Predict Tumor Progression Research Articles

Pregnancy During Active Surveillance of Papillary Thyroid Microcarcinoma

Abstract Introduction: Most patients diagnosed with papillary thyroid microcarcinoma (microPTC) classified as low risk and therefore eligible for active surveillance (AS) are women. Although age is a predictor of tumor progression (more frequent among young people), young adults are “appropriate” candidates for AS. Consequently, a proportion of patients with low-risk microPTC eligible for AS are women of childbearing age and knowledge of the effect of pregnancy on tumor progression is therefore important. In the Japanese population, Ito et al. observed this progression in only 8% of pregnancies. None of the series on the outcomes of AS in western populations has so far reported the behavior of microPTC in women who became pregnant during AS. Methods: We have submitted patients with low-risk microPTC to AS. Our management has been not to interrupt AS, i.e., not to indicate surgery when the patient wishes to become pregnant. We report here the results of five patients who became pregnant during AS and their follow-up up to 6 months after delivery. Results: The patients were 26 to 36 years old (median 29 years) when they became pregnant. None of them had a history of radiation exposure, one had a family history of PTC, one had associated Hashimoto’s thyroiditis, and all of them had only one tumor focus and were considered “appropriate” (but not “ideal”) candidates for AS. In fact, when pregnancy was diagnosed, the patients continued to exhibit the criterion for AS according to our initial protocol (tumor ≤ 1.2 cm, no apparent lymph node metastases [LNM] or extrathyroidal extension [ETE] on ultrasonography [US]). All women were monitored by monthly measurement of TSH and levothyroxine (L-T4) was administered during pregnancy to maintain TSH between 0.1 and 1 mIU/L. US was performed when pregnancy was diagnosed (between 6 and 9 weeks of gestation), around 22 weeks, at the end of pregnancy, and 6 months after delivery. During the evaluations, none of the patients had apparent LNM or ETE on US. None of the patients exhibited tumor growth, defined as an increase in diameter ≥ 3 mm. Tumor growth ≥ 50% was observed in only one patient, with a small reduction after delivery. Conclusions: Our preliminary results suggest that pregnancy is not associated with a high risk of progression of low-risk microPTC and that the desire to get pregnant or pregnancy should not be an exclusion factor for AS.

Application of a Machine Learning Approach for the Analysis of Clinical and Radiomic Features of Pretreatment [18F]-FDG PET/CT to Predict Prognosis of Patients with Endometrial Cancer

To examine the prognostic significance of pretreatment 2-deoxy-2-[18F]fluoro-D-glucose ([18F]-FDG) positron emission tomography (PET)-based radiomic features using a machine learning approach in patients with endometrial cancers. Included in this retrospective study were 53 patients with endometrial cancers who underwent [18F]-FDG PET/X-ray computed tomography (CT) before treatment. Since two different PET scanners were used, post-reconstruction harmonization was performed for all PET parameters using the ComBat harmonization method. Four clinical (age, histological type, stage, and treatment method) and 40 [18F]-FDG PET-based radiomic features were ranked, and a subset of useful features was selected based on the decrease in the Gini impurity in terms of associations with disease progression. The machine learning algorithms (random forest, neural network, k-nearest neighbors (kNN), naive Bayes, logistic regression, and support vector machine) were compared using the areas under the receiver operating characteristic curve (AUC) and validated by the random sampling method. Progression-free survival (PFS) and overall survival (OS) were assessed by the Cox regression analysis. The five best predictors of disease progression were coarseness, gray-level run length nonuniformity, stage, treatment method, and gray-level zone length nonuniformity. The kNN model obtained the best performance classifier for predicting the disease progression (AUC =0.890, accuracy =0.849, F1 score =0.848, precision =0.857, and recall =0.849). Coarseness which was the first ranked radiomic feature was selected for survival analyses, and only coarseness remained as a significant and independent factor for both PFS (hazard ratios (HR), 0.65; 95 % confidence interval [CI], 0.49-0.86; p=0.003) and OS (HR, 0.52; 95 % CI, 0.36-0.76; p<0.001) at multivariate Cox regression analysis. [18F]-FDG PET-based radiomic analysis using a machine learning approach may be useful for predicting tumor progression and prognosis in patients with endometrial cancers.

Serum CYFRA 21.1 Level Predicts Disease Course in Thyroid Cancer with Distant Metastasis.

Simple SummaryThe role of serum Cyfra 21.1 as a biomarker in thyroid cancer has yet to be validated. This study investigated the diagnostic or prognostic role of serum Cyfra 21.1 in thyroid cancer. In the present analysis, we found that serum Cyfra 21.1 was increased in thyroid cancer with distant metastasis compared with thyroid cancer without metastasis. Furthermore, in progressive disease when thyroglobulin was undetectable or thyroglobulin monitoring was useless because of thyroglobulin antibody, serial follow-up based on serum Cyfra 21.1 levels might be used as an alternative biomarker for disease monitoring.Background: Serum Cyfra 21.1, the soluble fragment of CK19, has been used as a prognostic tumor marker in various cancers, indicating poor tumor differentiation and increased metastasis. Methods: We analyzed the serum Cyfra 21.1 level in 51 consecutive patients with thyroid cancer manifesting distant metastasis treated with prior total thyroidectomy. Serum Cyfra 21.1 levels of 26 thyroid cancer patients without metastasis and 50 healthy individuals were used for comparison. Results: Higher serum Cyfra 21.1 levels were detected in thyroid cancer patients with distant metastasis compared with healthy subjects and thyroid cancer patients without metastasis (p = 0.012). Serum Cyfra 21.1 levels were significantly increased in patients with positive BRAF V600E mutation (p = 0.019), undergoing Tyrosine Kinase Inhibitor (TKI) therapy (p = 0.008), with radioiodine-refractory status (p = 0.047), and in disease progression compared with those manifesting stable disease (p = 0.007). In progressive disease with undetectable or unmonitored thyroglobulin because of thyroglobulin antibody, serum Cyfra 21.1 was useful as a biomarker for follow-up of disease course. Conclusion: Serum Cyfra 21.1 in thyroid cancer patients might represent an alternative biomarker predicting tumor progression, especially in cases not associated with serum Tg levels.

Squamous differentiation is a potential biomarker predicting tumor progression in patients treated with pembrolizumab for urothelial carcinoma

Immune checkpoint inhibitor (ICI) is widely used and highly effective for some cancer patients but may result in disease progression in others. Hyperprogressive disease in particular is characterized by an acceleration of tumor growth during ICI therapy and has been reported in patients including those with urothelial carcinoma. Biomarkers predicting treatment efficacy are crucial to avoid tumor progression and unnecessary adverse effects. This study aims to clarify the predictors of disease progression for ICI treatment in patients with urothelial carcinoma. We analyzed the response pattern of 23 urothelial carcinomas treated with pembrolizumab and its association with pathological features and potential immunohistochemical markers including EGFR, MDM2, p53, p16, and programmed cell death ligand-1 (PD-L1) expression and CD8- and CD204-positive cell infiltration. During ICI therapy, 13 (57 %) patients showed progressive disease including 6 (26 %) with hyperprogressive disease. Notably, squamous differentiation combined with MAC387 expression was observed exclusively in cases with progressive disease (6 of 13, 46 %); it was not present in cases with stable disease or partial/complete response (0 of 10, p = 0.0019). All tumors with squamous differentiation showed positive staining for EGFR. Additionally, the loss of p16 expression occurred more frequently in cases with progressive disease (8 of 13, 62 %) than in other cases (3 of 10, 30 %), but this finding did not reach statistical significance. Squamous differentiation was also significantly associated with shorter overall survival. Based on our observations, squamous differentiation may be a novel biomarker for predicting disease progression in patients with urothelial carcinoma who receive pembrolizumab.

MCM7 as a marker of postsurgical progression in non-functioning pituitary adenomas.

Current markers predicting tumour progression of pituitary adenomas after surgery are insufficient. Our objective was to investigate if minichromosome maintenance protein 7 (MCM7) expression predicts tumour progression in non-functioning pituitary adenomas (NFPAs). In a cohort study of surgically treated NFPAs, two groups with distinctly different behaviour of a residual tumour were selected: one group requiring reintervention due to tumour progression (reintervention group, n = 57) and one with residual tumours without progression (radiologically stable group, n = 40). MCM7, Ki-67, oestrogen receptor-α expression, mitotic index and tumour subtype were assessed by immunohistochemistry, and their association with tumour progression requiring reintervention was analysed. Median (IQR) MCM7 expression was 7.4% (2.4-15.2) in the reintervention group compared with 2.0% (0.6-5.3) in the radiologically stable group (P <0.0001). Cox regression analysis showed an association between high (>13%) MCM7 expression and reintervention (HR: 3.1; 95% CI:1.7-5.4; P = 0.00012). The probability for reintervention within 6 years for patients with high MCM7 was 93%. Ki-67 expression >3% (P = 0.00062), age ≤55 years (P = 0.00034) and mitotic index≥1 (P = 0.024) were also associated with reintervention. Using a receiver operating characteristics curve, a predictive model for reintervention with all the above predictors yielded an area under the curve of 82%. All eight patients with both high MCM7 and high Ki-67 needed reintervention. This cohort study shows that expression of MCM7 is a predictor for clinically significant postoperative tumour progression. Together with age, Ki-67 and mitotic index, MCM7 might be of added value as a predictive marker when managing patients with NFPA after surgery.

Evaluation of Serum Biomarker CEA and Ca-125 as Immunotherapy Response Predictors in Metastatic Non-small Cell Lung Cancer.

Treatment options for advanced non-small cell lung cancer (NSCLC) include immunotherapy. Elevated carcinoembryonic antigen (CEA) and cancer antigen 125 (Ca-125) levels are associated with poorer prognoses of resected NSCLC, but currently no predictive biomarkers exist for immunotherapy response. This study evaluated CEA and Ca-125 as predictive biomarkers for immunotherapy efficiency in patients with metastatic NSCLC. The single-centre observational retrospective study includes NSCLC stage III/IV patients treated with programmed death-ligand 1 (PD-L1) inhibitors nivolumab or pembrolizumab. The primary study endpoint was treatment response assessed by CT-scan following RECIST-criteria 1.1. CEA/Ca-125 serum values were determined at initiation of treatment and repeated every 2 weeks. Values closest to the day of CT-scan were compared to baseline values. A total of 136 patients were treated with mono-immunotherapy. Of these, 73 patients were included in the CEA group and 53 patients were included in the Ca-125 group. Baseline CEA and Ca-125 ranged from 8.14 to 5,909 and 1.1 to 4,238 respectively. The sensitivity for Ca-125 as predictor for tumor response was 62.9% (95% CI=61.8%-63.6%), specificity 61.1% (95% CI=60.2%-62.0%), with a positive predictive value (PPV) of 75.9% (95% CI=75.2%-76.7%). For CEA, the sensitivity was 72.0% (95% CI=71.5%-72.5%), specificity 47.1% (95% CI 46.4%-47.8%), with a PPV of 80.0% (95% CI=79.6%-80.4%). Increased serum CEA might predict tumor progression in NSCLC patients treated with PD-L1 inhibitors. Unconfirmed progression accompanied by increased CEA would support discontinuation of the immunotherapy, while continuation would be advised when serum CEA is not increased.

The Role of Serum 5-HIAA as a Predictor of Progression and an Alternative to 24-h Urine 5-HIAA in Well-Differentiated Neuroendocrine Neoplasms.

Simple Summary5-hydroxyinoloacetic acid (5HIAA) is the breakdown product of serotonin and it is traditionally measured in 24-h urinary samples in patients with neuroendocrine neoplasms (NENs). 5HIAA measurement in patient serum has recently become available and has started replacing the traditional method in many centers, as it is more convenient and often preferred by patients. In this prospective, single center study, we aimed to investigate the clinical utility of serum 5HIAA for diagnostic purposes and disease surveillance in a cohort of patients with well-differentiated NENs. Our analysis confirmed an association between serum 5HIAA and the presence of liver metastases, as well as the extent of liver tumor involvement, demonstrating that the biomarker becomes positive in advanced disease stages. However, there was no evident association between a change in serum 5HIAA and change in disease status. Additionally, with respect to diagnostic purposes as compared to urinary 5HIAA testing, there was a substantial agreement between the two methods. In conclusion, serum 5HIAA performs well compared to urinary testing for diagnostic purposes but does not seem adequate as a solo biomarker of disease progression.Our aim was to investigate the clinical utility of serum 5HIAA for disease surveillance and diagnostic purposes in a cohort of patients with well-differentiated neuroendocrine neoplasms (WD-NENs). Forty-eight patients with WD-NENs and concurrent serum and urinary 5HIAA testing, as well as CT/MRI imaging, were included. Analysis of matching-pairs did not reveal any association between RECIST 1.1 responses and changes in serum 5HIAA levels (p = 0.673). In addition, no correlation was evident between RECIST 1.1 responses and >10%, >25% or >50% changes in serum 5HIAA levels (Fisher’s exact test p = 0.380, p > 0.999, and p > 0.999, respectively). The presence of liver metastases and extensive liver tumor involvement were associated with higher serum 5HIAA levels (p = 0.045 and p = 0.041, respectively). We also confirmed a strong linear correlation between the measurements of serum and urine 5HIAA (n = 24, r = 0.791, p < 0.0001). The concordance rate of serum and urinary 5HIAA positivity at standardized laboratory cut-offs was 75%. In patients with normal renal function tests, the concordance between the two methods was as high as 89%, and a sensitivity and specificity of 80% and 88.9%, respectively, was evident (Cohen’s kappa coefficient = 0.685). In conclusion, serum 5HIAA performs well compared to urinary testing for diagnostic purposes, mainly in advanced disease stages, and corresponds well to liver tumor burden. However, it is not adequate to predict tumor progression.

Apparent diffusion coefficient as a prognostic factor in clival chordoma

Clival chordoma is a rare disease with high recurrence rates even after a combination of surgical resection and radiotherapy. Apparent diffusion coefficient (ADC) has been used to evaluate aggressive features of chordoma, but its utility for clival chordoma has not been explored specifically. In this study, the utility of preoperative ADC values was analyzed for predicting tumor progression and recurrence in patients with clival chordoma. Between 2012 and 2019, a total of 30 operated cases were analyzed with available preoperative ADC data. Receiver operating characteristic (ROC) analysis was used to obtain ADC cutoff values for predicting tumor aggressiveness. The mean and minimum ADC values were significantly lower in the aggressive tumor group than in the stable tumor group (both P < 0.001). ROC analysis showed that a mean cutoff ADC value of 1198 × 10−6 mm2/s and minimum ADC value of 895.5 × 10–6 mm2/s could be used to predict aggressive features of clival chordoma. Subtotal resection, partial resection, and mean and minimum ADC values that were lower than cutoff values were negative predictors of overall survival and progression-free survival. In conclusion, mean and minimum ADC values could be useful in predicting aggressiveness of clival chordoma.

Evaluation of annexin A2 and S100A4 expression as prognostic markers in endometrioid endometrial carcinoma

Background Annexin A2 (ANXA2) and S100A4 proteins might have important roles as biomarkers in progression and metastasis of several tumors. Aim The aim of this study was to investigate the expression of both ANXA2 and S100A4 in endometrioid carcinoma (EC) and to correlate their expression with the clinicopathological and prognostic features including patients’ survival. Patients and methods ANXA2 and S100A4 immunohistochemical expression was analyzed in 54 samples of EC and 20 proliferative endometrium. The overall survival (OS) and disease-free survival (DFS) were determined by Kaplan–Meier analysis. Results ANXA2 and S100A4 overexpression was detected in 64.8 and 74.1% of EC, respectively, which was significantly higher as compared with proliferative endometrium (P&lt;0.001). ANXA2 expression was significantly correlated with tumor grade (P=0.011). Furthermore, a significant correlation was identified between ANXA2 and S100A4 expression and advanced International (FIGO) Federation of Gynecology and Obstetrics stage (P=0.004 and 0.001, respectively), myometrial invasion (P=0.03 and 0.019, respectively), and lymph node metastasis (P=0.001 and P&lt;0.001, respectively). The expression of ANXA2 and S100A4 was positively correlated [Spearman correlation coefficient (r)=0.501, P&lt;0.05). Kaplan–Meier survival curves revealed a significant relation between ANXA2 and S100A4 overexpression and reduced DFS (P=0.001 and P=0.015, respectively) and worse OS (P=0.008 and 0.034, respectively). Analysis of the coexpression of both markers revealed that ANXA2/S100A4 high expression group exhibited the lowest 3-year DFS and OS in patients with EC as compared with the other groups. Conclusion Combined detection of ANXA2 and S100A4 may serve as an important index to estimate the biological behavior and predict tumor progression and prognosis of EC.

Spatiotemporal Heterogeneity in Multiparametric Physiologic MRI Is Associated with Patient Outcomes in IDH-Wildtype Glioblastoma.

Heterogeneity in glioblastomas is associated with poorer outcomes, and physiologic heterogeneity can be quantified with noninvasive imaging. We developed spatial habitats based on multiparametric physiologic MRI and evaluated associations between temporal changes in these habitats and progression-free survival (PFS) after concurrent chemoradiotherapy (CCRT) in patients with glioblastoma. Ninety-seven patients with isocitrate dehydrogenase (IDH)-wildtype glioblastoma were enrolled and two serial MRI examinations after CCRT were analyzed. Cerebral blood volumes and apparent diffusion coefficients were grouped using k-means clustering into three spatial habitats. Associations between temporal changes in spatial habitats and PFS were investigated using Cox proportional hazard modeling. The performance of significant predictors for PFS and overall survival (OS) was measured using a discrete increase of habitat (habitat risk score) in a temporal validation set from a prospective registry (n = 53, ClinicalTrials.gov NCT02619890). The site of progression was matched with the spatiotemporal habitats. Three spatial habitats of hypervascular cellular, hypovascular cellular, and nonviable tissue were identified. A short-term increase in the hypervascular cellular habitat (HR, 40.0; P = 0.001) and hypovascular cellular habitat was significantly associated with shorter PFS (HR, 3.78; P < 0.001) after CCRT. Combined with clinical predictors, the habitat risk score showed a C-index of 0.79 for PFS and 0.74 for OS and stratified patients with short, intermediate, and long PFS (P = 0.016). An increase in the hypovascular cellular habitat predicted tumor progression sites. Hypovascular cellular habitats derived from multiparametric physiologic MRIs may be useful predictors of clinical outcomes in patients with posttreatment glioblastoma.

High MCM6 Expression as a Potential Prognostic Marker in Clear-cell Renal Cell Carcinoma.

Minichromosome maintenance (MCM) proteins are involved in initiation of DNA replication and cell-cycle progression. Loss of MCM function results in genomic instability and causes carcinogenesis. Among MCM genes, the role and prognostic value of MCM6 expression in clear-cell renal cell carcinoma (ccRCC) has not been elucidated. We assessed the mRNA expression level of MCM6 using the Gene Expression Profiling Interactive Analysis database and investigated MCM6 protein expression by immunohistochemistry in 238 ccRCC cases. High MCM6 expression was significantly associated with increasing tumor size, pT, stage, tumor necrosis, and metastasis. Furthermore, high MCM6 expression was significantly associated with shorter overall and disease-free survival, and was an independent unfavorable prognostic marker. Regarding patients with metastasis, high MCM6-expressing ccRCC conferred significantly shorter survival than for those with low expression. A high MCM6 expression level may be a promising biomarker to predict tumor progression, metastasis, and survival in patients with ccRCC.

Commentary: Effect of Anatomic Segment Involvement on Stereotactic Radiosurgery for Facial Nerve Schwannomas: An International Multicenter Cohort Study.

Background Facial nerve schwannomas are rare, challenging tumors to manage due to their nerve of origin. Functional outcomes after stereotactic radiosurgery (SRS) are incompletely defined. Objective To analyze the effect of facial nerve segment involvement on functional outcome for these tumors. Methods Patients who underwent single-session SRS for facial nerve schwannomas with at least 3 mo follow-up at 11 participating centers were included. Preoperative and treatment variables were recorded. Outcome measures included radiological tumor response and neurological function. Results A total of 63 patients (34 females) were included in the present study. In total, 75% had preoperative facial weakness. Mean tumor volume and margin dose were 2.0 ± 2.4 cm3 and 12.2 ± 0.54 Gy, respectively. Mean radiological follow-up was 45.5 ± 38.9 mo. Progression-free survival at 2, 5, and 10 yr was 98.1%, 87.2%, and 87.2%, respectively. The cumulative proportion of patients with regressing tumors at 2, 5, and 10 yr was 43.1%, 63.6%, and 63.6%, respectively. The number of involved facial nerve segments significantly predicted tumor progression (P = .04). Facial nerve function was stable or improved in 57 patients (90%). Patients with involvement of the labyrinthine segment of the facial nerve were significantly more likely to have an improvement in facial nerve function after SRS (P = .03). Hearing worsened in at least 6% of patients. Otherwise, adverse radiation effects included facial twitching (3 patients), facial numbness (2 patients), and dizziness (2 patients). Conclusion SRS for facial nerve schwannomas is effective and spares facial nerve function in most patients. Some patients may have functional improvement after treatment, particularly if the labyrinthine segment is involved.

Effect of Anatomic Segment Involvement on Stereotactic Radiosurgery for Facial Nerve Schwannomas: An International Multicenter Cohort Study.

Facial nerve schwannomas are rare, challenging tumors to manage due to their nerve of origin. Functional outcomes after stereotactic radiosurgery (SRS) are incompletely defined. To analyze the effect of facial nerve segment involvement on functional outcome for these tumors. Patients who underwent single-session SRS for facial nerve schwannomas with at least 3 mo follow-up at 11 participating centers were included. Preoperative and treatment variables were recorded. Outcome measures included radiological tumor response and neurological function. A total of 63 patients (34 females) were included in the present study. In total, 75% had preoperative facial weakness. Mean tumor volume and margin dose were 2.0± 2.4cm3 and 12.2±0.54Gy, respectively. Mean radiological follow-up was 45.5±38.9 mo. Progression-free survival at 2, 5, and 10 yr was 98.1%, 87.2%, and 87.2%, respectively. The cumulative proportion of patients with regressing tumors at 2, 5, and 10 yr was 43.1%, 63.6%, and 63.6%, respectively. The number of involved facial nerve segments significantly predicted tumor progression (P=.04). Facial nerve function was stable or improved in 57 patients (90%). Patients with involvement of the labyrinthine segment of the facial nerve were significantly more likely to have an improvement in facial nerve function after SRS (P=.03). Hearing worsened in at least 6% of patients. Otherwise, adverse radiation effects included facial twitching (3 patients), facial numbness (2 patients), and dizziness (2patients). SRS for facial nerve schwannomas is effective and spares facial nerve function in most patients. Some patients may have functional improvement after treatment, particularly if the labyrinthine segment is involved.

A Risk Classifier Model that Predicts Tumor Progression in Cranial Base Chondrosarcoma Patients

A Risk Classifier Model that Predicts Tumor Progression in Cranial Base Chondrosarcoma Patients

Cyclin G2, a novel target of sulindac to inhibit cell cycle progression in colorectal cancer

Sulindac has shown significant clinical benefit in preventing colorectal cancer progression, but its mechanism of action has not been fully elucidated. We have found that sulindac sulfide (SS) is able to inhibit cell cycle progression in human colorectal cancer cells, particularly through G1 arrest. To understand the underlying mechanisms of sulindac inhibitory activity, we have demonstrated that Cyclin G2 up-regulation upon SS treatment can substantially delay cell cycle progression by enhancing the transcriptional activity of FOXO3a in human colorectal tumor cells. MiR-182, an oncogenic microRNA known to inhibit FOXO3a gene expression, is also involved in the suppressive effect of SS on cell cycle progression. This process begins with the down-regulation of miR-182, followed by the enhancement of FOXO3a transcriptional activity and the up-regulation of Cyclin G2. To further determine the clinical utility of this axis, we analyzed the expression of miR-182/FOXO3a/Cyclin G2 in human colorectal tumor samples. Our results show not only that there are significant differences in miR-182/FOXO3a/Cyclin G2 between tumors and normal tissues, but also that the synergetic effect of miR-182 and FOXO3a is associated with predicting tumor progression. Our study demonstrates a novel mechanistic axis consisting of miR-182/FOXO3a/Cyclin G2 that mediates sulindac inhibition of cell cycle progression.

Combining epigenetic and clinicopathological variables improves specificity in prognostic prediction in clear cell renal cell carcinoma

BackgroundMetastasized clear cell renal cell carcinoma (ccRCC) is associated with a poor prognosis. Almost one-third of patients with non-metastatic tumors at diagnosis will later progress with metastatic disease. These patients need to be identified already at diagnosis, to undertake closer follow up and/or adjuvant treatment. Today, clinicopathological variables are used to risk classify patients, but molecular biomarkers are needed to improve risk classification to identify the high-risk patients which will benefit most from modern adjuvant therapies. Interestingly, DNA methylation profiling has emerged as a promising prognostic biomarker in ccRCC. This study aimed to derive a model for prediction of tumor progression after nephrectomy in non-metastatic ccRCC by combining DNA methylation profiling with clinicopathological variables.MethodsA novel cluster analysis approach (Directed Cluster Analysis) was used to identify molecular biomarkers from genome-wide methylation array data. These novel DNA methylation biomarkers, together with previously identified CpG-site biomarkers and clinicopathological variables, were used to derive predictive classifiers for tumor progression.ResultsThe “triple classifier” which included both novel and previously identified DNA methylation biomarkers together with clinicopathological variables predicted tumor progression more accurately than the currently used Mayo scoring system, by increasing the specificity from 50% in Mayo to 64% in our triple classifier at 85% fixed sensitivity. The cumulative incidence of progress (pCIP5yr) was 7.5% in low-risk vs 44.7% in high-risk in M0 patients classified by the triple classifier at diagnosis.ConclusionsThe triple classifier panel that combines clinicopathological variables with genome-wide methylation data has the potential to improve specificity in prognosis prediction for patients with non-metastatic ccRCC.

Use of a Novel Thyroid-Stimulating Hormone Model for Predicting the Progression of Hepatocellular Carcinoma.

BackgroundIndividuals with hepatocellular carcinoma (HCC) are at risk of tumor recurrence after surgical resection, which affects their survival. The aim of the present study was to establish a model for predicting tumor progression in patients with HCC.MethodsTo develop and validate the efficacy of a novel prognostic model, a retrospective cohort with HCC (n = 1005) at Beijing Ditan Hospital was enrolled from January 2008 and June 2017. Furthermore, a prospective cohort (n = 77) was recruited to validate the association between thyroid-stimulating hormone (TSH) levels and tumor progression in patients with HCC.ResultsThe model used in predicting the progression of HCC included four variables (namely, Barcelona Clinic Liver Cancer [BCLC] stage, presence of portal vein tumor thrombus, alpha-fetoprotein level, and TSH level). The AUROC of the 1-year progression-free survival (PFS) model was 0.755 and 0.753 in the deriving cohort and validation cohort, respectively, and these values were significantly higher than those of the Child–Pugh score, Model for End-stage Liver Disease (MELD), tumor–lymph node–metastasis (TNM) staging system, Okuda classification, and CLIP score. A simple assessment using a nomogram showed the 1-year PFS rate of patients with HCC. In the prospective cohort, the KM curve showed that the high TSH level group had a shorter PFS than the low TSH level (p = 0.001).ConclusionThe prognostic model of HCC progression was superior to other well-known classical tumor scoring systems. A high TSH level was correlated to poor outcome, particularly those with advanced HCC.

A Comparison Study of Machine Learning (Random Survival Forest) and Classic Statistic (Cox Proportional Hazards) for Predicting Progression in High-Grade Glioma after Proton and Carbon Ion Radiotherapy.

BackgroundMachine learning (ML) algorithms are increasingly explored in glioma prognostication. Random survival forest (RSF) is a common ML approach in analyzing time-to-event survival data. However, it is controversial which method between RSF and traditional cornerstone method Cox proportional hazards (CPH) is better fitted. The purpose of this study was to compare RSF and CPH in predicting tumor progression of high-grade glioma (HGG) after particle beam radiotherapy (PBRT).MethodsThe study enrolled 82 consecutive HGG patients who were treated with PBRT at Shanghai Proton and Heavy Ion Center between 6/2015 and 11/2019. The entire cohort was split into the training and testing set in an 80/20 ratio. Ten variables from patient-related, tumor-related and treatment-related information were utilized for developing CPH and RSF for predicting progression-free survival (PFS). The model performance was compared in concordance index (C-index) for discrimination (accuracy), brier score (BS) for calibration (precision) and variable importance for interpretability.ResultsThe CPH model demonstrated a better performance in terms of integrated C-index (62.9%) and BS (0.159) compared to RSF model (C-index = 61.1%, BS = 0.174). In the context of variable importance, CPH model indicated that age (P = 0.024), WHO grade (P = 0.020), IDH gene (P = 0.019), and MGMT promoter status (P = 0.040) were significantly correlated with PFS in the univariate analysis; multivariate analysis showed that age (P = 0.041), surgical completeness (P = 0.084), IDH gene (P = 0.057), and MGMT promoter (P = 0.092) had a significant or trend toward the relation with PFS. RSF showed that merely IDH and age were of positive importance for predicting PFS. A final nomogram was developed to predict tumor progression at the individual level based on CPH model.ConclusionsIn a relatively small dataset with HGG patients treated with PBRT, CPH outperformed RSF for predicting tumor progression. A comprehensive criterion with accuracy, precision, and interpretability is recommended in evaluating ML prognostication approaches for clinical deployment.

ZEB1 as an additional predictor of tumor progression in Ewingʼs sarcoma. Results of a morphological study on a population of children and adolescents

Relevance. Ewingʼs sarcoma (ES) is a classic representative of the extensive family of ES tumors, which occupies one of the leading positions among the malignant pathology of the musculoskeletal system in children and adolescents. This group is characterized by an extremely large variety of morphological, immunohistochemical, and molecular genetic characters among its representatives. The absence of specific pathognomonic markers for ES, as well as the presence of wide variability of clinical manifestations complicates the differential diagnosis. Materials and methods. The study included patients of childhood and adolescence with a localized and generalized form of ES/PNEТ of various localizations undergoing treatment in the conditions of the Department of Pediatric Oncology of the Federal State Budgetary Research Center for Oncology from 2009 to 2019. As the material, the tissue of the primary tumor of ES/PNEТ from paraffin blocks was used, obtained from 67 patients during the primary biopsy, as well as after the surgical stage as part of a combined or complex treatment. The expression of ZEB1 was determined immunohistochemically.Results. The highest average level of expression of ZEB1 protein was observed in group 4 with a generalized form of ES (surgical material) and amounted to 60.8 ± 2.2 %, the minimum level was detected in group 2 with a localized form of ES (surgical material) and amounted to 29.2 ± 3.0 %. Between groups 2 (localized form) and 4 (generalized form) statistically significant differences were noted (p = 0.026).Conclusion. As a result of an immunohistochemical study, the ZEB1 protein showed its prognostic significance when comparing groups with a localized and generalized form of ES (p = 0.026). The predominance of the expression level of ZEB1 protein in the group with the generalized form statistically significantly increased the chances of metastasis by 3.6 times (95 % CI 1.13-11.8).

1185P [18F]FDG-PET/CT and long-term response to everolimus in advanced neuroendocrine neoplasia

In the last few years, 18F-fluorodeoxyglucose PET/CT (FDG-PET) has emerged as an important tool to define tumor aggressiveness and give relevant prognostic information, with several studies investigating its role in the diagnostic approach and during the follow-up of NENs. However, although a positive correlation between FDG-PET and other well-known predictors of response to anti-tumor therapy as Ki67 has been demonstrated, the ability of this diagnostic tool to predict treatment efficacy is not well established. Furthermore, the possible impact of positive FDG-PET on everolimus efficacy remains unclear. This study aims to identify, in these patients, potential correlation between FDG-PET findings and response to therapy in search of a predictor of long-term efficacy. Retrospective analysis of patients with sporadic, advanced, progressive NEN treated with everolimus, with available data on FDG-PET before commencing therapy. Data is expressed as median (25th – 75th IQR). Risk factor analysis and survival analysis are performed by logistic regression and Cox proportional-hazard regression and Kaplan-Meier curves, as appropriate. Sixty-six patients evaluated (NET G1 19.7%, NET G2 75.7%, NET G3 4.6%), including 45.4% with positive FDG-PET. Overall, disease stabilization and partial response were obtained in 71.2% and 6% of patients, respectively. Long-term response (> 24 months) was observed in 33% of patients. Ki67 was the only predictor for tumor progression (p=0.03). No significant difference in clinical outcome was observed between patients with positive or negative FDG-PET (median PFS was 24 months and 18 months, respectively, p=0.337; disease control rate was 83.3% and 70%, respectively, p=0.245). Everolimus is a valid therapeutic option for advanced, progressive, well-differentiated NENs, even in those patients with positive FDG-PET.