Lipid Nanovesicle Platforms for Hepatocellular Carcinoma Precision Medicine Therapeutics: Progress and Perspectives.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality globally. HCC is highly heterogenous with diverse etiologies leading to different driver mutations potentiating unique tumor immune microenvironments. Current therapeutic options, including immune checkpoint inhibitors and combinations, have achieved limited objective response rates for the majority of patients. Thus, a precision medicine approach is needed to tailor specific treatment options for molecular subsets of HCC patients. Lipid nanovesicle platforms, either liposome- (synthetic) or extracellular vesicle (natural)-derived present are improved drug delivery vehicles which may be modified to contain specific cargos for targeting specific tumor sites, with a natural affinity for liver with limited toxicity. This mini-review provides updates on the applications of novel lipid nanovesicle-based therapeutics for HCC precision medicine and the challenges associated with translating this therapeutic subclass from preclinical models to the clinic.

Lymphatic endothelial-like cells promote glioblastoma stem cell growth through cytokine-driven cholesterol metabolism.

Glioblastoma is the most lethal primary brain tumor with glioblastoma stem cells (GSCs) atop a cellular hierarchy. GSCs often reside in a perivascular niche, where they receive maintenance cues from endothelial cells, but the role of heterogeneous endothelial cell populations remains unresolved. Here, we show that lymphatic endothelial-like cells (LECs), while previously unrecognized in brain parenchyma, are present in glioblastomas and promote growth of CCR7-positive GSCs through CCL21 secretion. Disruption of CCL21-CCR7 paracrine communication between LECs and GSCs inhibited GSC proliferation and growth. LEC-derived CCL21 induced KAT5-mediated acetylation of HMGCS1 on K273 in GSCs to enhance HMGCS1 protein stability. HMGCS1 promoted cholesterol synthesis in GSCs, favorable for tumor growth. Expression of the CCL21-CCR7 axis correlated with KAT5 expression and HMGCS1K273 acetylation in glioblastoma specimens, informing patient outcome. Collectively, glioblastomas contain previously unrecognized LECs that promote the molecular crosstalk between endothelial and tumor cells, offering potentially alternative therapeutic strategies.

Mutational landscape and predictors of survival in head and neck mucosal melanoma.

KEY POINTS: Head and neck mucosal melanomas have a diverse mutational landscape with low mutational burden. A molecular subset (∼13%) has ROS1 mutations, which is an actionable driver mutation. ROS1-mutated patients have improved overall survival likely due to high mutational burden.

Battle of the biopsies: Role of tissue and liquid biopsy in hepatocellular carcinoma.

The diagnosis and management of hepatocellular carcinoma (HCC) have improved significantly in recent years. With the introduction of immunotherapy-based combination therapy, there has been a notable expansion in treatment options for patients with unresectable HCC. Simultaneously, innovative molecular tests for early detection and management of HCC are emerging. This progress prompts a key question: as liquid biopsy techniques rise in prominence, will they replace traditional tissue biopsies, or will both techniques remain relevant? Given the ongoing challenges of early HCC detection, including issues with ultrasound sensitivity, accessibility, and patient adherence to surveillance, the evolution of diagnostic techniques is more relevant than ever. Furthermore, the accurate stratification of HCC is limited by the absence of reliable biomarkers which can predict response to therapies. While the advantages of molecular diagnostics are evident, their potential has not yet been fully harnessed, largely because tissue biopsies are not routinely performed for HCC. Liquid biopsies, analysing components such as circulating tumour cells, DNA, and extracellular vesicles, provide a promising alternative, though they are still associated with challenges related to sensitivity, cost, and accessibility. The early results from multi-analyte liquid biopsy panels are promising and suggest they could play a transformative role in HCC detection and management; however, comprehensive clinical validation is still ongoing. In this review, we explore the challenges and potential of both tissue and liquid biopsy, highlighting that these diagnostic methods, while distinct in their approaches, are set to jointly reshape the future of HCC management.

Impact of Treatment Modalities upon Survival Outcomes in Skull Base and Clival Chordoma: An NCDB Analysis.

Objectives Skull base chordomas are locally aggressive malignant tumors derived from the notochord remnant. There are limited large-scale studies examining the role and extent of surgery and radiation therapy. Design Analysis of the National Cancer Database (NCDB) was performed to evaluate the survival outcomes of various treatments, and to assess for predictors of overall survival (OS). Participants This is a retrospective, population-based cohort study of patients diagnosed with a clival/skull base chordoma between 2004 and 2015 in the NCDB. Main Outcome Measures The primary outcome was overall survival (OS). Results In all, 468 cases were identified. Forty-nine percent of patients received surgery and 20.7% had positive margins. Mean age at diagnosis was 48.4 years in the surgical cohort, and 55% were males. Of the surgical cohort, 33.8% had negative margins, 20.7% had positive margins, and 45.5% had unknown margin status. Age ≥ 65 (hazard ratio [HR]: 3.07; 95% confidence interval [CI]: 1.63-5.76; p < 0.001), diagnosis between 2010 and 2015 (HR: 0.49; 95% CI: 0.26-0.90; p = 0.022), tumor size >5 cm (HR: 2.29; 95% CI: 1.26-4.15; p = 0.007), and government insurance (HR: 2.28; 95% CI: 1.24-4.2; p = 0.008) were independent predictors of OS. When comparing surgery with or without adjuvant radiation, no survival differences were found, regardless of margin status ( p = 0.66). Conclusion Surgery remains the mainstay of therapy. Advanced age (>65 years), large tumor size, and government insurance were predictors of worse OS. Whereas negative margins and the use of adjuvant radiation did not appear to impact OS, these may very well reduce local recurrences. A multidisciplinary approach is critical in achieving optimal outcomes in this challenging disease.

Refusal of Surgery in Pituitary Adenoma Patients: A Population-Based Analysis.

We characterized the clinical and sociodemographic factors predictive of surgery refusal in pituitary adenoma (PA) patients. We queried the National Cancer Database (NCDB) to identify adult PA patients treated from 2004−2015 receiving or refusing surgery. Multivariate logistic regression and Cox proportional-hazards analysis identified clinical and/or sociodemographic factors predictive of surgery refusal or mortality, respectively. Of the 34,226 patients identified, 280 (0.8%) refused surgery. On multivariate logistic regression, age > 65 (OR: 2.64; p < 0.001), African American race (OR: 1.70; p < 0.001), Charlson-Deyo Comorbidity (C/D) Index > 2 (OR: 1.52; p = 0.047), and government insurance (OR: 2.03; p < 0.001) or being uninsured (OR: 2.16; p = 0.03) were all significantly associated with surgery refusal. On multivariate cox-proportional hazard analysis, age > 65 (HR: 2.66; p < 0.001), tumor size > 2 cm (HR: 1.30; p < 0.001), C/D index > 1 (HR: 1.53; p < 0.001), having government insurance (HR: 1.66; p < 0.001) or being uninsured (HR: 1.67; p < 0.001), and surgery refusal (HR: 2.28; p < 0.001) were all significant predictors of increased mortality. Macroadenoma patients receiving surgery had a significant increase in overall survival (OS) compared to those who refused surgery (p < 0.001). There are significant sociodemographic factors that influence surgery refusal in PA patients. An individualized approach is warranted that considers functional status, clinical presentations, and patient choice.

Treatment selection towards active surveillance over definitive treatment for pituitary adenomas is influenced by sociodemographic factors.

BACKGROUND: Clinical and sociodemographic predictors of pituitary adenoma (PA) patients undergoing active surveillance (AS) versus definitive treatment (DT) are poorly understood. OBJECTIVE: This population-based analysis aims to identify clinical and sociodemographic predictors of undergoing AS versus DT. METHODS: The National Cancer Database (NCDB) was utilized to query PA patients diagnosed from 2010 to 2015 undergoing AS or DT. Independent-samples t-test and chi-squared test were used to compare differences in patient baseline characteristics and a stepwise binary logistic regression was performed to elucidate factors implicated in undergoing AS. RESULTS: The cohort consisted of 30,233 PA patients, with 5147 (17.0%) patients undergoing AS. On multivariable logistic regression, patients aged ≥ 65 years (OR=1.65; p < 0.001), African American race (OR=1.12; p = 0.035), having government insurance (OR=1.45; p < 0.001) or those uninsured (OR=1.58; p < 0.001) were significantly more likely to undergo AS compared to DT, while patients with larger tumors (OR=0.90; p < 0.001), receiving treatment at academic facilities (OR=0.75; p < 0.001), and living in West regions of the United States (OR=0.59; p < 0.001) were significantly less likely to undergo AS compared to DT. CONCLUSIONS: Significant sociodemographic disparities exist in patient selection for undergoing AS versus DT, which may modify patient clinical outcomes.

Endoscopic versus Nonendoscopic Surgery for Resection of Craniopharyngiomas.

OBJECTIVE: While surgery is a critical treatment option for craniopharyngiomas, the optimal surgical approach remains under debate. Herein, we studied a large cohort of craniopharyngioma patients to identify predictors of endoscopic surgery (ES) and to compare survival outcomes between patients undergoing ES versus nonendoscopic surgery (NES). METHODS: The National Cancer Database was queried for patients receiving definitive surgical treatment in 2010-2016. Cox proportional hazards and propensity score-adjusted Kaplan-Meier analyses assessed mortality risk and overall survival, respectively. Predictors of surgical approach were evaluated via logistic regression. RESULTS: Of 1721 patients, 508 (29.5%) underwent ES, 877 (50.9%) were female, and the average age was 41.8 ± 21.3 years. Matched ES and NES cohorts exhibited 5-year overall survival rates of 88.0% and 79.8%, respectively (P = 0.004). ES was associated with reduced mortality (Hazard Ratio = 0.634; 95% confidence interval [CI], 0.439-0.914; P = 0.015). Patients treated at academic facilities (Odds Ratio [OR] = 2.095; 95% CI, 1.529-2.904; P < 0.001) or diagnosed recently (OR = 1.132; 95% CI, 1.058-1.211; P < 0.001) were more likely to undergo ES, while those with tumor sizes >3 cm (OR = 0.604; 95% CI, 0.451-0.804; P < 0.001) or receiving adjuvant radiotherapy (OR = 0.641; 95% CI, 0.454-0.894; P = 0.010) were more likely to receive NES. Surgical inpatient stays were significantly shorter with ES compared to NES (8.0 vs. 10.5 days, P < 0.001). On linear regression, ES usage increased by 82.4% and NES usage decreased by 23.4% between 2010 and 2016 (R2 = 0.575, P = 0.031). CONCLUSIONS: ES of craniopharyngioma was associated with reduced mortality and shorter inpatient stays compared to NES. Factors including tumor size, extent of resection, facility type, and year of diagnosis may predict receiving ES. There is a trend towards increased usage of ES for surgical management of craniopharyngiomas.

Patterns of Opioid Usage and Predictors of Utilization Following Endoscopic Skull Base Surgery.

OBJECTIVE: Pain control is an important topic that has not been extensively studied in patients undergoing endoscopic skull base surgery (ESBS). The purpose of this study is to identify opioid requirements after ESBS and the risk factors predictive of increased use. METHODS: This study was a retrospective review of all patients undergoing ESBS at a tertiary academic skull base surgery program between July 2018 and August 2020. The primary outcome variable was total morphine equivalent dose (MED) requirements after surgery, calculated as the sum of all morphine milligram equivalents over a 24-h period, and summated across the duration of each participant's hospital course. RESULTS: 94 patients were included in this review. Average daily MED requirements were 14.00 ± 6.79 mg. Average total MED requirements were 83.78 ± 92.99 mg during hospitalization. Average length of stay (LOS) was 5.71 ± 4.42 days, with 22 (23.4%) patients not requiring opioid use upon discharge. On multivariate analysis, female sex (ß = 49.62; 95% CI [13.53, 85.71], p = 0.008), nasoseptal flap (NSF) reconstruction (ß = 49.56; 95% CI [13.51, 85.61], p = 0.008) and LOS (ß = 4.02; 95% CI [0.001, 8.04], p = 0.050) were independently associated with higher total MED requirements. CONCLUSIONS: We report average total MED requirements of 83.78 mg after ESBS, with female sex, intraoperative use of an NSF, and increased LOS as predictors of higher MED use. This data indicates a subset of patients who may benefit from more aggressive pain control strategies upfront, including consideration of non-opioid, multimodal pain regimens. LEVEL OF EVIDENCE: 3 Laryngoscope, 132:1939-1945, 2022.

Long-term outcomes in sinonasal squamous cell carcinoma arising from inverted papilloma: Systematic review.

Long-term survival and recurrence patterns of squamous cell carcinoma arising from inverted papilloma (IP-SCC) have not been thoroughly investigated. Four electronic databases were searched and primary studies describing overall survival (OS), recurrence, and mean time to recurrence of patients with IP-SCC were included for review. Our search yielded 662 studies. The 28 studies selected for inclusion identified 663 patients with IP-SCC. In 596 patients with reported T classification, 439 (73.7%) were T3/T4 on presentation. Of the 650 participants with recurrence data (local, regional, and distant), 155 (23.8%) experienced a recurrence, with an aggregate mean time-to-recurrence of 24.3 months. In 565 patients with 5-year OS rates, the aggregate 5-year OS was 62%. Based on the literature to date, IP-SCC is associated with a 5-year OS rate of 62%. 23.8% of patients experienced recurrence at a mean time of 24.3 months, suggesting the need for long-term surveillance.

Association Between 5-Item Modified Frailty Index and Short-term Outcomes in Complex Head and Neck Surgery.

OBJECTIVES: To evaluate the impact of preoperative frailty on short-term outcomes following complex head and neck surgeries (HNSs). STUDY DESIGN: Cross-sectional database analysis. SETTING: American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database. METHODS: The 2005 to 2017 ACS-NSQIP was queried for patients undergoing complex HNS. Five-item modified frailty index (mFI) was calculated based on functional status and history of diabetes, chronic obstructive pulmonary disease, congestive heart failure, and chronic hypertension. RESULTS: A total of 2786 patients (73.1% male) with a mean age of 62.0 ± 11.6 years were included. Compared to nonfrail patients (41.2%), patients with mFI ≥1 (58.8%) had shorter length of operation (P = .021), longer length of stay (LOS) (P < .001), and higher rates of 30-day reoperation (P = .009), medical complications (P < .001), discharge to nonhome facility (DNHF) (P < .001), and mortality (P = .047). These parameters remained statistically significant when compared across all individual mFI scores (all P < .05). After adjusting for age, sex, race, body mass index, smoking, and American Society of Anesthesiologists score via multivariate logistic regression, patients with mFI ≥1 were significantly more likely to undergo reoperation (odds ratio [OR], 1.39), surgical complications (OR, 1.19), medical complications (OR, 1.55), prolonged LOS (OR, 1.29), and DNHF (OR, 1.56) (all P < .05). Multivariate logistic regression also demonstrated that after adjusting for confounders, compared to patients with mFI = 1, patients with mFI = 2-5 (18.7%) were more likely to undergo shorter operations (OR, 0.74), have medical (OR, 1.46) or any complications (OR, 1.27), and have DNHF (OR, 1.62) (all P < .05). CONCLUSION: The 5-point mFI can independently predict short-term surgical outcomes following complex HNS. This simple and reliable metric can potentially lead to improved preoperative counseling and postoperative planning for complex HNS patients.

Adjuvant Therapy and Prognosticators of Survival in Head and Neck Mucosal Melanoma.

OBJECTIVES/HYPOTHESIS: To identify prognosticators and determine the efficacies of surgery with adjuvant radiotherapy (SR) and surgery with immunotherapy (SI) of head and neck mucosal melanoma (HNMM). STUDY DESIGN: Retrospective database study. METHODS: The 2004 to 2017 National Cancer Database was queried for HNMM patients. Cox proportional hazards and Kaplan-Meier analyses evaluated prognosticators of mortality and survival benefits conferred by SR, SI, or surgery with adjuvant radiotherapy and immunotherapy (SRI). Logistic regression identified predictors of adjuvant radiotherapy or immunotherapy use. RESULTS: Overall, 1,910 cases (845 surgery, 802 SR, 51 SI, 101 SRI) were analyzed, with 50.3% females and an average age of 68.6 ± 13.8 years. SI was associated with greater overall survival (OS) than surgery (hazard ratio [HR] 0.672; P = .036). SI (HR 0.425; P = .024) and SRI (HR 0.594; P = .045) were associated with superior OS than SR. Older age (HR 1.607; P < .001), female sex (HR 0.757; P = .006), paranasal sinus localization (HR 1.648; P < .001), T4 classification (HR 1.443; P < .001), N1 classification (HR 2.310; P < .001), M1 classification (HR 3.357; P < .001), and positive surgical margins (HR 1.454; P < .001) were survival prognosticators. Adjuvant radiotherapy use was negatively correlated with older age, oral cavity localization, and M0 or T3 tumors (all P < .05). Adjuvant immunotherapy use was positively correlated with younger age and M1 tumors (all P < .05). CONCLUSIONS: Although SR did not confer survival benefits in HNMM patients, SI and SRI yielded greater OS than surgery alone. SRI was associated with superior survival outcomes than SR. Certain demographic and clinical factors were associated with increased mortality risk. Patient age and certain tumor characteristics were predictors of adjuvant radiotherapy or immunotherapy use. LEVEL OF EVIDENCE: 4 Laryngoscope, 132:584-592, 2022.

Prognostic Factors and Outcomes of De Novo Sinonasal Squamous Cell Carcinoma: A Systematic Review and Meta-analysis.

OBJECTIVE: To review overall survival (OS), recurrence patterns, and prognostic factors of de novo sinonasal squamous cell carcinoma (DN-SCC). DATA SOURCES: PubMed, Scopus, OVID Medline, and Cochrane databases from 2006 to December 23, 2020. REVIEW METHODS: The study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Articles were required to report either recurrence patterns or survival outcomes of adults with DN-SCC. Case reports, books, reviews, meta-analyses, and database studies were all excluded. RESULTS: Forty-one studies reported on survival or recurrence outcomes. The aggregate 5-year OS was 54.5% (range, 18%-75%) from 35 studies (n = 1903). Patients undergoing open surgery were more likely to receive radiation therapy and present at an advanced stage compared to those receiving endoscopic surgery (all P < .001). Advanced T stage, presence of cervical nodal metastases, maxillary sinus primary site, and negative human papillomavirus (HPV) status were all correlated with significantly worse 5-year OS. Direct meta-analysis of 8 studies demonstrated patients with surgery were more likely to be alive at 5 years compared to those who did not receive surgery (odds ratio, 2.26; 95% CI, 1.48-3.47; P < .001). Recurrence was reported in 628 of 1471 patients from 26 studies (42.7%) with an aggregate 5-year locoregional control rate of 67.1% (range, 50.4%-93.3%). CONCLUSION: This systematic review and meta-analysis suggests that the 5-year OS rate for DN-SCC may approach 54.5% and recurrence rate approaches 42.7%. In addition, various tumor characteristics including advanced T stage, positive nodal status, maxillary sinus origin, and negative HPV status are all associated with decreased survival.

Association Between Olfactory Dysfunction and Critical Illness and Mortality in COVID-19: A Meta-analysis.

LEVEL OF EVIDENCE: 4.

Determinants of Survival in Skull Base Chondrosarcoma: A National Cancer Database Study.

OBJECTIVE: Chondrosarcomas of the skull base are rare tumors most commonly treated surgically with or without adjuvant radiation therapy. Using the National Cancer Database (NCDB), we analyzed overall survival (OS), treatment modalities, and prognosticators. METHODS: The NCDB was queried for all cases of histologically confirmed skull base chondrosarcoma treated between 2004 and 2015, excluding patients with more than 1 malignant tumor, on palliative care, receiving unrelated concurrent treatments, or having less than 1 month of follow-up. The χ2 test for categorical variables, Cox proportional hazards models, and Kaplan-Meier log-rank analysis were used to test associations with the use of adjuvant radiation, OS, and survival time. RESULTS: A total of 498 patients with skull base chondrosarcoma were identified in the NCDB. Of them, 224 (45.0%) and 198 (39.8%) were treated with either surgery alone or surgery with adjuvant radiation therapy, respectively. Patients more likely to undergo surgery with adjuvant radiation had higher tumor grade (P = 0.008), later year of diagnosis (P = 0.002), positive surgical margins (P < 0.001), and treatment at an academic institution (P = 0.02). Patient, tumor, and socioeconomic factors associated with worse OS on multivariate analysis included the Charlson/Deyo Comorbidity Score ≥2 (P = 0.017), as well as clear cell (P = 0.02) and dedifferentiated (P = 0.006) histology. Age, tumor grade, tumor size, treatment modality, insurance status, facility type, and urban/rural population did not show a statistically significant impact on OS. CONCLUSION: The mainstay of treatment for skull base chondrosarcoma is surgery, with consideration of adjuvant radiation. This study demonstrated worse overall survival associated with more frail patients and aggressive histology types. It is important to consider these factors when planning the clinical management of these patients.

Trends and patterns of neurotology drug prescriptions on a nationwide insurance database.

OBJECTIVE: To examine neurotologists' 2013 to 2016 Medicare Part-D data and evaluate commonly prescribed medications, longitudinal changes in prescribing patterns, presumed associated pathologies, and cost distribution across United States. METHODS: Comprehensive prescription data of Part-D-participating neurotologists was quiered from the 2013 to 2016 Medicare Part-D database. Outcome variables consisted of the 25 most commonly prescribed + refilled medications, cost distribution per medication, presumed associated pathologies, and standardized prescription cost across United States. RESULTS: Of the 594 available U.S. neurotologists, 336 (57%) were found in the Medicare Part-D database. In 2016, total prescription costs were $4 483 268 with an averaged $13 343 ± $18 698 per neurotologist. The three most frequently filled drugs were fluticasone propionate, ciprofloxacin, and triamterene-hydrochlorothiazide. From 2013 to 2016, the greatest change in prescription pattern was observed with azelastine (+188%), montelukast sodium (+104%), mupirocin (+63%), and mometasone (-91%), whereas the greatest change in relative drug cost distribution was seen in ofloxacin, (+695.7%) neomycin-polymyxin-hydrocortisone (+262.1%), and mometasone (-83%). Triamterene-hydrochlorothiazide, prednisone, montelukast, amoxicillin-clavulanate, azelastine, spironolactone, and mupirocin had statistically significant increases in average number of prescriptions per physician, whereas ofloxacin and mometasone had significant decreases. Medications presumably treating Eustachian tube dysfunction, Meniere's disease, and vestibular migraine had the greatest percent changes across years. Cost distribution of four drugs increased upwards of 100%. Geographic analysis demonstrated that Southern and Midwest regions had higher standardized prescription costs. CONCLUSIONS: This study is the first to analyze neurotologists' trends in prescribing patterns, regional prescription cost distributions, and commonly treated pathologies. This can lead to better standardization of prescribing patterns and cost in the future.

Association between modified frailty index and surgical outcomes in intradural skull base surgery.

The objective of this study is to evaluate the impact of preoperative frailty on short-term outcomes following intradural resection of skull base lesions. The 2005-2017 ACS-NSQIP database was queried for 30-day post-operative outcomes of patients undergoing intradural resection of the skull base, extracted by CPT codes 61601, 61606, 61608, and 61616. Five-item modified frailty index (mFI) was calculated based on the history of diabetes mellitus, chronic obstructive pulmonary disease, congestive heart failure, chronic hypertension, and functional status. A total of 701 patients (58.8% female, 72.0% white) were included with a mean age of 51.8 ± 14.7 years. Compared to patients with mFI = 0 (n = 403), patients with mFI ≥ 1 (n = 298) were more likely to have higher rates of reoperation (13.4% vs. 8.7%, p = 0.045), medical complications (20.5% vs. 9.2%, p < 0.001), surgical complications (13.8% vs. 8.4%, p = 0.024), discharge to non-home facility (DNHF) (24.8% vs. 13.3%, p < 0.001), and prolonged length of hospitalization (7.3 ± 6.8 days vs. 5.6 ± 5.0, p = 0.003). Moreover, mFI = 1-3 was also associated with higher BMI, non-white race, high ASA, and older age (all p < 0.05). Upon adjusting for age, BMI, race, ASA score, and surgical site, multivariate regression analysis demonstrated that higher mFI (treated as a continuous variable) was associated with higher odds of medical complications (OR = 1.630, CI = 1.153-2.308, p = 0.006), surgical complications (OR = 1.594, CI = 1.042-2.438, p < 0.031), and LOS ≥ 10 days (OR = 1.609, CI = 1.176-2.208, p = 0.003). In conclusion, the 5-item mFI can be an independent predictor of several important short-term surgical outcomes following intradural resection of skull base lesions, warranting further investigations into its clinical utility.