Multidisciplinary Decision-Making-ITAlian Consensus After Two Years of Real Practice on the Management of Severe Uncontrolled CRSwNP by Biologics (ITACA Study).

PURPOSE OF REVIEW: We aimed to reach an Italian multidisciplinary consensus on some crucial aspects of treatment decision making in CRSwNP, following 2 years of clinical experience in order to support specialists in the management of CRSwNP in clinical practice. We addressed issues relating to therapeutic decision-making and shared criteria for the treatment choice, as well as appropriate timing and criteria for evaluating treatment response, and highlighted the need for repeated multidisciplinary assessments. RECENT FINDINGS: A national survey has been conducted recently to understand how rhinology practice has changed in Italy with the advent of biologics and how this affects patients with uncontrolled, severe CRSwNP. Despite the many published consensus documents, practical recommendations, and protocols on the use of biologics in CRSwNP, heterogenous behaviors in practice are still observed mainly conditioned by the novelty of the topic. The consensus procedure followed a modified Delphi approach. The scientific board included 18 otorhinolaryngologists and 8 allergists, who selected the 4 main topics to be addressed and developed overall 20 statements. Consensus on these statements was sought by a larger group of 48 additional experts, through two rounds of voting, the first web-based, the second in presence with discussion and possible refinement of the statements. The statements reaching an average score ≥ 7 at the second voting round were approved. Five statements were proposed for each of the following topics: baseline evaluation of patients eligible for biologic therapy; choice between different therapeutic options; assessment of the response to biologic treatment; multidisciplinary management. At the first voting round, 19 out of the 20 statements reached a mean score ≥ 7. Following the discussion and a few consequent amendments, at the second round of voting all the 20 statements were approved.

Computer-aided designed 3D-printed polymeric scaffolds for personalized reconstruction of maxillary and mandibular defects: a proof-of-concept study.

PURPOSE: To investigate the potential reconstruction of complex maxillofacial defects using computer-aided design 3D-printed polymeric scaffolds by defining the production process, simulating the surgical procedure, and explore the feasibility and reproducibility of the whole algorithm. METHODS: This a preclinical study to investigate feasibility, reproducibility and efficacy of the reconstruction algorithm proposed. It encompassed 3 phases: (1) scaffold production (CAD and 3D-printing in polylactic acid); (2) surgical simulation on cadaver heads (navigation-guided osteotomies and scaffold fixation); (3) assessment of reconstruction (bone and occlusal morphological conformance, symmetry, and mechanical stress tests). RESULTS: Six cadaver heads were dissected. Six types of defects (3 mandibular and 3 maxillary) with different degree of complexity were tested. In all case the reconstruction algorithm could be successfully completed. Bone morphological conformance was optimal while the occlusal one was slightly higher. Mechanical stress tests were good (mean value, 318.6 and 286.4 N for maxillary and mandibular defects, respectively). CONCLUSIONS: Our reconstructive algorithm was feasible and reproducible in a preclinical setting. Functional and aesthetic outcomes were satisfactory independently of the complexity of the defect.

Training models and simulators for endoscopic transsphenoidal surgery: a systematic review.

Endoscopic transsphenoidal surgery is a novel surgical technique requiring specific training. Different models and simulators have been recently suggested for it, but no systematic review is available. To provide a systematic and critical literature review and up-to-date description of the training models or simulators dedicated to endoscopic transsphenoidal surgery. A search was performed on PubMed and Scopus databases for articles published until February 2023; Google was also searched to document commercially available. For each model, the following features were recorded: training performed, tumor/arachnoid reproduction, assessment and validation, and cost. Of the 1199 retrieved articles, 101 were included in the final analysis. The described models can be subdivided into 5 major categories: (1) enhanced cadaveric heads; (2) animal models; (3) training artificial solutions, with increasing complexity (from "box-trainers" to multi-material, ct-based models); (4) training simulators, based on virtual or augmented reality; (5) Pre-operative planning models and simulators. Each available training model has specific advantages and limitations. Costs are high for cadaver-based solutions and vary significantly for the other solutions. Cheaper solutions seem useful only for the first stages of training. Most models do not provide a simulation of the sellar tumor, and a realistic simulation of the suprasellar arachnoid. Most artificial models do not provide a realistic and cost-efficient simulation of the most delicate and relatively common phase of surgery, i.e., tumor removal with arachnoid preservation; current research should optimize this to train future neurosurgical generations efficiently and safely.

Regional disease in head and neck cutaneous squamous cell carcinoma: the role of primary tumor characteristics and number of nodal metastases.

PURPOSE: To identify potential risk factors impacting on overall survival (OS) of patients affected by lymph node metastasis from cutaneous squamous cell carcinoma (cSCC) of the head and neck (HN), with special emphasis on primary tumor characteristics and pattern of nodal recurrence (intraparotid and/or cervical). METHODS: A bi-institutional retrospective study on consecutive patients affected by cervical and/or intraparotid NM from HN cSCC and surgically treated with curative intent from May 2010 to January 2020 was conducted. OS was considered the outcome of interest. RESULTS: The study included 89 patients (M:F = 3.4:1; median age, 78 years; range, 22-99). Among the primary tumor characteristics, the most relevant prognostic factors were diameter ≥ 4 cm (hazard ratio [HR] = 2.56, p = 0.010) and depth of infiltration ≥ 6 mm (HR = 3.54, p = 0.027). Cervical NM was associated with worse OS (HR = 2.09, p = 0.016) compared to purely intraparotid NM (5-year OS: 60.9% vs. 28.1%, p = 0.014). At multivariable analysis, age, immunosuppression, pT3-T4 categories and a high burden of nodal disease (> 2 NM) confirmed to be independent risk factors, whereas adjuvant radiotherapy was independently associated with better outcome. CONCLUSION: This study confirms the association of several independent prognosticators related to the patient, primary tumor, and nodal burden status. Patients with cervical NM should be considered at risk for harboring a higher number of metastatic lymph nodes.

Transclival approaches for intradural pathologies: historical overview and present scenario.

Recently, endoscopic transsphenoidal transclival approaches have been developed and their role is widely accepted for extradural pathologies. Their application to intradural pathologies is still debated, but is undoubtedly increasing. In the past five decades, different authors have reported various extracranial, anterior transclival approaches for intradural pathologies. The aim of this review is to provide a historical overview of transclival approaches applied to intradural pathologies. PubMed was searched in October 2018 using the terms transcliv*, cliv* intradural, transsphenoidal transcliv*, transoral transcliv*, transcervical transcliv*, transsphenoidal brainstem, and transoral brainstem. Exclusion criteria included not reporting reconstruction technique, anatomical studies, reviews without new data, and transcranial approaches. Ninety-one studies were included in the systematic review. Since 1966, transcervical, transoral, transsphenoidal microsurgical, and, recently, endoscopic routes have been used as a corridor for transclival approaches to treat intradural pathologies. Each approach presents a curve that follows Scott's parabola, with evident phases of enthusiasm that quickly faded, possibly due to high post-operative CSF leak rates and other complications. It is evident that the introduction of the endoscope has led to a significant increase in reports of transclival approaches for intradural pathologies. Various reconstruction techniques and materials have been used, although rates of CSF leak remain relatively high. Transclival approaches for intradural pathologies have a long history. We are now in a new era of interest, but achieving effective dural and skull base reconstruction must still be definitively addressed, possibly with the use of newly available technologies.

Transorbital endoscopic approaches to the skull base: a systematic literature review and anatomical description.

Transorbital endoscopic approaches are increasing in popularity as they provide corridors to reach various areas of the ventral skull base through the orbit. They can be used either alone or in combination with different approaches when dealing with the pathologies of the skull base. The objective of the current study is to evaluate the surgical anatomy of transorbital endoscopic approaches by cadaver dissections as well as providing objective clinical data on their actual employment and morbidity through a systematic review of the current literature. Four cadaveric specimens were dissected, and step-by-step dissection of each endoscopic transorbital approach was performed to identify the main anatomic landmarks and corridors. A systematic review with pooled analysis of the current literature from January 2000 to April 2020 was performed and the related studies were analyzed. Main anatomical landmarks are presented based on the anatomical study and systematic review of the literature. With emphasis on the specific transorbital approach used, indications, surgical technique, and complications are reviewed through the systematic review of 42 studies (19 in vivo and 23 anatomical dissections) including 193 patients. In conclusion, transorbital endoscopic approaches are promising and appear as feasible techniques for the surgical treatment of skull base lesions. Surgical anatomy of transorbital endoscopic approaches can be mastered through knowledge of a number of anatomical landmarks. Based on data available in the literature, transorbital endoscopic approaches represent an important complementary that should be included in the armamentarium of a skull base team.

Skull base osteomyelitis: clinical and radiologic analysis of a rare and multifaceted pathological entity.

Skull base osteomyelitis (SBO) is a potentially life-threatening inflammation of cranial base bony structures of variable origin. Criteria for diagnosis and treatment are still controversial. Demographics, predisposing factors, symptoms, imaging, and clinical, laboratory, histological, and microbiological data of patients managed for SBO at the University Hospital of Brescia (ASST Spedali Civili) between 2002 and 2017 were retrospectively reviewed. Patients were included in different etiological groups. The topographic distribution of magnetic resonance (MR) abnormalities was recorded on a bi-dimensional model of skull base, on which three different patterns of inflammatory changes (edematous, solid, or necrotic) were reported. In patients with a history of radiotherapy, the spatial distribution of SBO was compared with irradiation fields. The association between variables and etiological groups was verified with appropriate statistical tests. A classification tree analysis was performed with the aim of inferring a clinical-radiological diagnostic algorithm for SBO. The study included 47 patients, divided into 5 etiological groups: otogenic (n = 5), radio-induced (n = 16), fungal (n = 14), immune-mediated (n = 6), and idiopathic (n = 6). At MR, five types of topographical distribution were identified (central symmetric, central asymmetric, orbital apex, sinonasal, maxillary). In patients with a history of radiotherapy, the probability to develop SBO was significantly increased in areas receiving the highest radiation dosage. The analysis of patients allowed for design of a classification tree for the diagnosis of SBO. The integration of clinical and radiologic information is an efficient strategy to categorize SBO and potentially guide its complex management.

Paranasal mucoceles in children with cystic fibrosis: Management of a not so rare clinical condition.

PURPOSE: Paranasal mucocele (PM) is reported as a complication in children with cystic fibrosis (CF) in up to 4% of patients. The objective of this study was to identify PMs in the personal large series of children with CF and to assess their diagnosis and treatment. MATERIAL AND METHODS: Medical records of children with CF and PM who were admitted and treated by means of endoscopic nasal surgery between 2004 and 2020 were retrospectively reviewed. RESULTS: Thirty-four patients were included in the study (mean age 7.7 years). CT scan of sinuses showed a total of 53 PMs. Nasal endoscopic findings suggestive for PM were present in almost 80% of patients. PMs were located in the maxillary, ethmoid, and sphenoid sinuses in 29/34 (85.3%, bilateral in 17 cases), 4/34 (11.8%) and 1/34 (2.9%) patients, respectively. Marsupialization of PMs was performed in all patients using an endoscopic transnasal approach. No complications were observed. Resolution of symptoms and normalization of the endoscopic nasal picture was evident in all patients. After a mean follow-up of 85 months, no recurrences were observed. CONCLUSIONS: To the best of our knowledge, this is the largest series of CF patients with PMs. Even if not frequently reported in the literature, PMs should not be considered an uncommon finding in patients affected by CF. Routine nasal endoscopy is mandatory to favor early diagnosis. Endoscopic transnasal marsupialization represents the gold standard of care for patients with CF and PM(s).

Management of sinonasal adenocarcinomas with anterior skull base extension.

INTRODUCTION: Sinonasal adenocarcinomas (SNAC) are rare and heterogeneous. Management of SNAC follows a rather standardized and internationally accepted paradigm. Several refinements have been introduced during the last decade. METHODS: A narrative review of most updated literature on SNACs has been conducted. RESULTS: SNACs are classified as intestinal-type and non-intestinal-type, which are further categorized according to grade. Preoperative work-up should include magnetic resonance imaging (or contrast-enhanced computed tomography as a secondary or complementary choice) and biopsy under general anesthesia, or under local anesthesia in case of a history of exposure to wood and/or leather dust. Positron emission tomography, neck ultrasound, and fine-needle aspiration cytology are indicated in selected cases. Surgery represents the most common upfront modality of treatment and is usually accomplished via a transnasal endoscopic approach. Adjuvant radiation therapy is indicated for high-grade, locally advanced tumors and/or in case of margins involvement. Neoadjuvant chemotherapy with cisplatin, 5-fluorouracil and leucovorin may offer high response rates and long-term control in a subgroup of patients affected by intestinal-type adenocarcinoma, and in particular in those whose tumors harbor a functional p53 protein. Most of the bio- and immune-therapeutic potentials on SNACs still remain theoretical, and no clinical data are currently available. CONCLUSIONS: Management of SNAC consists of histological diagnosis, radiological staging, radical surgery, and adjuvant radiation therapy. Neoadjuvant chemotherapy can be indicated in selected cases. The role of biotherapy and immune therapy still needs to be elucidated.

Pituitary adenomas and neuropsychological status: a systematic literature review.

Neurocognitive and psychological dysfunctions associated with pituitary adenomas (PAs) are clinically relevant, though probably under-reported. The aim of the current review is to provide an update on neuropsychological status, psychopathology, and perceived quality of life (QoL) in patients with PAs. A systematic research was performed in PubMed and Scopus in order to identify reports on neurocognitive, psychiatric, and psychological disorders in PAs. Prevalence of alterations, QoL evaluation, and used tests were also recorded. PRISMA guidelines were followed. Of 62,448 identified articles, 102 studies were included in the systematic review. The prevalence of neurocognitive dysfunctions was 15-83% in Cushing's Disease (CD), 2-33% in acromegaly, mostly affecting memory and attention. Memory was altered in 22% of nonfunctioning (NF) PAs. Worsened QoL was reported in 40% of CD patients. The prevalence of psychiatric disorders in CD reached 77% and in acromegaly 63%, mostly involving depression, followed by psychosis, and anxiety. The prevalence of psychopathology was up to 83% in CD, and 35% in acromegaly. Postoperative improvement in patients with CD was observed for: learning processes, overall memory, visuospatial skills, and language skills. Short-term memory and psychomotor speed improved in NFPAs. Postoperative improvement of QoL, somatic symptoms, obsessive-compulsive disorder, and coping strategies was seen in CD and acromegaly. Reports after radiotherapy are discordant. There is wide variability in used tests. PAs have been recently shown to be associated with altered neurocognitive and neuropsychological functions, as well as QoL. These data suggest the importance of a multidisciplinary evaluation for an optimal management.

Quantitative anatomical comparison of transnasal and transcranial approaches to the clivus.

BACKGROUND AND OBJECTIVE: The clivus was defined as "no man's land" in the early 1990s, but since then, multiple approaches have been described to access it. This study is aimed at quantitatively comparing endoscopic transnasal and microsurgical transcranial approaches to the clivus in a preclinical setting, using a recently developed research method. METHODS: Multiple approaches were performed in 5 head and neck specimens that underwent high-resolution computed tomography (CT): endoscopic transnasal (transclival, with hypophysiopexy and with far-medial extension), microsurgical anterolateral (supraorbital, mini-pterional, pterional, pterional transzygomatic, fronto-temporal-orbito-zygomatic), lateral (subtemporal and subtemporal transzygomatic), and posterolateral (retrosigmoid, far-lateral, retrolabyrinthine, translabyrinthine, and transcochlear). An optic neuronavigation system and dedicated software were used to quantify the working volume of each approach and calculate the exposure of different clival regions. Mixed linear models with random intersections were used for statistical analyses. RESULTS: Endoscopic transnasal approaches showed higher working volume and larger exposure compared with microsurgical transcranial approaches. Increased exposure of the upper clivus was achieved by the transnasal endoscopic transclival approach with intradural hypophysiopexy. Anterolateral microsurgical transcranial approaches provided a direct route to the anterior surface of the posterior clinoid process. The transnasal endoscopic approach with far-medial extension ensured a statistically larger exposure of jugular tubercles as compared with other approaches. Presigmoid approaches provided a relatively limited exposure of the ipsilateral clivus, which increased in proportion to their invasiveness. CONCLUSIONS: This is the first anatomical study that quantitatively compares in a holistic way exposure and working volumes offered by the most used modern approaches to the clivus.

Primary parotid carcinoma: analysis of risk factors and validation of a prognostic index.

OBJECTIVES: Primary cancer of the parotid gland (PG) is a rare disease characterized by a wide variety of histologies and subtypes. The aim of the study was to identify factors influencing survival and validate the prognostic scores (PS1 and PS2) by Vander Poorten et al. STUDY DESIGN: Retrospective cohort study. METHODS: All patients with previously untreated PG epithelial malignancies who underwent surgery with curative intent from 2002 to 2015 at a single center were retrospectively reviewed. RESULTS: 104 patients were included. Mean age was 60.2 years (range 14-88). Definitive pT staging was: 26 (25%) pT1, 19 (18.3%) pT2, 15 (14.4%) pT3, 41 (39.4%) pT4a, and 3 (2.9%) pT4b. Lateral neck nodal metastases were diagnosed in 27 (26%) patients. Five- and 10-year overall survival was 74.7% and 69.4%, respectively. Disease-specific survival at 5 and 10 years was 80.4% and 76.5%, respectively. Recurrence-free survival at 5 and 10 years was 66.9%. PS-1 and PS-2 scores correlated with prognosis. The most critical prognostic variables were grading, nodal metastases, perineural infiltration, lympho-vascular invasion, and skin infiltration. CONCLUSIONS: Major risk factors in primary PG carcinomas can effectively identify high-risk patients. The prognostic score by Vander Poorten et al. is a highly reliable tool to predict the prognostic profile.

The ethmoidal arteries: a cadaveric study based on cone beam computed tomography and endoscopic dissection.

PURPOSE: To describe the anatomical variability of the ethmoidal arteries (EAs). To evaluate the reliability of cone beam computed tomography (CBCT) in preoperative assessment of EAs. METHODS: Fourteen cadaver heads underwent CBCT and endoscopic dissection. The following anatomical features were evaluated for anterior (AEA), middle (MEA), and posterior (PEA) EAs: presence, cranio-caudal position, antero-posterior position, and dehiscence of the bony canal. Accuracy of radiological assessment was calculated. RESULTS: AEA, MEA, and PEA were identified in 100, 28.6, and 100% of sides. They were caudal to the skull base in 60.7, 25, and 17.9%, respectively. CBCT showed a high accuracy in identifying these features. The antero-posterior position of EAs, which was highly variable, was correctly assessed by CBCT. A dehiscent bony canal of AEA, MEA, and PEA was found in 46.4, 12.5, and 28.6% of sides, respectively. Accuracy of CBCT in picking up this feature was poor but negative predictive value was high. CONCLUSIONS: CBCT was adequate in identifying and localizing EAs. In addition, it can be used to exclude the presence of MEA and dehiscence of ethmoidal canals, whereas the accuracy in detecting these anatomic variants was low.

Compartmental surgery for T4b oral squamous cell carcinoma involving the masticatory space.

PURPOSE OF REVIEW: This review aims to describe the oncological outcomes of T4b oral squamous cell carcinomas (OSCC) with masticatory space involvement as well as the surgical approaches that are able to achieve compartmental 'en bloc' resection of these lesions. RECENT FINDINGS: The masticatory space is subdivided into infra-notch and supra-notch spaces according to the axial plane passing through the mandibular notch between the coronoid process and the condyle neck. Compartmental resection for T4b OSCC with masticatory space invasion can be successfully achieved via purely external approaches or combining external and transnasal endoscopic routes. Infra-notch T4b OSCC showed survival outcomes comparable to T4a OSCC, thus prompting treatment with curative intent. SUMMARY: Compartmental resection of the masticatory space is technically feasible with comprehensive control of tumour margins. Use of a transnasal endoscopic anterior route within a multiportal approach may provide better control of margins at the level of the pterygo-maxillary fissure. Equivalent survival outcomes between T4a and infra-notch T4b OSCC are reported. Thus, a downstaging of the latter to T4a is advisable and compartmental surgery of such advanced lesions could be considered as a first-line treatment option in selected patients.

Measuring financial toxicity in head and neck cancer: a systematic review.

Objective: The current study systematically reviews the literature about financial toxicity (FT) in head and neck cancer patients. Three databases were reviewed: PubMed, Scopus and Web of Science. Methods: Full text English papers published from 2000 to 2022 reporting on quantitative results about FT in head and neck cancer survivors collected through structured questionnaires or interviews were included. Results: Twenty-seven articles were included. Most of the articles were published after 2015 and from United States. There was a slight prevalence of papers dealing with oropharyngeal cancer, squamous-cell carcinoma and locally advanced head and neck cancer. Measures of FT were obtained through validated questionnaires like COST, FIT and FDQ. Collected data were mostly referrable to financial spending, financial resources, psychosocial aspect, support seeking, coping care and coping lifestyle subdomain. FT scores by COST were found to be worse in the COVID era. Financial counseling and adequate information about the costs of treatment were two effective strategies to mitigate FT. Conclusions: FT is a relatively new challenge in head and neck cancer treatment, whose expenses are higher than therapies for other cancers. A universal method to assess FT and a unified guideline for the administration of questionnaires are needed to mitigate FT and to improve patient outcomes.

Stability of circulating miRNA in saliva: The influence of sample associated pre-analytical variables.

BACKGROUND AND AIMS: Increasing evidence supports the practicability of salivary cell-free (cf) miRNA as liquid biopsy markers in cancers. Its successful translation in the clinical setting requires reproducible approaches for saliva manipulation, in order to control for pre-analytical variables influencing miRNA stability. This study aims to define the optimal conditions to maintain the integrity of saliva during collection, transport and processing with respect to cf-miRNA quantification. MATERIALS AND METHODS: Saliva was collected from 20 healthy subjects and 8 oral cancer patients. Two sampling methods were tested and different storage temperatures and times were evaluated. Salivary expression level of target miRNAs was quantified by qPCR. Comparison between group mean values at specific conditions were performed using paired t-tests. Agreement between measurements was evaluated using a Bland-Altman plot. RESULTS: Different collection methods revealed comparable levels of salivary miR-484 and miR-106b-5p in both subject cohorts. MiRNAs were stable for up to 48 h at 4 °C in saliva supernatant, showing significant alteration after 96 h. Mid-term storage of supernatant at -20 °C decreased miRNA stability significantly compared to standard -80 °C. CONCLUSIONS: Cf-miRNA in saliva were slightly altered by collection methods and storage conditions, both in healthy and in pathological contexts, and remained stable for a period of time compatible with main clinical routine needs.

Thyroid cartilage infiltration in advanced laryngeal cancer: prognostic implications and predictive modelling.

Objective: Detection of laryngeal cartilage invasion is of great importance in staging of laryngeal squamous cell carcinoma (LSCC). The role of prognosticators in locally advanced laryngeal cancer are still widely debated. This study aimed to assess the impact of volume of thyroid cartilage infiltration, as well as other histopathologic variables, on patient survival. Materials and methods: We retrospectively analysed 74 patients affected by pT4 LSCC and treated with total laryngectomy between 2005 and 2021 at the Department of Otorhinolaryngology - Head and Neck Surgery of the University of Brescia, Italy. We considered as potential prognosticators histological grade, perineural (PNI) and lympho-vascular invasion (LVI), thyroid cartilage infiltration, and pTN staging. Pre-operative CT or MRI were analysed to quantify the volume of cartilage infiltration using 3D Slicer software. Results: The 1-, 3-, and 5-year disease free survivals (DFS) were 76%, 66%, and 64%, respectively. Using machine learning models, we found that the volume of thyroid cartilage infiltration had high correlation with DFS. Patients with a higher volume (>670 mm3) of infiltration had a worse prognosis compared to those with a lower volume. Conclusions: Our study confirms the essential role of LVI as prognosticator in advanced LSCC and, more innovatively, highlights the volume of thyroid cartilage infiltration as another promising prognostic factor.

MRI radiomics in head and neck cancer from reproducibility to combined approaches.

The clinical applicability of radiomics in oncology depends on its transferability to real-world settings. However, the absence of standardized radiomics pipelines combined with methodological variability and insufficient reporting may hamper the reproducibility of radiomic analyses, impeding its translation to clinics. This study aimed to identify and replicate published, reproducible radiomic signatures based on magnetic resonance imaging (MRI), for prognosis of overall survival in head and neck squamous cell carcinoma (HNSCC) patients. Seven signatures were identified and reproduced on 58 HNSCC patients from the DB2Decide Project. The analysis focused on: assessing the signatures' reproducibility and replicating them by addressing the insufficient reporting; evaluating their relationship and performances; and proposing a cluster-based approach to combine radiomic signatures, enhancing the prognostic performance. The analysis revealed key insights: (1) despite the signatures were based on different features, high correlations among signatures and features suggested consistency in the description of lesion properties; (2) although the uncertainties in reproducing the signatures, they exhibited a moderate prognostic capability on an external dataset; (3) clustering approaches improved prognostic performance compared to individual signatures. Thus, transparent methodology not only facilitates replication on external datasets but also advances the field, refining prognostic models for potential personalized medicine applications.