorado e que não são sempre detetados nem bem segmentados pelos atuais sistemas de IA. Por conseguinte, considerei apropriado preparar uma publicação adicional para alertar a comunidade médica relativamente aos tipos de cancro do pulmão associados aos espaços aéreos císticos. Em resumo, foi confirmada a hipótese central de que a volumetria dos nódulos detetados no RCP pode ser afetada pelos valores de atenuação do parênquima pulmonar que rodeia o nódulo. Estes resultados foram publicados para alertar que é necessária uma análise crítica do parênquima que rodeia o nódulo antes de aceitar cegamente os valores numéricos da volumetria dos nódulos para definir a estabilidade ou crescimento. A observação de inconsistências na abordagem aos resultados acidentais e aos tipos de cancro do pulmão cístico levou à decisão de publicar os dois artigos adicionais relacionados com esta investigação

Post-intervention Status in Patients With Refractory Myasthenia Gravis Treated With Eculizumab During REGAIN and Its Open-Label Extension

OBJECTIVE: To evaluate whether eculizumab helps patients with anti-acetylcholine receptor-positive (AChR+) refractory generalized myasthenia gravis (gMG) achieve the Myasthenia Gravis Foundation of America (MGFA) post-intervention status of minimal manifestations (MM), we assessed patients' status throughout REGAIN (Safety and Efficacy of Eculizumab in AChR+ Refractory Generalized Myasthenia Gravis) and its open-label extension. METHODS: Patients who completed the REGAIN randomized controlled trial and continued into the open-label extension were included in this tertiary endpoint analysis. Patients were assessed for the MGFA post-intervention status of improved, unchanged, worse, MM, and pharmacologic remission at defined time points during REGAIN and through week 130 of the open-label study. RESULTS: A total of 117 patients completed REGAIN and continued into the open-label study (eculizumab/eculizumab: 56; placebo/eculizumab: 61). At week 26 of REGAIN, more eculizumab-treated patients than placebo-treated patients achieved a status of improved (60.7% vs 41.7%) or MM (25.0% vs 13.3%; common OR: 2.3; 95% CI: 1.1-4.5). After 130 weeks of eculizumab treatment, 88.0% of patients achieved improved status and 57.3% of patients achieved MM status. The safety profile of eculizumab was consistent with its known profile and no new safety signals were detected. CONCLUSION: Eculizumab led to rapid and sustained achievement of MM in patients with AChR+ refractory gMG. These findings support the use of eculizumab in this previously difficult-to-treat patient population. CLINICALTRIALSGOV IDENTIFIER: REGAIN, NCT01997229; REGAIN open-label extension, NCT02301624. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that, after 26 weeks of eculizumab treatment, 25.0% of adults with AChR+ refractory gMG achieved MM, compared with 13.3% who received placebo

Minimal Symptom Expression' in Patients With Acetylcholine Receptor Antibody-Positive Refractory Generalized Myasthenia Gravis Treated With Eculizumab

The efficacy and tolerability of eculizumab were assessed in REGAIN, a 26-week, phase 3, randomized, double-blind, placebo-controlled study in anti-acetylcholine receptor antibody-positive (AChR+) refractory generalized myasthenia gravis (gMG), and its open-label extension

Computed tomography on lung cancer screening is useful for adjuvant comorbidity diagnosis in developing countries

Purpose The aim of this study was to analyse and quantify the prevalence of six comorbidities from lung cancer screening (LCS) on computed tomography (CT) scans of patients from developing countries. Methods For this retrospective study, low-dose CT scans (n=775) were examined from patients who underwent LCS in a tertiary hospital between 2016 and 2020. An age- and sex-matched control group was obtained for comparison (n=370). Using the software, coronary artery calcification (CAC), the skeletal muscle area, interstitial lung abnormalities, emphysema, osteoporosis and hepatic steatosis were accessed. Clinical characteristics of each participant were identified. A t-test and Chi-squared test were used to examine differences between these values. Interclass correlation coefficients (ICCs) and interobserver agreement (assessed by calculating kappa coefficients) were calculated to assess the correlation of measures interpreted by two observers. p-values <0.05 were considered significant. Results One or more comorbidities were identified in 86.6% of the patients and in 40% of the controls. The most prevalent comorbidity was osteoporosis, present in 44.2% of patients and in 24.8% of controls. New diagnoses of cardiovascular disease, emphysema and osteoporosis were made in 25%, 7% and 46% of cases, respectively. The kappa coefficient for CAC was 0.906 (p<0.001). ICCs for measures of liver, spleen and bone density were 0.88, 0.93 and 0.96, respectively (p<0.001). Conclusions CT data acquired during LCS led to the identification of previously undiagnosed comorbidities. The LCS is useful to facilitate comorbidity diagnosis in developing countries, providing opportunities for its prevention and treatment

Consistent improvement with eculizumab across muscle groups in myasthenia gravis

Objective: To assess whether eculizumab, a terminal complement inhibitor, improves patient- and physician-reported outcomes (evaluated using the myasthenia gravis activities of daily living profile and the quantitative myasthenia gravis scale, respectively) in patients with refractory anti-acetylcholine receptor antibody-positive generalized myasthenia gravis across four domains, representing ocular, bulbar, respiratory, and limb/gross motor muscle groups. Methods: Patients with refractory anti-acetylcholine receptor antibody-positive generalized myasthenia gravis were randomized 1:1 to receive either placebo or eculizumab during the REGAIN study (NCT01997229). Patients who completed REGAIN were eligible to continue into the open-label extension trial (NCT02301624) for up to 4 years. The four domain scores of each of the myasthenia gravis activities of daily living profile and the quantitative myasthenia gravis scale recorded throughout REGAIN and through 130 weeks of the open-label extension were analyzed. Results: Of the 125 patients who participated in REGAIN, 117 enrolled in the open-label extension; 61 had received placebo and 56 had received eculizumab during REGAIN. Patients experienced rapid improvements in total scores and all four domain scores of both the myasthenia gravis activities of daily living profile and the quantitative myasthenia gravis scale with eculizumab treatment. These improvements were sustained through 130 weeks of the open-label extension. Interpretation: Eculizumab treatment elicits rapid and sustained improvements in muscle strength across ocular, bulbar, respiratory, and limb/gross motor muscle groups and in associated daily activities in patients with refractory anti-acetylcholine receptor antibody-positive generalized myasthenia gravis

Long-term safety and efficacy of eculizumab in generalized myasthenia gravis

Introduction: Eculizumab is effective and well tolerated in patients with antiacetylcholine receptor antibody-positive refractory generalized myasthenia gravis (gMG; REGAIN; NCT01997229). We report an interim analysis of an open-label extension of REGAIN, evaluating eculizumab's long-term safety and efficacy. Methods: Eculizumab (1,200 mg every 2 weeks for 22.7 months [median]) was administered to 117 patients. Results: The safety profile of eculizumab was consistent with REGAIN; no cases of meningococcal infection were reported during the interim analysis period. Myasthenia gravis exacerbation rate was reduced by 75% from the year before REGAIN (P < 0.0001). Improvements with eculizumab in activities of daily living, muscle strength, functional ability, and quality of life in REGAIN were maintained through 3 years; 56% of patients achieved minimal manifestations or pharmacological remission. Patients who had received placebo during REGAIN experienced rapid and sustained improvements during open-label eculizumab (P < 0.0001). Discussion: These findings provide evidence for the long-term safety and sustained efficacy of eculizumab for refractory gMG. Muscle Nerve 2019

Eculizumab in refractory generalized myasthenia gravis previously treated with rituximab: subgroup analysis of REGAIN and its extension study

Introduction/Aims Individuals with refractory generalized myasthenia gravis (gMG) who have a history of rituximab use and experience persistent symptoms represent a population with unmet treatment needs. The aim of this analysis was to evaluate the efficacy and safety of eculizumab in patients with refractory anti‐acetylcholine receptor antibody‐positive (AChR+) gMG previously treated with rituximab. Methods This post hoc subgroup analysis of the phase 3 REGAIN study (NCT01997229) and its open‐label extension (OLE; NCT02301624) compared baseline characteristics, safety, and response to eculizumab in participants who had previously received rituximab with those who had not. Rituximab use was not permitted within the 6 months before screening or during REGAIN/OLE. Results Of 125 REGAIN participants, 14 had received rituximab previously (7 received placebo and 7 received eculizumab). In the previous‐rituximab group, 57% had used at least four other immunosuppressants compared with 16% in the no‐previous‐rituximab group. Myasthenia Gravis Activities of Daily Living total scores from eculizumab baseline to week 130 of eculizumab treatment improved in both the previous‐rituximab and no‐previous‐rituximab groups (least‐squares mean −4.4, standard error of the mean [SEM] 1.0 [n = 9] and least‐squares mean −4.6, SEM 0.3 [n = 67], respectively; difference = 0.2, 95% confidence interval −1.88 to 2.22). In addition, in both groups, most patients who were treated with eculizumab for 130 weeks achieved a Myasthenia Gravis Foundation of America post‐intervention status of minimal manifestations (66.7% and 65.0%, respectively). The eculizumab safety profile was similar between groups and consistent with its established profile. Discussion Eculizumab is an effective therapy for patients with refractory AChR+ gMG, irrespective of whether they had received rituximab treatment previously

Correction to: Eculizumab improves fatigue in refractory generalized myasthenia gravis (Quality of Life Research, (2019), 28, 8, (2247-2254), 10.1007/s11136-019-02148-2)

The article “Eculizumab improves fatigue in refractory generalized myasthenia gravis”, written by “Henning Andersen, Renato Mantegazza, Jing Jing Wang, Fanny O’Brien, Kaushik Patra, James F. Howard Jr. and The REGAIN Study Group” was originally published electronically on the publisher’s internet portal (currently SpringerLink) on 23 March 2019 without open access

Safety and efficacy of eculizumab in anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis (REGAIN): a phase 3, randomised, double-blind, placebo-controlled, multicentre study

Background Complement is likely to have a role in refractory generalised myasthenia gravis, but no approved therapies specifically target this system. Results from a phase 2 study suggested that eculizumab, a terminal complement inhibitor, produced clinically meaningful improvements in patients with anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis. We further assessed the efficacy and safety of eculizumab in this patient population in a phase 3 trial. Methods We did a phase 3, randomised, double-blind, placebo-controlled, multicentre study (REGAIN) in 76 hospitals and specialised clinics in 17 countries across North America, Latin America, Europe, and Asia. Eligible patients were aged at least 18 years, with a Myasthenia Gravis-Activities of Daily Living (MG-ADL) score of 6 or more, Myasthenia Gravis Foundation of America (MGFA) class II\ue2\u80\u93IV disease, vaccination against Neisseria meningitides, and previous treatment with at least two immunosuppressive therapies or one immunosuppressive therapy and chronic intravenous immunoglobulin or plasma exchange for 12 months without symptom control. Patients with a history of thymoma or thymic neoplasms, thymectomy within 12 months before screening, or use of intravenous immunoglobulin or plasma exchange within 4 weeks before randomisation, or rituximab within 6 months before screening, were excluded. We randomly assigned participants (1:1) to either intravenous eculizumab or intravenous matched placebo for 26 weeks. Dosing for eculizumab was 900 mg on day 1 and at weeks 1, 2, and 3; 1200 mg at week 4; and 1200 mg given every second week thereafter as maintenance dosing. Randomisation was done centrally with an interactive voice or web-response system with patients stratified to one of four groups based on MGFA disease classification. Where possible, patients were maintained on existing myasthenia gravis therapies and rescue medication was allowed at the study physician's discretion. Patients, investigators, staff, and outcome assessors were masked to treatment assignment. The primary efficacy endpoint was the change from baseline to week 26 in MG-ADL total score measured by worst-rank ANCOVA. The efficacy population set was defined as all patients randomly assigned to treatment groups who received at least one dose of study drug, had a valid baseline MG-ADL assessment, and at least one post-baseline MG-ADL assessment. The safety analyses included all randomly assigned patients who received eculizumab or placebo. This trial is registered with ClinicalTrials.gov, number NCT01997229. Findings Between April 30, 2014, and Feb 19, 2016, we randomly assigned and treated 125 patients, 62 with eculizumab and 63 with placebo. The primary analysis showed no significant difference between eculizumab and placebo (least-squares mean rank 56\uc2\ub76 [SEM 4\uc2\ub75] vs 68\uc2\ub73 [4\uc2\ub75]; rank-based treatment difference \ue2\u88\u9211\uc2\ub77, 95% CI \ue2\u88\u9224\uc2\ub73 to 0\uc2\ub796; p=0\uc2\ub70698). No deaths or cases of meningococcal infection occurred during the study. The most common adverse events in both groups were headache and upper respiratory tract infection (ten [16%] for both events in the eculizumab group and 12 [19%] for both in the placebo group). Myasthenia gravis exacerbations were reported by six (10%) patients in the eculizumab group and 15 (24%) in the placebo group. Six (10%) patients in the eculizumab group and 12 (19%) in the placebo group required rescue therapy. Interpretation The change in the MG-ADL score was not statistically significant between eculizumab and placebo, as measured by the worst-rank analysis. Eculizumab was well tolerated. The use of a worst-rank analytical approach proved to be an important limitation of this study since the secondary and sensitivity analyses results were inconsistent with the primary endpoint result; further research into the role of complement is needed. Funding Alexion Pharmaceuticals