Outcomes of Patients With Early and Locally Advanced Lung Cancer: Protocol for the Italian Lung Cancer Observational Study (LUCENT).

BACKGROUND: Lung cancer, predominantly non-small cell lung cancer (NSCLC), remains a formidable challenge, necessitating an in-depth understanding of evolving treatment paradigms. The Italian Lung Cancer Observational Study (LUCENT) addresses this need by investigating the outcomes of patients with early and locally advanced lung cancer in Italy. OBJECTIVE: With a focus on real-world data and patient registries, this study aims to provide comprehensive insights into clinical, psychosocial, and economic impacts, contributing to informed decision-making in health care. METHODS: LUCENT is a prospective observational multicenter cohort study enrolling patients eligible for minimally invasive manual, robot-assisted, or traditional open surgery. The study will develop a web-based registry to collect longitudinal surgical, oncological, and socioeconomic outcome data. The primary objectives include performance assessment through the establishment of national benchmarks based on risk-adjusted outcomes and processes of care indicators. The secondary objectives encompass economic and psychosocial impact assessments of innovative technologies and treatment pathways. The multicenter design ensures a diverse and representative study population. RESULTS: The evolving landscape of NSCLC treatment necessitates a nuanced approach with consideration of the dynamic shifts in therapeutic strategies. LUCENT strives to fill existing knowledge gaps by providing a platform for collecting and analyzing real-world data, emphasizing the importance of patient-reported outcomes in enhancing the understanding of the disease. By developing a web-based registry, the study not only facilitates efficient data collection but also addresses the limitations of traditional methods, such as suboptimal response rates and costs associated with paper-and-pencil questionnaires. Recruitment will be conducted from January 01, 2024, to December 31, 2026. Follow-up will be performed for a minimum of 2 years. The study will be completed in the year 2028. CONCLUSIONS: LUCENT's potential implications are substantial. Establishing national benchmarks will enable a thorough evaluation of outcomes and care processes, guiding clinicians and policymakers in optimizing patient management. Furthermore, the study's secondary objectives, focusing on economic and psychosocial impacts, align with the contemporary emphasis on holistic cancer care. Insights gained from this study may influence treatment strategies, resource utilization, and patient well-being, thereby contributing to the ongoing refinement of lung cancer management. TRIAL REGISTRATION: ClinicalTrials.gov NCT05851755; https://clinicaltrials.gov/study/NCT05851755. ISRCTN 67197140; https://www.isrctn.com/ISRCTN67197140. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/57183.

Optimal planning and management strategies for minimally invasive lung segmentectomies: an international Delphi consensus report.

OBJECTIVES: CALGB140503/JCOG0802 RCTs comparing lobectomy with sublobar resection in stage IA NSCLC have confirmed the non-inferiority of segmentectomy. Additional insight is needed to improve preoperative work-up and intraoperative strategies to increase safety and promote the dissemination of minimally invasive segmentectomy (MIS). A Delphi panel study assessed the level of consensus among surgeons for the planning and management of MIS. METHODS: Twenty-one expert lung surgeons represented academic institutions, major teaching hospitals, and community hospitals from Europe, North America, and Asia. A 3-round Delphi methodology was used to analyse the answers of each panellist. Recognizing that questions with fewer response options have a higher consensus probability due to limited variability, weighted consensus thresholds were modified based on the number of response options. RESULTS: The 21 panellists responded to all 3 rounds of questions. Based on the most robust consensus (94.4%), 3D chest CT reconstructions are recommended only when planning complex segmentectomies. Surgeons should perform 3D reconstructions chest CT scans (consensus = 83.3%). The most effective and safest technique is image-guided VATS in a hybrid operating room (consensus = 83.3%). Dyes with intravenous administration are the safest technique for identifying the intersegmental plane during MIS (consensus = 72.2%). Augmented/mixed reality will probably not immediately help reduce perioperative complications (consensus = 72.2%). CONCLUSIONS: This Delphi consensus supports 3D reconstructions and preoperative pulmonary nodule localization before complex MIS. These recommendations should be considered when allocating resources to improve MIS's safety and oncologic efficacy for patients with small, early-stage lung cancers.

Prospective randomized study on the efficacy of three-dimensional reconstructions of bronchovascular structures on preoperative chest CT scan in patients who are candidates for pulmonary segmentectomy surgery: the PATCHES (Prospective rAndomized sTudy efficaCy of tHree-dimensional rEconstructions Segmentecomy) study protocol.

INTRODUCTION: Pulmonary segmentectomy, when combined with hilar and mediastinal lymphadenectomy, is currently considered the gold standard treatment for early-stage lung tumors (NSCLC) smaller than 2 cm in diameter. The preoperative planning for segmentectomies usually includes a contrast-enhanced CT with 2D reconstructions (axial, coronary, and sagittal). Recent technological advances allow 3D (volume rendering) reconstructions of preoperative CT scans, intended to improve the surgeon's understanding of the segmental anatomy. The study aims to investigate the added value of 3D reconstruction in enhancing the surgeon's understanding of anatomical structures, thus facilitating surgical planning and improving oncological outcomes. METHODS AND ANALYSIS: This is a prospective, randomized, controlled study. Patients will be randomized into two groups: 1. Group 2D: the preoperative workup for these patients will consist of a contrast-enhanced chest CT with two-dimensional (2D) reconstructions (axial, coronary, and sagittal); 2. Group 3D: the preoperative workup for these patients will consist of a contrast-enhanced chest CT with two-dimensional (2D) reconstructions (axial, coronary, and sagittal) and a 3D reconstruction (volume rendering) of the same chest CT employing dedicated software. The primary endpoints will be negative margin (R0) resection rate, resection margin (staple line-to-tumor distance), and thoracotomy conversions. We will use Fisher's exact test for binary outcomes and Mann-Whitney U test for continuous outcomes. For subgroup analyses, we will use regression. Multivariable analyses will be based on logistic regression for binary outcomes and linear regression for continuous outcomes. ETHICS AND DISSEMINATION: The protocol and the model informed consent forms have been reviewed and approved by the ethics committee (N.: 1-2023) concerning scientific content and compliance with applicable research and human subject regulations. A Subcommittee on Publications was established to review all publications and report its recommendations to the steering committee. The anonymized participant-level dataset and statistical code for generating the results will not be publicly available. TRIAL REGISTRATION: The protocol was registered at ClinicalTrials.gov (ID: NCT05716815; Prospective rAndomized sTudy efficaCy tHree-dimensional rEconstructions Segmentectomy - Full-Text View - ClinicalTrials.gov). Jan 19, 2023.

Prolonged air leak after video-assisted thoracic anatomical pulmonary resections: a clinical predicting model based on data from the Italian VATS group registry, a machine learning approach.

Background: Prolonged air leak (PAL) is a frequent complication after lung resection surgery and has a high clinical and economic impact. A useful risk predictor model can help recognize those patients who might benefit from additional preventive procedures. Currently, no risk model has sufficient discriminatory capacity to be used in common clinical practice. The aim of this study is to identify predictive risk factors for PAL after video-assisted thoracoscopic surgery (VATS) anatomical resections in the Italian VATS group database and to evaluate their clinical and statistical performance. Methods: We processed data collected in the second edition of the Italian VATS group registry. It includes patients that underwent a thoracoscopic anatomical resection for benign or malignant diseases, between November 2015 and December 2020. We used recursive feature elimination (RFE), using a backward selection process, to find the optimal combination of predictors. The study population was randomly split based on the outcome into a derivation (80%) and an internal validation cohort (20%). Discrimination of the model was measured using the area under the curve, or C-statistic. Calibration was displayed using a calibration plot and was measured using Emax and Eavg, the maximum and the average difference in predicted versus loess calibrated probabilities. Results: A cohort of 6,236 patients was eligible for the study after application of the exclusion criteria. Five-day PAL rate in this patient cohort was 11.3%. For the construction of our predictive model, we used both preoperative and intraoperative variables, with a total of 320 variables. The presence of variables with missing values greater than 5% led to 120 remaining predictors. RFE algorithm recommended 8 features for the model that are relevant in predicting the target variable. Conclusions: We confirmed significant prognostic risk factors for the prediction of PAL: decreased DLCO/VA ratio, longer duration of surgery, male sex, the need for adhesiolysis, COPD, and right side. We identified middle lobe resections and ground glass opacity as protective factors. After internal validation, a C statistic of 0.63 was revealed, which is too low to generate a reliable score in clinical practice.

A Delphi Consensus report from the "Prolonged Air Leak: A Survey" study group on prevention and management of postoperative air leaks after minimally invasive anatomical resections.

OBJECTIVES: This study reports the results of an international expert consensus process evaluating the assessment of intraoperative air leaks (IAL) and treatment of postoperative prolonged air leaks (PAL) utilizing a Delphi process, with the aim of helping standardization and improving practice. METHODS: A panel of 45 questions was developed and submitted to an international working group of experts in minimally invasive lung cancer surgery. Modified Delphi methodology was used to review responses, including 3 rounds of voting. The consensus was defined a priori as >50% agreement among the experts. Clinical practice standards were graded as recommended or highly recommended if 50-74% or >75% of the experts reached an agreement, respectively. RESULTS: A total of 32 experts from 18 countries completed the questionnaires in all 3 rounds. Respondents agreed that PAL are defined as >5 days and that current risk models are rarely used. The consensus was reached in 33/45 issues (73.3%). IAL were classified as mild (<100 ml/min; 81%), moderate (100-400 ml/min; 71%) and severe (>400 ml/min; 74%). If mild IAL are detected, 68% do not treat; if moderate, consensus was not; if severe, 90% favoured treatment. CONCLUSIONS: This expert consensus working group reached an agreement on the majority of issues regarding the detection and management of IAL and PAL. In the absence of prospective, randomized evidence supporting most of these clinical decisions, this document may serve as a guideline to reduce practice variation.

Is It Possible to Establish a Reliable Correlation between Maximum Standardized Uptake Value of 18-Fluorine Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography and Histological Types of Non-Small Cell Lung Cancer? Analysis of the Italian VATS Group Database.

BACKGROUND: Although positron emission tomography/computed tomography, often integrated with 2-deoxy-2-[fluorine-18] fluorine-D-glucose (18F-FDG-PET/CT), is fundamental in the assessment of lung cancer, the relationship between metabolic avidity of different histotypes and maximum standardized uptake value (SUVmax) has not yet been thoroughly investigated. The aim of the study is to establish a reliable correlation between Suvmax and histology in non-small cell lung cancer (NSCLC), in order to facilitate patient management. METHODS: We retrospectively assessed the data about lung cancer patients entered in the Italian Registry of VATS Group from January 2014 to October 2019, after establishing the eligibility criteria of the study. In total, 8139 patients undergoing VATS lobectomy were enrolled: 3260 females and 4879 males. The relationship between SUVmax and tumor size was also analyzed. RESULTS: The mean values of SUVmax in the most frequent types of lung cancer were as follows: (a) 4.88 ± 3.82 for preinvasive adenocarcinoma; (b) 5.49 ± 4.10 for minimally invasive adenocarcinoma; (c) 5.87 ± 4.18 for invasive adenocarcinoma; and (d) 8.85 ± 6.70 for squamous cell carcinoma. Processing these data, we displayed a statistically difference (p < 0.000001) of FDG avidity between adenocarcinoma and squamous cell carcinoma. Moreover, by classifying patients into five groups based on tumor diameter and after evaluating the SUVmax value for each group, we noted a statistical correlation (p < 0.000001) between size and FDG uptake, also confirmed by the post hoc analysis. CONCLUSIONS: There is a correlation between SUVmax, histopathology outcomes and tumor size in NSCLC. Further clinical trials should be performed in order to confirm our data.

Work in progress report of a multicentre retrospective observational study to evaluate the association between the airflows and the intrapleural pressures digitally recorded after video-assisted lobectomy.

OBJECTIVES: Digital chest drainage systems allow real-time and continuous monitoring and recording of air leak flow rate and intrapleural pressure (IPP) from the immediate postoperative period to the chest drainage removal. A multicentre retrospective observational analysis of consecutive patients undergoing pulmonary lobectomy for lung cancer was performed to evaluate the association between the airflow and IPP digitally recorded during the immediate postoperative period after video-assisted thoracic surgery (VATS) lobectomy for lung cancer. Here, we present a work in progress report. METHODS: All patients treated with VATS lobectomies for lung cancer were included. Multiple airflow measurements and minimum and maximum IPP through the chest tubes were digitally monitored and recorded using microelectronic mechanical sensor technology. The PALs were defined as an air leak lasting >5 days from the conclusion of the surgical procedure. The cessation of air leaks was defined as an airflow <10 ml/min during 6 consecutive hours. RESULTS: This analysis comprised 76 patients who underwent VATS lobectomy for lung cancer. Nineteen patients (25%) showed prolonged air leaks (PAL) (≥5 days). The operative time was higher in the PAL group (mean difference = 44 min) without a statistically significant difference. Before the 7th postoperative hours, there were no statistically significant differences in IPPs. CONCLUSIONS: Patients with PAL showed less negative IPP in the first 24 postoperative hours. Therefore, the 7th-24th postoperative hours were critical in PAL prediction since the mechanism for PAL seems to develop after the 7th postoperative hour.

Are Thoracic Wall Blocks Efficient After Video-Assisted Thoracoscopy Surgery-Lobectomy Pain? A Comparison Between Serratus Anterior Plane Block and Intercostal Nerve Block.

OBJECTIVES: Video-assisted thoracoscopy surgery-lobectomy is less invasive than conventional thoracotomy and is associated with fewer complications. However, the pain related is classified as moderate and requires adequate treatment. Ultrasound-guided serratus anterior plane block (SAPB) provides analgesia by blocking the lateral branches of the intercostal nerves, avoiding the complications of epidural analgesia and paravertebral block. The aim of the present study was to evaluate the efficacy and safety of the SAPB compared with the intercostal nerve block (ICNB). DESIGN: This was a non-randomized prospective study, in which surgery-lobectomy pain after video-assisted thoracoscopy was treated with the following multimodal approach: SAPB or ICNB, morphine-patient controlled analgesia, and paracetamol. SETTING: The study was undertaken in a single community hospital. PARTICIPANTS: The study comprised 40 patients. INTERVENTIONS: Execution of ultrasound-guided SAPB. MEASUREMENTS AND MAIN RESULTS: Nineteen (47.5%) men and 21 (52.5%) women were enrolled, and the mean age was 67.22 ± 11 years. Both groups showed any visual analog scale values >4, which was significantly lower in the SAPB group at the 6th hour and at the 12th and 24th hours only during coughing (p < 0.05). The sedation score was significantly lower in the ICNB group at 0 and at the 2nd and 4th hours; it was lower in the SAPB group at the 6th hour. All patients had a sedation score <1, and they all were awake and oriented. After 24 hours, the total morphine requirement was 19.3 ± 14.4 mg and 11.3 ± 8.5 mg (p = 0.038); after 48 hours, it was 12.2 ± 7.9 mg and 8.2 ± 5.8 mg in the ICNB and SAPB groups, respectively. CONCLUSIONS: The multimodal approach of SAPB, morphine-patient controlled analgesia, and paracetamol is effective, safe, and time efficient.

Predicting a Prolonged Air Leak After Video-Assisted Thoracic Surgery, Is It Really Possible?

Validation of predictive risk models for prolonged air leak (PAL) is essential to understand if they can help to reduce its incidence and complications. This study aimed to evaluate both the clinical and statistical performances of 4 existing models. We selected 4 predictive PAL risk models based on their scientific relevance. We referred to these models as Chicago, Bordeaux, Leeds and Pittsburgh model, respectively, according to the affiliation place of the first author. These predicting risk models were retrospectively applied to patients recorded on the second edition of the Italian Video-Assisted Thoracoscopic Surgery Group registry. Predictions for each patient were calculated based on the logistic regression coefficient values provided in the original manuscripts. All models were tested for their overall performance, discrimination, and calibration. We recalibrated the original models with the re-estimation of the model intercept and slope. We used curve decision analysis to describe and compare the clinical effects of the studied risk models. Better statistical metrics characterize the models developed on larger populations (Chicago and Bordeaux models). However, no model has a valid benefit for threshold probability greater than 0.30. The Net benefit of the most performing model (Bordeaux model) at the threshold probability of 0.11 is 23 of 1000 patients, burdened by 333 false positive cases. One of 1000 is the Net benefit at the threshold probability of 0.3. The use of PAL scores based on preoperative predictive factors cannot be currently used in a clinical setting because of a high false positive rate and low positive predictive value.

Intraoperative complications during VATS lobectomies from conversion to minimally-invasive "trouble-shooting".

The aim of this study was to explore intraoperative complications during video-assisted thoracoscopic surgery (VATS) lobectomy. Vascular and bronchial injuries, after a robust learning curve, can be sometimes successfully managed by VATS. During a VATS lobectomy, it is necessary: to be prepared in potentially dangerous situations; to think about strategies to handle intraoperative complications and to share these strategies with your own staff. Herein we present some videos showing cases where vascular injuries led to conversion and others where a minimally-invasive trouble shooting of intraoperative complications was achieved.

Surgery for T4 lung cancer invading the thoracic aorta: Do we push the limits?

BACKGROUND: Few investigators have described en bloc resection of non-small cell lung cancer (NSCLC) invading the aorta. AIM OF STUDY: Analysis of outcome and prognostic factors for en bloc resections of NSCLC invading the aorta. METHODS: Thirty-five patients (27 males, 8 females; mean age 63 ± 8.6 years) were operated between 1994 and 2015 in four European Centers. HISTOLOGY: 12 (34.3%) squamous cell carcinoma, and 6 (17.1%) undifferentiated/large cell carcinoma. The site of aortic infiltration was the descending thoracic aorta in 24 (68.6%) patients, the aortic arch in 9 (25.7%), and the aortic arch and supraortic trunks in 2 (5.7%). RESULTS: Lung resection consisted of pneumonectomy in 19 (54.3%) patients and lobectomy in 16 (45.7%). Aortic resection management was undertaken by endograft positioning (37.1%), subadventitial dissection (37.1%), cardiopulmonary/aorto-aortic bypass (17.2%), and direct clamping (8.6%). A tubular graft replacement was carried out in five cases, a synthetic patch repair in 6. Mortality was 2.9%, morbidity 37.1%. Patients undergoing pneumonectomy had a significantly higher morbidity rate compared with lobectomy (52% vs 18.7%; P = 0.003), although patients managed with aortic endografting had a lower complication rate. Median overall and disease-free survival rates were 31.3 and 22.2 months, respectively. Gender and site of aortic infiltration were independent prognostic factors. CONCLUSIONS: Resection of NSCLC combined with an infiltrated aorta is a challenging procedure that can be performed with reasonable morbidity and mortality in highly selected patients.

Can a standardised Ventilation Mechanical Test for quantitative intraoperative air leak grading reduce the length of hospital stay after video-assisted thoracoscopic surgery lobectomy?

We standardised a Ventilation Mechanical Test (VMT) after video-assisted thoracoscopic surgery (VATS) lobectomy that classifies intraoperative alveolar air leaks (IOAALs) in mild, moderate and severe. We assumed that mild IOAALs (<100 mL/min) are self-limiting, whereas severe IOAALs (>400 mL/min) must be treated. An IOAAL between 100 and 400 mL/min was defined moderate and constituted the study population of a prospective multicentre randomised trial on the use of a polymeric biodegradable sealant (ProgelTM Pleural Air Leak Sealant, Bard Davol, USA) in case of moderate IOAAL compared with no treatment. We assumed that the standardised VMT allows to accurately selected patients needing treatment, thus limiting unnecessary sealant use. We analysed data of the randomised trial to assess the cost-effectiveness of Progel treatment in VMT selected patients. This is a multicenter randomised controlled trial. Patients with moderate IOAAL were randomised to Progel (group A) or "no treatment" (group B).The primary efficacy endpoint of the study was the postoperative duration of air leakage. The secondary outcome measures included: mean time to chest drain removal, mean length of hospitalisation, the percentage of postoperative complications occurring within two months, and cost of treatment. Between January 2015 and January 2017, 255 VATS lobectomies were performed in 4 centres, 55 met the inclusion criteria, and they were randomly assigned to 2 different groups (28 in the Progel and 27 in the control group). The mean air leakage duration was statistically different between the two groups: in the group A was 1.60 vs. 5.04 days in group B (P<0.001). The average duration of chest drainage was statistically shorter in group A than in the control group (4.1 vs. 6.74 days; P=0.008). The mean time to hospital discharge was also statistically shorter in group A than in group B (5.75 vs. 7.85 days, P=0.026). In the Progel group, a statistically significant reduction of hospitalisation costs compared with the control group was observed (Progel group =12,905£, Control group =39,690£; P<0.001). Our standardised VMT helps in reducing the length of hospital stay after VATS lobectomy because in case of IOAALs between 100 and 400 mL/min the use of ProgelTM significantly reduces postoperative air leak, time to drain removal and length of hospitalisation compared with no treatment. This shorter hospital stays results in significant cost saving benefits. Selection of patients with standardised VMT is essential to limit unnecessary intraoperative sealant treatments, thus contributing to limit the costs.

Cost-effectiveness analysis of sealant impact in management of moderate intraoperative alveolar air leaks during video-assisted thoracoscopic surgery lobectomy: a multicentre randomised controlled trial.

BACKGROUND: Intraoperative alveolar air leak (IOAAL) is one of most common complications after video-assisted thoracoscopic surgery (VATS) lobectomy. The study aimed to evaluate if, in moderate IOAAL, intraoperative polymeric biodegradable sealant (ProgelTM) reduced postoperative air leak (PAL) and consequently was cost-effective. METHODS: Patients with moderate IOAAL were randomised in a multicentre trial to intraoperative use of a sealant (Sealant group) or standard management of air leaks (Control group). Primary endpoint was the postoperative duration of air leakage. Secondary outcomes included: time to drainage removal, length of hospital stay, postoperative complications within 2 months, and cost analysis. RESULTS: Between January 2015 and January 2017, 255 VATS lobectomies were performed in four centres. Fifty-five met inclusion criteria and were randomly assigned to Sealant group [28] and Control group [27]. The mean air leakage duration was statistically different between groups (Sealant group =1.60 days, Control group =5.04 days; P<0.001). The average length of drainage was significantly (P=0.008) shorter in Sealant group (4.1 days) than in Controls (6.74 days). The mean time of hospital stay was statistically shorter in sealant group (Sealant =5.75 days, Control =7.85 days; P=0.026). Sealant group observed a statistically significant reduction of costs. CONCLUSIONS: In moderate IOAAL after VATS lobectomy, polymeric biodegradable sealants are safe and efficient. Compared with standard treatments, sealant significantly reduces PAL, time to drain removal and length of hospital stay resulting in significant costs benefits.

Endovascular repair of a paraanastomotic aneurysm with inverted limb infrarenal bifurcated graft.

A typical complication after conventional aortic prosthetic reconstruction is paraanastomotic aneurysm formation. Endovascular exclusion of paraanastomotic aneurysms has been shown to be a viable alternative to open surgical repair and to greatly reduce morbidity and mortality rates. We present a case report of asymptomatic proximal anastomotic pseudoaneurysm, measuring 4.5 cm in diameter, that was successfully treated by endovascular repair with a custom-made inverted limb infrarenal bifurcated graft.

Impact of the IASLC/ATS/ERS classification in pN0 pulmonary adenocarcinomas: a study with radiological-pathological comparisons and survival analyses.

The aim of this study was: (1) to compare the new pathological findings as detected by the IASLC/ATS/ERS classification with the traditional radiological features in pulmonary pN0 adenocarcinomas, (2) to evaluate their prognostic significance on overall survival (OS). A total of 42 surgically resected pN0 pulmonary adenocarcinomas were analyzed. On CT scans, the following radiological data were recorded: sphericity, predominant margins, cavitation and bronchogram, attenuation and percentage of ground glass opacity (GGO). On pathological examination, tumors were categorized according to the IASLC/ATS/ERS classification; Sica score and grade, pathological stage, tumor major axis, pleural invasion, vascular and lymphatic invasion, peritumoral lymphoid infiltration, and cytological features were also determined. Clinical follow up was available in 37 cases (range 1-117 months). Radiologically, 31 solid and 11 semisolid tumors were found. Morphologically, 2 minimally invasive and 40 invasive adenocarcinomas were diagnosed. In radiological-pathological comparisons, (1) the acinar pattern was higher in tumors with solid attenuation and low GGO (p=0.018); (2) the lepidic pattern was more elevated in tumors with high GGO (p=0.012). In multivariate survival analyses with stage, predominant margins on CT scans (p=0.036) and Sica score (p=0.028) significantly affected OS. This study confirms the validity of the new classification of pulmonary adenocarcinomas in radiological-pathological comparisons and underlines the importance of both radiological and pathological findings in correctly identifying their prognostic features.