Stratification System Research Articles

TFE3 gene rearrangement and protein expression contribute to a poor prognosis of renal cell carcinoma

BackgroundTFE3-rearranged renal cell carcinoma (TFE3-rearranged RCC) is a type of kidney cancer with a low incidence, with no consensus about whether it has a worse prognosis than clear cell renal cell carcinoma (ccRCC). This study attempted to elucidate the impact of TFE3-rearranged RCC by analyzing its clinical features and prognosis. MethodsPatients treated in Sun Yat-sen Memorial Hospital (SYSMH) who were suspected to be diagnosed with TFE3-rearranged RCC were divided into two groups, TFE3-rearranged RCC and ccRCC with positive TFE3 protein expression on immunohistochemistry [TFE3(+) ccRCC], by dual-color, break-apart fluorescence in situ hybridization (FISH). After balancing the baseline characteristics with TFE3(+) ccRCC using the propensity score matching (PSM) method in a ratio of 2, we selected patients diagnosed with ccRCC with negative TFE3 protein expression on immunohistochemistry [TFE3(−) ccRCC]. The impact of TFE3 gene rearrangement and protein expression on renal cell carcinoma was determined by feature comparison with a nonparametric test and survival analysis with the Kaplan‒Meier method. ResultsAmong 37 patients suspected of having TFE3-rearranged RCC, 13 patients were diagnosed with TFE3-rearranged RCC, and 24 patients had TFE3(+) ccRCC. The recurrence and new metastasis of TFE3-rearranged RCC was relatively common, even if the tumor stage was early at the first diagnosis. Through feature comparison and survival analysis, we found that TFE3-rearranged RCC was quite similar to TFE3(+) ccRCC. Compared with TFE3(−) ccRCC, TFE3(+) ccRCC tended to have a larger tumor diameter (P = 0.011), higher neutrophil/lymphocyte ratio (NLR) (P = 0.017) and metastatic potential (P = 0.022), and worse overall survival (OS) (P = 0.043) and PFS (P = 0.016). The survival analysis showed that TFE3-rearranged RCC had a worse PFS than ccRCC (P = 0.002), and TFE3(+) RCC had a worse PFS than TFE3(−) RCC (P = 0.001). According to the stratification system based on the combination of TFE3 and lymphovascular invasion (LVI), we further found that the prognosis from good to poor was TFE3(−) LVI(−), TFE3(+) LVI(−), TFE3(+) LVI(+) and TFE3(−) LVI(+), with statistically significant differences in both OS (P = 0.001) and PFS (P < 0.001). In addition, we also reported two cases with poor prognosis, of which one was TFE3-rearranged RCC and the other was TFE3(+) ccRCC. ConclusionsThis is a novel finding that both FISH confirmed TFE3 gene rearrangement-mediated TFE3-rearranged RCC and IHC confirmed positive TFE3 protein expression [TFE3(+)] contribute to a poor prognosis in RCC, suggesting more active treatment and careful follow-up for TFE3(+) RCC patients. The combination of TFE3 and LVI may be a new risk stratification system for RCC.

Identification of anoikis-related subtypes and development of risk stratification system in skin cutaneous melanoma

BackgroundAnoikis, a form of apoptosis induced by cell detachment, plays a key role in cancer metastasis. However, the potential roles of anoikis-related genes (ARGs) in assessing the prognosis of skin cutaneous melanoma (SKCM) and the tumor microenvironment (TME) remain unclear. MethodsThe data from TCGA corresponding to transcriptomic expression patterns for patients with SKCM were downloaded and utilized to screen distinct molecular subtypes by a non-negative matrix factorization algorithm. The prognostic signature was constructed by least absolute shrinkage and selection operator (LASSO) Cox regression and was validated in SKCM patients from the GEO cohort. Moreover, the relationship of the ARG_score with prognosis, tumor-infiltrating immune cells, gene mutation, microsatellite instability (MSI), and immunotherapy efficacy. ResultsWe screened 100 anoikis-related differentially expressed genes between SKCM tissues and normal skin tissues, which could divide all patients into three different subtypes with significantly distinct prognosis and immune cell infiltration. Then, an anoikis-related signature was developed based on subtype-related DEGs, which could classify all SKCM patients into low and high ARG_score groups with differing overall survival (OS) rates. ARG_score was confirmed to be a strong independent prognostic indicator for SKCM patients. By combining ARG_score with clinicopathological features, a nomogram was constructed, which could accurately predict the individual OS of patients with SKCM. Moreover, low ARG_score patients presented with higher levels of immune cell infiltration, TME score, higher tumor mutation burden, and better immunotherapy responses. ConclusionsOur comprehensive analysis of ARGs in SKCM provides important insights into the immunological microenvironment within the tumor of SKCM patients and helps to forecast prognosis and the response to immunotherapy in SKCM patients, thereby making it easier to tailor more effective treatment strategies to individual patients.

Molecular Testing Predicts Incomplete Response to Initial Therapy in Differentiated Thyroid Carcinoma Without Lateral Neck or Distant Metastasis at Presentation: Retrospective Cohort Study.

Background: Molecular testing (MT) is emerging as a potential prognostic factor that can be available before treatment of differentiated thyroid carcinoma begins. Among patients eligible for either lobectomy or total thyroidectomy as their initial therapy, our study aims were to assess (1) if conventionally available preoperative factors are associated with incomplete response to initial therapy, and (2) if MT results can be a surrogate for the ATA Risk Stratification System (RSS) to estimate risk of recurrence. Methods: The data of consecutive thyroid cancer patients without preoperative lateral neck disease or distant metastasis who underwent index thyroidectomy between November 1, 2017 and October 31, 2021 were reviewed. Logistic regression models including preoperative variables such as MT and/or the postoperatively available RSS were constructed to predict disease recurrence, either structural or biochemical. Model discrimination using the c-statistic and goodness-of-fit test were compared. Results: Among 945 patients studied, 50 (5.2%) recurred with 18-month median follow-up. Recurrences were detected in 17 (2.9%), 20 (6.7%), and 13 (22.8%) patients with RSS-low, -intermediate, and -high cancers, respectively (p < 0.001). In multivariable analysis, only tumor size was associated with recurrence (odds ratio [OR] 1.3, 95% confidence interval [CI] 1.1-1.5). In a different model analyzing 440 (46.6%) patients with available MT results, recurrence was associated with both larger tumor size (OR 1.4 [95% CI 1.1-1.8]) and MT results (p < 0.001). Including MT improved the c-statistic by 27%, which was statistically no different than the model incorporating only the RSS (p = 0.15). Conclusions: Disease recurrence was observed across all ATA RSS categories in short-term follow-up, and tumor size was the only conventional preoperative factor associated with recurrence. When MT results were incorporated, they not only improved predictive ability beyond tumor size alone, but also yielded similar ability as the gold standard ATA RSS. Thus, MT results might aid the development of novel preoperative risk stratification algorithms.

Lymph node ratio-based prognostic model for risk stratification and individualized adjuvant therapy for postoperative major salivary duct carcinoma.

To investigate the value of lymph node ratio (LNR) for postoperative major salivary duct carcinoma (MSDC) and to establish a model for prognosis assessment and treatment optimization. Data of MSDC were retrieved in public database, and prognostic factors were identified by univariate and multivariate analyses. A nomogram and risk stratification system were constructed. Four hundred and eleven eligible patients were included (training cohort vs. validation cohort: 287: 124). LNR ≥0.09 was associated with worse overall survival (OS). Age at diagnosis, sex, T stage, and LNR were identified as prognostic factors and integrated into nomogram. Low-risk patients were found to have better OS than high-risk patients. Furthermore, postoperative radiotherapy (PORT) significantly improved OS in the high-risk subgroup, but chemotherapy did not confer a long-term survival benefit. A nomogram model integrating LNR could better assess postoperative prognosis and risk stratification in MSDC, and identify patients who might benefit from PORT to avoid overtreatment.

Effect of the categorization method on the diagnostic performance of ultrasound risk stratification systems for thyroid nodules.

To evaluate whether the categorization methods of risk stratification systems (RSSs) is a decisive factor that influenced the diagnostic performances and unnecessary FNA rates in order to choose optimal RSS for the management of thyroid nodules. From July 2013 to January 2019, 2667 patients with 3944 thyroid nodules had undergone pathological diagnosis after thyroidectomy and/or US-guided FNA. US categories were assigned according to the six RSSs. The diagnostic performances and unnecessary FNA rates were calculated and compared according to the US-based final assessment categories and the unified size thresholds for biopsy proposed by ACR-TIRADS, respectively. A total of 1781 (45.2%) thyroid nodules were diagnosed as malignant after thyroidectomy or biopsy. Significantly lowest specificity and accuracy, along with the highest unnecessary FNA rates were seen in EU-TIRADS for both US categories (47.9%, 70.2%, and 39.4%, respectively, all P < 0.05) and indications for FNA (54.2%, 50.0%, and 55.4%, respectively, all P < 0.05). Diagnostic performances for US-based final assessment categories exhibited similar accuracy for AI-TIRADS, Kwak-TIRADS, C-TIRADS, and ATA guidelines (78.0%, 77.8%, 77.9%, and 76.3%, respectively, all P > 0.05), while the lowest unnecessary FNA rate was seen in C-TIRADS (30.9%) and without significant differences to that of AI-TIRADS, Kwak-TIRADS, and ATA guideline (31.5%, 31.7%, and 33.6%, respectively, all P > 0.05). Diagnostic performance for US-FNA indications showed similar accuracy for ACR-TIRADS, Kwak-TIRADS, C-TIRADS and ATA guidelines (58.0%, 59.7%, 58.7%, and 57.1%, respectively, all P > 0.05). The highest accuracy and lowest unnecessary FNA rate were seen in AI-TIRADS (61.9%, 38.6%) and without significant differences to that of Kwak-TIRADS(59.7%, 42.9%) and C-TIRADS 58.7%, 43.9%, all P > 0.05). The different US categorization methods used by each RSS were not determinant influential factors in diagnostic performance and unnecessary FNA rate. For daily clinical practice, the score-based counting RSS was an optimal choice.

An MRI-Based Prognostic Stratification System for Medical Decision-Making of Multinodular Hepatocellular Carcinoma Patients Beyond the Milan Criteria.

The suitability of hepatectomy among patients with multinodular hepatocellular carcinoma (MHCC) beyond the Milan criteria remains controversial. There is a need for a reliable risk stratification tool among these patients for the selection of ideal candidates of curative resection. To determine the clinicoradiological prognostic factors for patients with MHCC beyond the Milan criteria to further develop a stratification system. Retrospective. 176 patients with pathologically confirmed MHCC beyond the Milan criteria. The 1.5 T scanner, including T1-, T2-, diffusion-weighted imaging, in/out-phase imaging, and dynamic contrast-enhanced imaging. Conventional MRI features and preoperative laboratory data including aspartate aminotransferase (AST) and α-fetoprotein (AFP) were collected and analyzed. Two nomograms incorporating clinicoradiological variables were independently constructed to predict recurrence-free survival (RFS) and overall survival (OS) with Cox regression analyses and verified with 5-fold cross validation. Based on the nomograms, two prognostic stratification systems for RFS and OS were further developed. The Cohen's kappa/intraclass correlation coefficient, C-index, calibration curve, Kaplan-Meier curve, log-rank test. A P value <0.05 was considered statistically significant. AST > 40 U/L, increased tumor burden score, radiological liver cirrhosis and nonsmooth tumor margin were independent predictors for poor RFS, while AST > 40 U/L, AFP > 400 ng/mL and radiological liver cirrhosis were independent predictors for poor OS. The two nomograms demonstrated good discrimination performance with C-index of 0.653 (95% confidence interval [CI], 0.602-0.794) and 0.685 (95% CI, 0.623-0.747) for RFS and OS, respectively. The 5-fold cross validation further validated the discrimination capability of the nomograms. Based on the nomogram models, MHCC patients beyond the Milan criteria were stratified into low-/medium-/high-risk groups with significantly different RFS and OS. The proposed MRI-based prognostic stratification system facilitates the refinement and further subclassification of patients with MHCC beyond the Milan criteria. 4. 2.

CONNECTOR, fitting and clustering of longitudinal data to reveal a new risk stratification system.

The transition from evaluating a single time point to examining the entire dynamic evolution of a system is possible only in the presence of the proper framework. The strong variability of dynamic evolution makes the definition of an explanatory procedure for data fitting and clustering challenging. We developed CONNECTOR, a data-driven framework able to analyze and inspect longitudinal data in a straightforward and revealing way. When used to analyze tumor growth kinetics over time in 1599 patient-derived xenograft growth curves from ovarian and colorectal cancers, CONNECTOR allowed the aggregation of time-series data through an unsupervised approach in informative clusters. We give a new perspective of mechanism interpretation, specifically, we define novel model aggregations and we identify unanticipated molecular associations with response to clinically approved therapies. CONNECTOR is freely available under GNU GPL license at https://qbioturin.github.io/connector and dx.doi.org/10.17504/protocols.io.8epv56e74g1b/v1. Supplementary data are available at Bioinformatics online.

Stratifying Severity of Acute Respiratory Failure Severity in Cyanotic Congenital Heart Disease.

Hypoxemia is used to stratify severity in acute respiratory failure (ARF) but is less useful in cyanotic congenital heart disease (CCHD) due to an inability to differentiate hypoxemia from lung injury versus cardiac shunting. Therefore, we aimed to determine whether variables related to respiratory mechanics were associated with outcomes to assist in stratifying ARF severity in pediatric CCHD. We performed a retrospective cohort study from a single cardiac intensive care unit enrolling children with CCHD with ARF requiring mechanical ventilation between 2011 and 2019. Time-averaged ventilator settings and oxygenation data in the first 24h of ARF were screened for association with the primary outcome of 28-day mortality. Of 344 eligible patients, peak inspiratory pressure (PIP) and driving pressure (ΔP) were selected as candidate variables to stratify ARF severity. PIP (OR 1.10, 95% CI 1.02-1.19) and ΔP (1.11, 95% CI 1.01-1.24) were associated with higher mortality and fewer ventilator-free days (VFDs) at 28days after adjusting for age, severity of cardiac history, and FiO2. A three-level (mild, moderate, severe) severity stratification was established for both PIP (≤ 20, 21-29, ≥ 30) andΔP (≤ 16, 17-24, ≥ 25), showing increasing mortality (both P < 0.01), decreasing VFDs and increasing ventilator days in survivors (all P < 0.05) across increasing pressures. Overall, we found that higher PIP and ΔP were associated with mortality and duration of ventilation across a three-level severity stratification system in pediatric CCHD with ARF, providing a practical method to prognosticate in subjects with multifactorial etiologies for hypoxemia.

Validation and application of the 2019 International Working Group on the Diabetic Foot risk stratification for diabetic foot in Chinese patients.

The purpose of the present study was to evaluate the validation and application of the 2019 International Working Group on the Diabetic Foot (IWGDF) risk stratification system among Chinese patients with diabetes. A retrospective cohort study was carried out with 254 patients with diabetes, but without an active diabetic foot (DF) ulcer. Patients hospitalized from January to May 2017 were enrolled, and the follow-up period was from January to May 2020. Patients were stratified into four risk groups based on the 2019 IWGDF risk stratification system. Of the 254 patients, four of 31 patients at risk 1 were diagnosed with DF within 3 years, whereas 12 of 26 patients at risk 2 and 16 of 20 patients at risk 3 developed DF. The area under the curve was 0.919 (P < 0.01, 95% confidence interval 0.893-0.945). Because DF risk 2 and greater (risk 2 + risk 3) was the optimal cut-off point, we simplified the risk stratification system by using two tiers, namely, low risk (risk 0 + 1) and high risk (risk 2 + 3). For the simplified risk stratification system, the sensitivity, specificity, positive likelihood ratio, percent agreement, positive predictive value and negative predictive value were 87.5%, 91.8%, 10.607, 91.3%, 60.8% and 98.1%, respectively. The χ2 -test showed that the odds ratio of the high-risk group (risk 2 + 3) was 29.33-fold that of the low-risk group (risk 0 + 1). The 2019 IWGDF risk stratification system showed high validity and primary screening value in Chinese patients with diabetes. Thus, a simplified, two-tiered IWGDF stratification might be more efficient and cost-effective for predicting DF ulcers.

Malignancy Risk of Thyroid Nodules That Are Not Classifiable by the American Thyroid Association Ultrasound Risk Stratification System: A Systematic Review and Meta-Analysis.

Background: Sonographic evaluation is fundamental to thyroid nodule assessment. The American Thyroid Association (ATA) ultrasound risk stratification system (USRSS) is widely used, but the appearance of some nodules has been considered nonclassifiable (NC-ATA). The risk of malignancy (RoM) of NC-ATA nodules varies widely between studies, leading to uncertainty in clinical management. The aim of this study was to comprehensively evaluate the prevalence and malignancy risk of NC-ATA nodules. Methods: A systematic review was performed searching PubMed/MEDLINE and EMBASE to identify original studies of thyroid nodules classified using the ATA USRSS from 2016 to 2022 and reporting the outcome of NC-ATA nodules. Meta-analysis was conducted to obtain pooled RoM estimates and meta-regression sensitivity analyses were used to explore sources of between-study heterogeneity. Results: Of 6377 screened studies, 135 underwent full-text review, and 16 studies reporting 21,271 nodules were included. Within these, the pooled prevalence of NC-ATA nodules was 7.8% (1872 nodules; [confidence interval; CI 5.1-11.1]). The pooled RoM estimate for NC-ATA nodules was 20.3% [CI 13.0-28.7] and there was significant heterogeneity between studies (I2 = 92.8%, p < 0.001). NC-ATA nodule RoM estimates were significantly different by study type: single-center versus multicenter studies (24.8% vs. 12.3%, respectively, p = 0.031) and study design: retrospective versus prospective studies (25.1% vs. 8.5%, respectively, p = 0.003). No significant difference was observed in RoM based on inclusion of <1 cm nodules or geographic region. Meta-regression analysis showed study design and use of surgical histology for diagnostic criteria contributed significantly to differences in the reported RoM estimates. Conclusion: In this first meta-analysis comprehensively assessing the RoM of NC-ATA nodules, the malignancy risk was found to be comparable with the current ATA USRSS intermediate suspicion category. Significant heterogeneity was observed between studies and limits the interpretation of these results. In future iterations of the ATA USRSS that seek into incorporate categorization of NC-ATA nodules, these meta-analysis data may help to inform proper malignancy risk stratification. The study protocol was registered on PROSPERO, the international prospective register of systematic reviews (CRD42020182498), on July 14, 2020.

Neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio as predictive markers in hepatoblastoma.

The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) have been presented to be a prognostic indicator in several cancers. We were supposed to evaluate the prognostic role of such inflammatory markers in hepatoblastoma (HB). Total of 101 children, diagnosed with hepatoblastoma between January 2010 and January 2018, were enrolled before treatment in the study. The clinicopathological parameters, and outcomes were collected through laboratory analyses and patient follow-up. The association between NLR, PLR, and clinicopathological characters were analyzed with Wilcoxon test, Chi-Squared test, Kaplan-Meier, Log-rank and Cox regression analyses. NLR and PLR were significantly elevated in HB patients (P < 0.001), and related to age (P < 0.001), risk stratification system (P < 0.001), and pretreatment extent of disease (P < 0.0001). NLR was significantly related to alpha-fetoprotein (P = 0.034) and lactate dehydrogenase (P = 0.026). The 3-year overall survival (OS) and event-free survival (EFS) were poor in the high-NLR group (OS: 44.3% vs. 90.3%, P < 0.0001, EFS: 38.6% vs. 80.6%, P = 0.0001). The 3-year OS and EFS were poor in the high-PLR group (OS: 49.1% vs. 68.8%, P = 0.016, EFS: 39.6% vs. 64.6%, P = 0.0117). The multivariate analysis suggested that NLR (HR: 11.359, 95% CI: 1.218-105.947; P = 0.033) and risk stratification (HR: 44.905, 95% CI: 2.458-820.36; P = 0.01), were independent predictors of OS. Our research showed that elevated NLR and PLR were the poor prognostic factors in HB patients before treatment. The NLR was an independent prognostic factor for OS.

Development of a prognostic nomogram and risk stratification system for upper thoracic esophageal squamous cell carcinoma.

The study aimed to develop a nomogram model to predict overall survival (OS) and construct a risk stratification system of upper thoracic esophageal squamous cell carcinoma (ESCC). Newly diagnosed 568 patients with upper ESCC at Fujian Medical University Cancer Hospital were taken as a training cohort, and additional 155 patients with upper ESCC from Sichuan Cancer Hospital Institute were used as a validation cohort. A nomogram was established using Cox proportional hazard regression to identify prognostic factors for OS. The predictive power of nomogram model was evaluated by using 4 indices: concordance statistics (C-index), time-dependent ROC (ROCt) curve, net reclassification index (NRI) and integrated discrimination improvement (IDI). In this study, multivariate analysis revealed that gender, clinical T stage, clinical N stage and primary gross tumor volume were independent prognostic factors for OS in the training cohort. The nomogram based on these factors presented favorable prognostic efficacy in the both training and validation cohorts, with concordance statistics (C-index) of 0.622, 0.713, and area under the curve (AUC) value of 0.709, 0.739, respectively, which appeared superior to those of the American Joint Committee on Cancer (AJCC) staging system. Additionally, net reclassification index (NRI) and integrated discrimination improvement (IDI) of the nomogram presented better discrimination ability to predict survival than those of AJCC staging. Furthermore, decision curve analysis (DCA) of the nomogram exhibited greater clinical performance than that of AJCC staging. Finally, the nomogram fairly distinguished the OS rates among low, moderate, and high risk groups, whereas the OS curves of clinical stage could not be well separated among clinical AJCC stage. We built an effective nomogram model for predicting OS of upper ESCC, which may improve clinicians' abilities to predict individualized survival and facilitate to further stratify the management of patients at risk.

Return emergency department visits for recurrent pulmonary embolism symptoms in children and adolescents

AbstractRates of pulmonary embolism (PE) in children have steadily increased over the past 2 decades. Patient outcomes after hospital discharge are poorly understood, and many patients experience recurrent or persistent chest pain or dyspnea, prompting a return to care. This retrospective cohort study of patients diagnosed with PE at a large children’s hospital over a 9.5-year period was performed to evaluate rates of return to the emergency department (ED) for PE-related symptoms, and to determine the utility of repeat computed tomography angiography (CTA) in this population. Ninety-six patients were diagnosed with PE during the study period. Forty-two percent of patients (n = 40) returned to the ED for PE-related symptoms and a total of 74 repeat CTAs were performed. Among those who had return visits, the mean number of return visits was 3 and the mean number of repeat CTAs was 1.8. The median time to return to the ED was 34 days. Logistic regression analysis identified increased age and female sex as risk factors for return ED visits. Eight percent of the cohort experienced PE recurrence. Recurrent PE was observed only in those with persistent or new thrombotic risk factors and was uncommon in those who remained on appropriate anticoagulation. Future work should focus on the development of a risk stratification system to identify patients at low risk of recurrence in order to minimize repeat CTA imaging.

Preoperative Risk Stratification of Follicular-patterned Thyroid Lesions on Core Needle Biopsy by Histologic Subtyping and RAS Variant-specific Immunohistochemistry.

Follicular-patterned lesions often have indeterminate results (diagnostic category III or IV) by core needle biopsy (CNB) and fine needle aspiration (FNA). However, CNB diagnoses follicular neoplasm (category IV) more frequently than FNA. Therefore, we aimed to develop a risk stratification system for CNB samples with category III/IV using immunohistochemistry (IHC). The specificity of the RAS Q61R antibody was validated on 58 thyroid nodules with six different types ofRASgenetic variants and 40 cases of RAS wild-type. We then applied IHC analysis of RAS Q61R to 207 CNB samples with category III/IV in which all patients underwent surgical resection. RAS Q61R IHC had 98% sensitivity and 98% specificity for detectingthe RASp.Q16R variant. In an independent dataset, the positive rate of RAS Q61R was significantly higher in NIFTP (48%) and malignancies (45%) than in benign tumors (19%). The risk of NIFTP/malignancy was highest in the group with nuclear atypia and RAS Q61R expression (86%) and lowest in the group without both parameters (32%). The high-risk group with either nuclear atypia or RAS Q61R had 67.3% sensitivity, 73.4% specificity, 75.2% positive predictive value, and 65.1% negative predictive value for identifying NIFTP/malignancy. We conclude that RAS Q61R IHC can be a rule-in diagnostic test for NIFTP/malignancy in CNB category III/IV results. Combining of the histologic parameter (nuclear atypia) with RAS Q61R IHC results can further stratify CNB category III/IV into a high-risk group, which is sufficient for a surgical referral, and a low-risk group sufficient for observation.

Validation and refinement of the 2022 European LeukemiaNet genetic risk stratification of acute myeloid leukemia

The revised 2022 European LeukemiaNet (ELN) AML risk stratification system requires validation in large, homogeneously treated cohorts. We studied 1118 newly diagnosed AML patients (median age, 58 years; range, 18–86 years) who received cytarabine-based induction chemotherapy between 1999 and 2012 and compared ELN-2022 to the previous ELN-2017 risk classification. Key findings were validated in a cohort of 1160 mostly younger patients. ELN-2022 reclassified 15% of patients, 3% into more favorable, and 12% into more adverse risk groups. This was mainly driven by patients reclassified from intermediate- to adverse-risk based on additional myelodysplasia-related mutations being included as adverse-risk markers. These patients (n = 79) had significantly better outcomes than patients with other adverse-risk genotypes (5-year OS, 26% vs. 12%) and resembled the remaining intermediate-risk group. Overall, time-dependent ROC curves and Harrel’s C-index controlling for age, sex, and AML type (de novo vs. sAML/tAML) show slightly worse prognostic discrimination of ELN-2022 compared to ELN-2017 for OS. Further refinement of ELN-2022 without including additional genetic markers is possible, in particular by recognizing TP53-mutated patients with complex karyotypes as “very adverse”. In summary, the ELN-2022 risk classification identifies a larger group of adverse-risk patients at the cost of slightly reduced prognostic accuracy compared to ELN-2017.

Abstract 6168: Implementation and adoption of a web tool to support precision diagnostic and treatment decisions for patient with myelodysplastic syndromes

Abstract Despite a detailed understanding of the genes mutated in myelodysplastic syndromes (MDS), diagnostic and treatment decisions for patients with MDS rely primarily on clinical and cytogenetic variables as considered by the Revised International Prognostic Scoring System (IPSS-R). Here we describe the recently developed Molecular IPSS (IPSS-M), a clinico-genomic risk stratification system that considers clinical, cytogenetic and genetic parameters; the implementation of a web portal to facilitate its adoption, a strategy to handle missing variables, and the worldwide utilization of the web calculator as a clinical support tool. The IPSS-M was trained on 2,957 clinically annotated diagnostic MDS samples profiled for mutations in 156 driver genes. To maximize the clinical applicability of the IPSS-M and account for missing genetic data (i.e genes missing from a sequencing panel), we implemented a strategy to calculate a risk score under three scenarios: best, worst and average. Last, we developed an online calculator as a standalone single-page web application using VueJs, and D3Js for the interactive visualizations, deployed through a CI/CD pipeline on AWS, where collection of anonymous usage analytics allows to track adoption and usability of the new proposed model. The model incorporates clinical, morphological, genetic variables informed by cytogenetics and constructed from the presence of oncogenic mutations in 31 genes. It delivers a unique risk score for each individual patient, as well as an assignment to one of six IPSS-M risk strata. Compared to the IPSS-R the IPSS-M re-stratified 46% of MDS patients. The model was validated in an external dataset of 754 MDS patients. We released an open-access IPSS-M web calculator available at https://mds-risk-model.com. By specifying the patient clinical and molecular profiles, the tool returns the patient-specific IPSS-M risk score and category, and the probability estimates over time for three clinical endpoints, i.e. leukemia free survival (LFS), overall survival, and incidence of leukemic transformation. Since its launch in June 2022, the calculator has been used by &amp;gt;6000 users in &amp;gt;75 countries, reaching a daily average of 100 users per day. Risks have been calculated for &amp;gt;45,000 patient profiles. 99.28% of the sessions initiated reach an IPSS-M score, suggesting that the calculator is intuitive and easy to use. We trained and validated the IPSS-M on 3,711 patients, a patient tailored risk stratification tool for patients with MDS that considers clinical, morphological and genetic variables inclusive of cytogenetics and mutations in one of 31 genes. The development of a web based tool was instrumental to the global dissemination of the model, enabling non-expert users to leverage the power of molecular biomarkers in risk stratification for patients with MDS. Citation Format: Elsa Bernard, Juan E. Arango Ossa, Heinz Tuechler, Peter L. Greenberg, Robert P. Hasserjian, Yasuhito Nannya, Sean M. Devlin, Maria Creignou, Philippe Pinel, Lily Monier, Juan S. Medina-Martinez, Dylan Domenico, Martin Jädersten, Ulrich Germing, Guillermo Sanz, Arjan A. van de Loosdrecht, Olivier Kosmider, Matilde Y. Follo, Felicitas Thol, Lurdes Zamora, Ronald F. Pinheiro, Andrea Pellagatti, Detlef Haase, Pierre Fenaux, Monika Belickova, Michael R. Savona, Virginia M. Klimek, Fabio P. Santos, Jacqueline Boultwood, Ioannis Kotsianidis, Valeria Santini, Francesc Solé, Uwe Platzbecker, Michael Heuser, Peter Valent, Kazuma Ohyashiki, Carlo Finelli, Maria Teresa Voso, Lee-Yung Shih, Michaela Fontenay, Joop H. Jansen, José Cervera, Norbert Gattermann, Benjamin L. Ebert, Rafael Bejar, Luca Malcovati, Mario Cazzola, Seishi Ogawa, Eva Hellström-Lindberg, Elli Papaemmanuil. Implementation and adoption of a web tool to support precision diagnostic and treatment decisions for patient with myelodysplastic syndromes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6168.

MP55-07 CAN NEURONAL NETWORK-BASED MACHINE LEARNING PREDICT PATHOLOGICALLY SIGNIFICANT PROSTATE CANCER IN PATIENTS DIAGNOSED WITH GLEASON GRADE 6 ON PRE-OPERATIVE PROSTATE BIOPSY

You have accessJournal of UrologyCME1 Apr 2023MP55-07 CAN NEURONAL NETWORK-BASED MACHINE LEARNING PREDICT PATHOLOGICALLY SIGNIFICANT PROSTATE CANCER IN PATIENTS DIAGNOSED WITH GLEASON GRADE 6 ON PRE-OPERATIVE PROSTATE BIOPSY Omri Nativ, Ehud Berger, Kamil Malshy, Omer Sadeh, Alexander Kastin, Alexander Kravtzov, Edmond Sabo, Azik Hoffman, and Gilad Amiel Omri NativOmri Nativ More articles by this author , Ehud BergerEhud Berger More articles by this author , Kamil MalshyKamil Malshy More articles by this author , Omer SadehOmer Sadeh More articles by this author , Alexander KastinAlexander Kastin More articles by this author , Alexander KravtzovAlexander Kravtzov More articles by this author , Edmond SaboEdmond Sabo More articles by this author , Azik HoffmanAzik Hoffman More articles by this author , and Gilad AmielGilad Amiel More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003308.07AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The management of PCa is based on a risk stratification where in the case of localized disease the patients are elected for either active surveillance or an invasive treatment. This risk stratification system is based on three main parameters: PSA level, Gleason grade and the clinical stage of the disease. Despite the clinical definition of a low-risk disease, in certain cases the disease biology is actually aggressive with a potential to become a significant disease or in other cases a sampling error has undegraded the true disease pathology. The aim of our study was to determine the probability of Gleason score upgrading to a clinically significant disease using neuronal network machine learning. METHODS: Using our local radical prostatectomy registry, we have retrospectively reviewed patients' medical records for Age, BMI, PSA level at diagnosis, prostate biopsy findings, prostate volume, PSA-D, D'Amico risk classification, Gleason grade group and pathological staging following prostate biopsy and surgery. Clinically significant (CS) PCa was defined as Gleason 7(3+4) and higher (≥ GG 2). Univariant and multivariant analyses were used to predict significant PCa at radical prostatectomy specimens. Fisher exact and Mann-Whitney U tests were used for categorical and continuous variables, respectively. Next, a neural network (NN) machine learning model was trained using the above variables in order to predict the probability of pathologically upgrading to a CS disease. A back propagation algorithm was used for validation of the NN. RESULTS: 428 patients underwent robotic-assisted radical prostatectomy between 2012 and 2021 in our institution. 72 patients (17%) had a clinically insignificant disease determined by prostate biopsy. of which 34 patients (72%) were upgraded to a CS disease on the final pathology. On univariate and multivariate analysis, the only preoperative variable that predicted a CS final pathology was the PSA-density (PSAD) with a sensitivity and specificity of 36% and 74% respectively. When using the NN machine learning the probability to predict disease upgrading was more accurate with a sensitivity and specificity of 94.1% and 97.1% respectively. CONCLUSIONS: NN machine learning can be trained and used for predicting the probability of PCa upgrading in patients with a biopsy proven Gleason 6 disease. In our cohort the NN sensitivity and specificity were superior compared to the traditional descriptive statistics. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e765 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Omri Nativ More articles by this author Ehud Berger More articles by this author Kamil Malshy More articles by this author Omer Sadeh More articles by this author Alexander Kastin More articles by this author Alexander Kravtzov More articles by this author Edmond Sabo More articles by this author Azik Hoffman More articles by this author Gilad Amiel More articles by this author Expand All Advertisement PDF downloadLoading ...

5613423 TREATMENT OF ERYTHROID PRECURSOR CELLS FROM β-THALASSEMIC PATIENTS WITH ISOXAZOLE DERIVATIVES: POTENT INDUCTION OF FETAL HEMOGLOBIN

Background: Increased production of fetal hemoglobin (HbF) can be beneficial for β-thalassemia patients and several clinical trials in β-thalassemia and/or sickle-cell disease (SCD) are ongoing using HbF inducers, such as NCT01245179 (based on the HDAC inhibitor Panobinostat), NCT00790127 (based on 2,2-dimethylbutyrate, HQK-1001) and NCT03877809 (based on the mTOR inhibitor sirolimus). Methods: In this context, new molecules able to induce HbF are needed. In this communication, we have studied in deep a new class of promising HbF inducers characterized by an isoxazole chemical skeleton. These derivatives are 3,4-isoxazolediamide compounds recently synthesized in our laboratories. The original structures of two natural molecules, geldanamycin and radicicol, known to be natural Hsp (Heat Shot Protein) inhibitors, were modified to lead to a novel class of synthetic compounds, containing the isoxazole nucleus, and displaying potent and selective inhibition of Hsp90. Here we used erythroid precursors cells (ErPCs) isolated from β-thalassemic patients and treated with appropriate concentrations of 8 isoxazole derivatives previously demonstrated to be able to induce erythroid differentiation of K562 cells. Results: We demonstrated the high efficacy of the analyzed isoxazoles in inducing HbF. Some derivatives demonstrated an activity even higher than other HbF inducers used as positive controls, such as Hydroxyurea (HU) or Sirolimus. Most of the isoxazole derivatives displayed high effects in decreasing the excess of free α-globin chains in treated ErPCs. All the compounds were assayed for genotoxicity through the Ames test, employing the histidine-requiring Salmonella typhimurium mutant TA 97A, TA98, TA100 and TA1535 strains that allow to check frameshift mutation and base-pair substitution, with and without metabolic activation induced by S9 Mix. These assays excluded any drawbacks related to genotoxicity. Summary - Conclusion: We may therefore conclude that these novel isoxazoles could be proposed for clinical studies for possible therapeutic application for the treatment of β-thalassemia. These compounds have been recently patented as potential therapeutic agents for β-thalassemia (US Patent 11077116). Acknowledgements This study was sustained by the Wellcome Trust (innovator award 208872/Z/17/Z), by AIFA (AIFA-2016-02364887) and by the UE THALAMOSS Project (Thalassemia Modular Stratification System for Personalized Therapy of Βeta-Thalassemia; no. 306201-FP7-HEALTH-2012-INNOVATION-1). We thank A.L.T. (Associazione per la lotta alla Talassemia) “Rino Vullo” - Ferrara, and A.V.L.T. (Associazione Veneta per la Lotta alla Talassemia) “Elio Zago” - APS – Rovigo.

The R2-ISS in a Multicenter Cohort of Chinese Patients With Newly Diagnosed Multiple Myeloma.

The R2-ISS in a Multicenter Cohort of Chinese Patients With Newly Diagnosed Multiple Myeloma.

5613417 CO-TREATMENT OF ERYTHROID CELLS ISOLATED FROM Β039-THALASSEMIA PATIENTS WITH CRISPR-CAS9 GENE EDITING AND FETAL HEMOGLOBIN INDUCTION

Background: Gene editing (GE) can be considered among the most promising strategies to correct hereditary mutations in a variety of monogenetic diseases, including β-thalassemia. We have elsewhere reported that CRISPR-Cas9 gene editing can be proposed for efficient correction of the β039-thalassemia mutation. GE is suitable for personalized approaches in precision medicine for β-thalassemia [1]. Aims: On the other hand, robust evidence demonstrate that increased production of fetal hemoglobin (HbF) can be beneficial for β-thalassemia patients. This can be obtained also using CRISPR-Cas9 based protocols. In this case, the objective of the gene editing strategy is (a) the silencing of transcriptional repressors of the γ-globin genes (such as BCL11A), (b) the disruption of their regulatory binding sites within the γ-globin genes, or (c) the induction of natural hereditary persistence of fetal hemoglobin mutations in the γ-globin gene or the b-like-globin gene cluster. Our study aimed to verify whether the de novo production of adult hemoglobin (HbA) using CRISPR-Cas9 gene editing can be combined with HbF induction protocols based on the use of repositioned drugs. Results: Gene Editing of the β039-thalassemia mutation was obtained by the CRISPR-Cas9 method; gene correction and transcription of the corrected gene have been analyzed by allele-specific droplet digital PCR and RT-qPCR, respectively; production of HbA and HbF was studied by HPLC and Western blotting. For HbF induction, the repurposed drug sirolimus (rapamycin) was used. The data obtained conclusively demonstrate that maximal production of HbA and HbF is obtained in GE-corrected, sirolimus-induced erythroid progenitors from β039-thalassemia patients. In conclusion, GE and HbF in-duction might be used in combination in order to achieve the de novo production of HbA together with increased production of induced HbF. Acknowledgements This study was sustained by the Wellcome Trust (innovator award 208872/Z/17/Z) and by AIFA (AIFA-2016-02364887). The research leading to these results has received funding also from the UE THALAMOSS Project (Thalassemia Modular Stratification System for Personalized Therapy of Βeta-Thalassemia; no. 306201-FP7-HEALTH-2012-INNOVATION-1). We thanks A.L.T. (Associazione per la lotta alla Talassemia) “Rino Vullo” - Ferrara, and A.V.L.T. (Associazione Veneta per la Lotta alla Talassemia) “Elio Zago” - APS – Rovigo and Association “Tutti per Chiara”, Montagnana, PD, Italy. Reference 1. Cosenza L.C., Gasparello J., Romanini N., Zurlo M., Zuccato C., Gambari R., Finotti A. Efficient CRISPR-Cas9-based genome editing of β-globin gene on erythroid cells from homozygous β039-thalassemia patients. Mol Ther Methods Clin Dev 2021;21:507−523. https://doi.org/10.1016/j.omtm.2021.03.025