Indwelling pleural catheter insertion technique.

This video tutorial is a step-by-step demonstration of the indwelling pleural catheter insertion technique in a patient who was diagnosed with malignant pleural effusions due to multiple metastases. Placing an indwelling pleural catheter is a novel method to treat chronic pleural effusions, especially secondary to malignancies. This method is particularly useful in patients with a trapped lung or with reduced life expectancy in whom more-invasive procedures are contraindicated. Indwelling pleural catheters are well tolerated.

EGFR Mutation is a Prognostic Factor in Lung Cancer Patients with Pleural Dissemination Detected During or After Surgery.

BACKGROUND: Primary lung tumors are sometimes resected when either pleural dissemination (PD) or malignant pleural effusion (MPE) exists. This study clarified the prognostic factors for non-small cell lung cancer (NSCLC) with either PD and MPE, or both, detected during or after surgery. PATIENTS AND METHODS: We examined patients with NSCLC from a multicenter database who had either PD, MPE, or both, detected during or after surgery between 2005 and 2015. Hazard ratios and 95% confidence intervals were estimated using the Cox proportional hazards model adjusted for potential confounding factors. RESULTS: Among 9463 registered patients, PD, MPE, or both, were found in 114 patients with NSCLC during or after surgery. Primary tumor resection and exploratory thoracotomy were performed in 65 and 49 patients, respectively. In univariate analysis, adenocarcinoma, clinically undetected lymph node metastasis (c-N0 or unknown), EGFR mutation, and combination of chemotherapy or tyrosine kinase inhibitors after surgery were better prognostic factors for overall survival (OS), whereas in the multivariate analysis, adenocarcinoma, clinically undetected lymph node metastasis, and EGFR mutation were favorable independent prognostic factors in OS. Additionally, limited to patients with EGFR mutation, patients with primary lung tumor resection showed a significantly better 5-year OS than those with exploratory thoracotomy (86.4 vs. 44.8%; p < 0.001). CONCLUSION: Our findings show that surgical resection of primary tumors could improve the prognosis of patients with PD, MPE, or both, detected during or after surgery when the tumors harbor an EGFR mutation.

Erector spine plane block as single loco-regional anesthesia in non-intubated video-assisted thoracic surgery for unfit patients: a case-match study.

In the present study, we analyzed the safety and efficacy of non-intubated video-assisted thoracoscopy (NI-VATS) for the diagnosis and palliation of malignant pleural effusion in the elderly population using erector-spinae plane block (ESPB) as single loco-regional anesthesia. From January 2016 to December 2020 a consecutive series of 158 patients who underwent surgery for malignant pleural effusion was analyzed. Of these, 20 patients were operated using ESPB NI-VATS, while 138 were operated under general anesthesia (GA). After propensity score matching, the NI-VATS population was older (81 vs. 76 years p 0.006), and had more severe pre-existing comorbidities, evaluated using Charlson Comorbidity Index (p = 0.029) and ASA score (p < 0.001). GA and NI-VATS patients did not differ in terms of postoperative opioid consumption, complication rate and postoperative hospitalization. Both short- and long-term efficacy of talc poudrage was equal in the two populations. The overall length of stay in the operative room was significantly shorter for the NI-VATS than for the GA-VATS group (67.5 vs. 105 min, p < 0.001), and operative time significantly differed in the two groups (35 vs. 47.5 min, respectively, p < 0.001). ESPB NI-VATS can be a safe and effective option for the diagnosis and palliation of malignant pleural effusion for elderly and frail patients.

Surgical intervention for non-small-cell lung cancer with minimal malignant pleural effusion.

PURPOSE: We assessed the clinical significance of minimal malignant pleural effusion (MPE) using liquid-based cytology (LBC) and immunocytochemistry and reviewed the postoperative outcomes of patients with non-small-cell lung cancer (NSCLC). METHODS: We reviewed 240 patients with cM0 NSCLC who underwent lobectomy. Carcinoembryonic antigen (CEA) immunocytochemistry was performed with LBC to aid in the diagnosis of minimal MPE. We assessed the efficacy of this diagnostic method, relevant clinical factors, and postoperative outcomes. RESULTS: LBC showed positive results in two patients and suspicious results in 21. Of the 21 patients, immunocytochemistry showed minimal MPE in 10 (47.6%); therefore, a total of 12 patients (5%) showed minimal MPE. Minimal MPE is associated with an older age, increased consolidation tumor ratio, and adenocarcinoma histology. The 12 patients with minimal MPE had a 3-year overall survival rate of 90%. Postoperative recurrence was observed in seven patients (58.3%), four of whom were treated with epidermal growth factor receptor-tyrosine kinase inhibitors or immune checkpoint inhibitors, while three are still undergoing treatment, with a survival of 2.2, 2.5 and 5.5 years. CONCLUSIONS: CEA immunocytochemistry offers high sensitivity for the diagnosis of minimal MPE. Surgical intervention may be considered for select patients with NSCLC showing minimal MPE.

Recommendations of the Spanish Society of Thoracic Surgery for the management of malignant pleural effusion.

This article summarizes the clinical guidelines for the diagnosis and treatment of malignant pleural effusion (MPE) sponsored by the Spanish Society of Thoracic Surgery (SECT). Ten clinical controversies were elaborated under the methodology of PICO (Patient, Intervention, Comparison, Outcome) questions and the quality of the evidence and grading of the strength of the recommendations was based on the GRADE system. Immunocytochemical and molecular analyses of pleural fluid may avoid further invasive diagnostic procedures. Currently, the definitive control of MPE can be achieved either by pleurodesis (talc poudrage or slurry) or the insertion of a indwelling pleural catheter (IPC). It is likely that the combination of both techniques (i.e., thoracoscopy with talc poudrage and insertion of a IPC, or instillation of talc slurry through a IPC) will have a predominant role in the future therapeutic management.

Incidence and management of pleural effusions in patients with Wilms tumor: A Pediatric Surgical Oncology Research Collaborative study.

Wilms tumor (WT) is the most common renal malignancy in children. Children with favorable histology WT achieve survival rates of over 90%. Twelve percent of patients present with metastatic disease, most commonly to the lungs. The presence of a pleural effusion at the time of diagnosis of WT may be noted on staging imaging; however, minimal data exist regarding the significance and prognostic importance of this finding. The objectives of our study are to identify the incidence of pleural effusions in patients with WT, and to determine the potential impact on oncologic outcomes. A multi-institutional retrospective review was performed from January 2009 to December 2019, including children with WT and a pleural effusion on diagnostic imaging treated at Pediatric Surgical Oncology Research Collaborative (PSORC) participating institutions. Of 1259 children with a new WT diagnosis, 94 (7.5%) had a pleural effusion. Patients with a pleural effusion were older than those without (median 4.3 vs 3.5 years; P = .004), and advanced stages were more common (local stage III 85.9% vs 51.9%; P < .0001). Only 14 patients underwent a thoracentesis for fluid evaluation; 3 had cytopathologic evidence of malignant cells. Event-free and overall survival of all children with WT and pleural effusions was 86.2% and 91.5%, respectively. The rate and significance of malignant cells present in pleural fluid is unknown due to low incidence of cytopathologic analysis in our cohort; therefore, the presence of an effusion does not appear to necessitate a change in therapy. Excellent survival can be expected with current stage-specific treatment regimens.

Postoperative outcome after palliative treatment of malignant pleural effusion.

BACKGROUND: The objective of this nationwide, registry-based study was to compare the two most frequently used procedures for the palliative treatment of a malignant pleural effusion (MPE) and to evaluate differentiated indications for these two procedures. METHODS: This was a retrospective observational study based on data of the "PLEURATUMOR" registry of the German Society for Thoracic Surgery. Patients who were documented in the period from January 2015 to November 2021 and had video-assisted thoracic surgery (VATS) talc pleurodesis or implantation of an indwelling pleural catheter (IPC) were included. RESULTS: A total of 543 patients were evaluated. The majority suffered from secondary pleural carcinomatosis (n = 402; 74%). VATS talc pleurodesis (n = 361; 66.5%) was performed about twice as often as IPC implantation (n = 182; 33.5%). The duration of surgery was significantly shorter in IPC-patients with 30 min compared to VATS talc pleurodesis (38 min; p = 0.000). Postoperative complication rate was 11.8% overall and slightly higher after VATS talc pleurodesis (n = 49; 13.6%) than after IPC implantation (n = 15; 8.2%). After VATS talc pleurodesis patients were hospitalized significantly longer compared to the IPC group (6 vs. 3.5 days; p = 0.000). There was no significant difference in postoperative wound infections between the groups (p = 0.10). The 30-day mortality was 7.9% (n = 41). CONCLUSION: The implantation of an IPC can significantly shorten the duration of surgery and the hospital stay. For this reason, the procedure should be matched with the patient's expectations preoperatively and the use of an IPC should be considered not only in the case of a trapped lung.

Higher concordance of PD-L1 expression between biopsies and effusions in epithelioid than in nonepithelioid pleural mesothelioma.

BACKGROUND: Malignant mesothelioma (MM) is a therapy-resistant tumor, often causing an effusion. Drugs targeting the programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway have shown promising results, but assessment of PD-L1 expression to select patients for therapy has mainly been performed on histologic tissue samples. In a previous study, we showed that MM effusions are suitable for PD-L1 assessment with results comparable to those reported in histologic studies, but no studies have compared PD-L1 expression in histologic and cytologic samples. METHODS: PD-L1 expression was determined immunohistochemically (clone 28-8) in 61 paired samples of effusions and biopsies from patients with pleural MM, obtained at the time of diagnosis. Only cases with >100 tumor cells were included. Membranous staining in tumor cells was considered positive at ≥1%, >5%, >10%, and >50% cutoff levels. RESULTS: Of 61 histologic samples, PD-L1 expression was found in 28 and 7 samples at ≥1% and >50% cutoffs, respectively; the corresponding figures for cytology were 21 and 5, respectively. The overall percentage agreement between histology and cytology was 69% and 84%, with a kappa (κ) of 0.36 and 0.08 at ≥1% and >50% cutoffs, respectively. The concordance between cytology and histology tended to be higher for epithelioid MM versus nonepithelioid MM at a ≥1% cutoff. PD-L1 positivity in biopsies, but not in effusions, correlated with the histologic subtype at a ≥1% cutoff. CONCLUSIONS: A moderate concordance of PD-L1 expression between biopsies and effusions from pleural MM, especially for the epithelioid subtype, indicates biological differences between the 2 types of specimens. Cytology and histology may be complementary.

Indwelling pleural catheters for malignancy related pleural effusions.

OBJECTIVE: Malignant Pleural Effusion (MPE) carries significant morbidity and mortality. Indwelling pleural catheters (IPCs) are established in the management pathway. Large case reviews add to the evidence base regarding safety and efficacy. PATIENTS AND METHODS: 168 patients had an IPC inserted between January 2012 and December 2018 in a large pleural centre. Data on outcomes and complications were obtained from the patients' notes, laboratory and radiographic findings. A descriptive statistical methodology was applied. RESULTS: 168 IPCs were inserted in a predominantly male population. The overall complication rate is 13%. The incidence of any individual complication such as infection, metastatic seeding, drain displacement, and loculations are all less than previously described. CONCLUSIONS: This case review adds to the large body of evidence that IPCs are safe and have minimal complications. Specific factors enabling this are the use of pre-operative antibiotics, the use of theatre space, and the experience of the pleural interventional physicians.

Intrathoracic hemangioma.

We report the very rare case of recurrent unilateral pleural effusion in a 53-year-old male. Computed tomography (CT) scan and magnetic resonance imaging revealed a left-sided paravertebral mass at D3 level. Multiple biopsy and CT scan lead us to the diagnosis of "Angiomatous Malformation." The lesion was excised surgically which on final histopathological report termed hemangioma.

Usefulness of methylthioadenosine phosphorylase and BRCA-associated protein 1 immunohistochemistry in the diagnosis of malignant mesothelioma in effusion cytology specimens.

BACKGROUND: The separation of benign from malignant mesothelial proliferations on effusion cytology can be difficult. Loss of methylthioadenosine phosphorylase (MTAP) by immunohistochemistry is an established marker of malignancy in mesothelial proliferations, but to the authors' knowledge largely has been applied only to biopsies. The current study was conducted to determine the usefulness of MTAP immunohistochemistry in the diagnosis of malignant mesothelioma in effusion cytology specimens. METHODS: A total of 21 effusion cytology cases of malignant mesothelioma were stained for MTAP and BRCA-associated protein 1 (BAP1), with 15 reactive mesothelial cytology cases used as a control. Fourteen cases had a paired surgical specimen for comparison, and 7 cases were run for CDKN2A deletion by fluorescence in situ hybridization. RESULTS: Complete loss of MTAP cytoplasmic staining was noted in 7 of 21 effusion samples (33%), and no loss was observed in 11 effusion samples (52%); 11 of these cases had a matching surgical specimen and all 11 specimens demonstrated the same MTAP pattern. Partial loss was observed in 3 effusion specimens (80%, 40%, and 40% intact staining, respectively), but in all 3 the surgical specimen demonstrated 100% staining. None of the 15 reactive mesothelial cytology specimens demonstrated MTAP cytoplasmic loss. CDKN2A FISH demonstrated concordance in 5 of 7 cases (71%). MTAP immunohistochemistry had a sensitivity of 33% and a specificity of 100% for this differential diagnosis. CONCLUSIONS: MTAP staining demonstrated generally good concordance between the cytologic and surgical specimens and appears to be useful in the diagnosis of mesothelioma on effusion specimens. Complete loss of MTAP is a reliable marker of malignancy, but the significance of partial loss of MTAP staining is unclear.

Are postoperative pain and patient satisfaction influenced by the number of ports in VATS for malignant pleural effusion treatment?

Objectives: The aim of this research is by using sociological methods of scientific research for tracking the pain and satisfaction indicators to prove that decreasing the number of ports in the VATS (Video-assisted thoracic surgery) for Malignant Pleural Effusion reduces postoperative pain and improves patient's satisfaction.Methods: Our study included 117 VATS procedures performed in the period from 01 January 2013 to 31 September 2016. The sociological method used to measure the pain indicator was an interview. The severity of postoperative pain was determined and reported according to a ten-point pain visual analogue scale (VAS). The degree of satisfaction was determined and reported according to a six-point and ten-point grading systems on the basis of a research interview procedure.Results: In the single-port method, the verbal pain scale for all the days covered by the research study statistically showed significantly lower values (P Ë‚ 0.0001) in comparison with the conventional method (P Ë‚ 0.0001). With regard to the patient's satisfaction, determined on the basis of the six-point system, the results were as follows: conventional VATS approach - average 3.1 with a standard deviation of 1.1 and ranging from 0 to 5; single-port VATS approach - average 4.3 with a standard deviation of 1.0 and within the range from 0 to 6. Conventional VATS approach - 6.8 - neutral. Single-port VATS approach - 8.1 - prevailing satisfaction.Conclusions: Based on our study and the studies of other authors, it can be concluded that postoperative pain and satisfaction after VATS in patients with MPE (Malignant pleural effusion) are influenced by the number of ports and the one-port technique shows better results than the conventional three-port method.The research study was registered and approved by the Clinical Research and Ethics Committee at the 'Prof. Dr. Stoyan Kirkovich' AD University Multi-Profile Hospital for Active Treatment Hospital, Stara Zagora. According to Protocol No. 11, Ref. No. 12471/30.10.2015 approved are the methods used by the sociological research study which uses predefined indicators to track patients who have undergone conventional VATS and single-port VATS. Indicators: postoperative pain and satisfaction.

Prognostic value of a new score using serum alkaline phosphatase and pleural effusion lactate dehydrogenase for patients with malignant pleural effusion.

BACKGROUND: The objective of our study was to analyze the prognostic value of the combination of serum ALP and pleural effusion LDH (AL score) for malignant pleural effusion (MPE) patients. METHODS: This study includes retrospective, descriptive and observational research from 1 June 2006 to 1 December 2017, which aimed to identify prognostic factors related to MPE patients. We analyzed the association of various clinical features, routinely tested markers from peripheral blood and MPE at diagnosis and overall survival (OS). All MPE patients were assigned to three groups according to their AL score. The impact of the AL score and other prognostic factors were evaluated with multivariable regression. RESULTS: According to their AL score, 193 patients were assigned to three groups with 25 in group 0 (sALP < 65 U/L and pLDH < 155 U/L), 121 in group 1 (sALP > 65 U/L or pLDH > 155 U/L) and 47 (sALP > 65 U/L and pLDH > 155 U/L) in group 2. For groups 0, 1 and 2, median survival times (MST) were 23, 15 and 7 months, respectively. Among the three groups, MST, serum albumin level, C reactive protein, erythrocyte sedimentation rate, the ratios of platelet-to-lymphocyte, neutrophil-to-lymphocyte showed significant differences. The counts of neutrophils, monocytes, platelets and AL score (0 vs. 1, P = 0.038, hazard ratio [HR]: 1.858, 95% confidence interval [CI]: [1.034, 3.339]; 0 vs. 2, P = 0.001, HR: 2.993, 95% CI: [1.556, 5.531]) were independent prognostic indicators for OS of MPE patients. CONCLUSION: AL score is a promising indicator which can be used to predict the prognosis of MPE patients. It can assist physicians in the selection of patients for appropriate palliative treatment. KEY POINTS: To our knowledge, this paper is the first study that combined two enzymes (sALP and pLDH) from serum and pleural effusion and studied the prognostic value for MPE patients. It has been proved to be a promising indicator to assist physicians select patients for appropriate palliative treatment.

Inter-observer variation in image interpretation and the prognostic importance of non-expansile lung in malignant pleural effusion.

BACKGROUND AND OBJECTIVE: Non-expansile lung (NEL) frequently complicates management of malignant pleural effusion (MPE) and is an important factor in clinical practice and trials. NEL is frequently diagnosed on a single radiographic observation, but neither the inter-observer agreement of this approach nor the prognostic importance of NEL in MPE has been reported. METHODS: A multicentre retrospective cohort study was performed in two UK pleural centres. NEL was defined as <50% pleural re-apposition on post-drainage radiographs by primary and secondary assessors at each site. Inter-observer agreement was assessed by Cohen's kappa (κ). Kaplan-Meier methodology and multivariate Cox models were used to assess the prognostic impact of NEL versus no NEL and 'complete NEL' versus 'complete expansion', based on a single assessor's results from each site. RESULTS: NEL was identified by the primary assessor in 33 of 97 (34%) in Cohort 1 and 15 of 86 (17%) in Cohort 2. Inter-observer agreement between assessors was only fair-to-moderate (Cohort 1 κ: 0.38 (95% CI: 0.21-0.55), Cohort 2 κ: 0.51 (95% CI: 0.30-0.72)). In both cohorts, NEL was associated with shorter median overall survival (Cohort 1: 188 vs 371 days, Cohort 2: 192 vs 412 days). This prognostic association was independent in Cohort 1 (hazard ratio (HR): 2.19, 95% CI: 1.31-3.66) but not in Cohort 2 (HR: 1.42, 95% CI: 0.71-2.87). Survival was inferior in both cohorts in cases of complete NEL versus complete expansion. CONCLUSION: Radiographic NEL is common but inter-observer agreement is only fair-to-moderate. NEL is associated with adverse survival. These data do not support the use of single radiographic assessments to classify NEL.

Giant Solitary Fibrous Tumor of Pleura Presenting Both Benign and Malignant Features.

BACKGROUND The incidence of solitary fibrous tumor of the pleura (SFTP) is less than 5% of all pleural tumors. It is important to determine whether the tumor is benign or malignant in deciding on treatment and estimating prognosis, but this can sometimes be difficult. CASE REPORT A 59-year-old woman with no prior medical history presented with a 4-month history of right back pain and dyspnea. Contrast-enhanced computed tomography revealed a giant oval mass with inhomogeneous intensities, and bloody pleural effusion in the right thoracic cavity, proved to be solitary fibrous tumor of pleura (SFTP) under the complete thoracoscopic resection. The resected tumor seemed to have several malignant features, including large size of tumor, inhomogeneous intensities, and pleural effusion due to intratumor hemorrhage; however, Ki-67 (MIB-I) proliferation index was less than 1%, with no recurrence seen within 2 year after symptom onset. CONCLUSIONS We managed a case of SFTP presenting both malignant and benign features. In patients with SFTP, multi-disciplinary discussion among the clinician, radiologist, and pathologist was considered to be needed for estimating disease prognosis.

A case report of an expensive yet necessary thoracentesis: Expanding the boundaries of endoscopic ultrasound transbronchial needle aspiration.

RATIONALE: Endobronchial ultrasound has revolutionized the field of bronchoscopy and has become one of the most important tools for the diagnosis of intrathoracic lymphadenopathy and para-bronchial structures. The reach of this technique has not been limited to these structures and pleural lesions have been at times accessible. To our knowledge, pleural fluid collections have not been accessed with endobronchial ultrasound (EBUS). PATIENT CONCERNS: 52-year-old women with dyspnea, fever and a new loculated pleural effusion that was suspected to be the source of the fever but was not accessible through traditional thoracentesis. DIAGNOSIS: Malignant pleural effusion. INTERVENTIONS: Sampling and drainage of the loculated pleural fluid collection using EBUS scope introduced via the esophagus. OUTCOMES: Infection excluded. Resolution of fever and improved dyspnea after drainage of effusion. LESSONS: The convex curvilinear ultrasound bronchoscope allows unprecedented access to thoracic structures. The reach is not limited to mediastinal lymph nodes and parenchymal masses adjacent to the airways, and pleural space and pleural fluid are at times accessible, particularly when one considers the esophageal approach.

Primary tumour resection in non-small-cell lung cancer patients with ipsilateral pleural dissemination (M1a): a population-based study.

OBJECTIVES: Non-small-cell lung cancer (NSCLC) patients with ipsilateral pleural dissemination (M1a) are generally contraindicated for surgery. However, several small-sample studies have demonstrated that they might benefit from surgery. We investigated the effects of primary tumour resection on survival in these patients. METHODS: Stage IV NSCLC patients with ipsilateral pleural dissemination were identified from the US National Cancer Institute Surveillance, Epidemiology and End Results database entries from 2010 to 2015. Survival analysis was performed before and after matching. Multivariable regression models were built to identify prognostic factors. RESULTS: Of the 5513 patients with ipsilateral pleural dissemination, 309 underwent primary tumour resection. In the entire cohort, surgery was associated with improved overall survival (OS) in both the unmatched and matched cohorts (both log rank, P < 0.001). In the surgery-recommended cohort, patients treated with surgery also had significantly longer OS before and after matching. Multivariable regression models showed that surgery was an independent favourable prognostic factor for OS [hazard ratio (HR) 0.56, 95% confidence interval (CI) 0.48-0.65; P < 0.001] and lung cancer-specific mortality (subhazard ratio 0.60, 95% CI 0.51-0.70; P < 0.001). Surgery was independently associated with improved survival in all subgroups except for those with pericardial effusion (P = 0.065) or N3 disease (P = 0.17). In the surgical cohort, patients who underwent lobe/bilobectomy had significantly better OS than those who underwent sublobar resection (log rank, P < 0.001). CONCLUSIONS: Inclusion of primary tumour resection in multimodal therapy of NSCLC was associated with improved survival in selected patients with ipsilateral pleural dissemination, except for those with pericardial effusion or N3 disease.

MesoTRAP: a feasibility study that includes a pilot clinical trial comparing video-assisted thoracoscopic partial pleurectomy decortication with indwelling pleural catheter in patients with trapped lung due to malignant pleural mesothelioma designed to address recruitment and randomisation uncertainties and sample size requirements for a phase III trial.

Introduction: One of the most debilitating symptoms of malignant pleural mesothelioma (MPM) is dyspnoea caused by pleural effusion. MPM can be complicated by the presence of tumour on the visceral pleura preventing the lung from re-expanding, known as trapped lung (TL). There is currently no consensus on the best way to manage TL. One approach is insertion of an indwelling pleural catheter (IPC) under local anaesthesia. Another is video-assisted thoracoscopic partial pleurectomy/decortication (VAT-PD). Performed under general anaesthesia, VAT-PD permits surgical removal of the rind of tumour from the visceral pleura thereby allowing the lung to fully re-expand. Methods and analysis: MesoTRAP is a feasibility study that includes a pilot multicentre, randomised controlled clinical trial comparing VAT-PD with IPC in patients with TL and pleural effusion due to MPM. The primary objective is to measure the SD of visual analogue scale scores for dyspnoea following randomisation and examine the patterns of change over time in each treatment group. Secondary objectives include documenting survival and adverse events, estimating the incidence and prevalence of TL in patients with MPM, examining completion of alternative forms of data capture for economic evaluation and determining the ability to randomise 38 patients in 18 months. Ethics and dissemination: This study was approved by the East of England-Cambridge Central Research Ethics Committee and the Health Research Authority (reference number 16/EE/0370). We aim to publish the outputs of this work in international peer-reviewed journals compliant with an Open Access policy. Trial registration: NCT03412357.