scholarly journals S-GRAS score for prognostic classification of adrenocortical carcinoma: an international, multicenter ENSAT study

2021 ◽  
Author(s):  
Yasir S Elhassan ◽  
Barbara Altieri ◽  
Sarah Berhane ◽  
Deborah Cosentini ◽  
Anna Calabrese ◽  
...  
Keyword(s):  
Adrenocortical Carcinoma ◽  
Progression Free Survival ◽  
Ki67 Index ◽  
Tumour Stage ◽  
Discriminative Performance ◽  
Prognostic Performance ◽  
Prognostic Stratification ◽  
The Individual ◽  
Stage 1 ◽  
Individual Scores

Objective: Adrenocortical carcinoma (ACC) has an aggressive but variable clinical course. Prognostic stratification based on ENSAT tumour stage and Ki67 index is limited. We aimed to demonstrate the prognostic role of a points-based score (S-GRAS) in a large cohort of patients with ACC. Design: Multicentre retrospective study on ACC patients who underwent adrenalectomy. Methods: The S-GRAS score was calculated as a sum of the following points: tumour Stage (1-2=0; 3=1; 4=2), Grade (Ki67 index 0-9%=0; 10-19%=1; ≥20%=2 points), Resection (R)-status (R0=0; RX=1; R1=2; R2=3), Age (<50yr=0; ≥50yr=1), Symptoms (no=0; yes=1), and categorised, generating four groups (0-1, 2-3, 4-5, and 6-9). Endpoints were progression-free survival (PFS) and disease-specific survival (DSS). The discriminative performance of S-GRAS and its components was tested by Harrell’s C-index and Royston-Sauerbrei’s R2D statistic. Results: We included 942 ACC patients. The S-GRAS score showed superior prognostic performance for both PFS and DSS, with best discrimination obtained using the individual scores (0-9) (C-index=0.73, R2D=0.30, and C-index=0.79, R2D=0.45, respectively, all P<0.01 vs each component). The superiority of S-GRAS score remained when comparing patients treated or not with adjuvant mitotane (n=481 vs 314). In particular, the risk of recurrence was significantly reduced as a result of adjuvant mitotane only in patients with S-GRAS 4-5. Conclusion: The prognostic performance of S-GRAS is superior to tumour stage and Ki67 in operated ACC patients, independently from adjuvant mitotane. S-GRAS score provides a new important guide for personalised management of ACC (i.e. radiological surveillance and adjuvant treatment).

scholarly journals Modified GRAS Score for Prognostic Classification of Adrenocortical Carcinoma: An ENSAT Multicentre Study

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A165-A166
Author(s):  
Yasir Elhassan ◽  
Barbara Altieri ◽  
Sarah Berhane ◽  
Deborah Cosentini ◽  
Anna Calabrese ◽  
...  
Keyword(s):  
Adrenocortical Carcinoma ◽  
Progression Free Survival ◽  
Proliferation Index ◽  
Discriminative Performance ◽  
Resection Status ◽  
Secondary Endpoints ◽  
Risk Of Disease ◽  
Personalised Treatment ◽  
The Individual ◽  
Stage 1

Abstract Background: Adrenocortical carcinoma (ACC) has an aggressive but heterogeneous behaviour. ENSAT stage and Ki67 proliferation index are used to predict clinical outcome but are limited in distinguishing patients with different risk of disease progress. We aimed to validate the prognostic role of a previously proposed points-based score (mGRAS) in a large ACC cohort. Methods: We included ACC patients who underwent adrenalectomy between 2010 and 2019, had complete clinical and histopathological data, and did not participate in our previous studies (Libe et al. Ann Oncol 2015; Lippert et al. JCEM 2018). The mGRAS score was calculated as follows: age (&lt;50yr=0; ≥50yr =1), symptoms (no=0; yes=1), ENSAT stage (1–2=0; 3=1; 4=2), resection status (R0=0; RX=1; R1=2; R2=3), and Ki67 (0–9%=0; 10–19%=1; ≥20%=2 points), generating scores from 0 to 9 and four mGRAS groups (scores 0–1, 2–3, 4–5, and 6–9). Progression-free survival (PFS) and disease-specific survival (DSS) were the primary and secondary endpoints, respectively. The discriminative performance of mGRAS was investigated using the Harrell’s C-index and Royston-Sauerbrei’s R2D statistic. Results: A total of 942 ACC patients from 14 ENSAT centres were included (38% men; median age 50yrs (interquartile range 38, 61)). The four mGRAS groups showed superior prognostic discrimination compared to the individual clinical and histological parameters for both PFS and DSS (C-index 0.71, R2D=0.30 and 0.77, R2D=0.46, respectively); ENSAT staging was the second best discriminator (C-index 0.67, R2D 0.21 and 0.72, R2D=0.35, respectively). An even better prognostic discrimination was observed using the ten mGRAS scores individually (C-index 0.73, R2D=0.30, and 0.79, R2D=0.45 for PFS and DSS, respectively). The superiority of mGRAS was confirmed when separately considering patients treated or untreated with adjuvant mitotane (n=481 vs 314). In mitotane-treated patients, the four mGRAS groups showed better performance in predicting PFS than Ki67 index (C-index 0.66, R2D 0.18 vs C-index 0.62, R2D 0.12). Conclusion: The prognostic performance of mGRAS is superior to that of ENSAT staging and Ki67. This simple score may guide personalised treatment decisions in patients with ACC, e.g. regarding the need for adjuvant therapy and frequency of monitoring.

scholarly journals SAT-180 Adrenocortical Carcinoma - A Tertiary Center’s Recent 5-Year Experience

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Michal Ehrenwald ◽  
Karen Michele Tordjman ◽  
Naftali Stern ◽  
Joseph Klausner ◽  
Ido Nachmany ◽  
...  
Keyword(s):  
Rare Disease ◽  
Adrenocortical Carcinoma ◽  
Poor Prognosis ◽  
Progression Free Survival ◽  
Second Primary ◽  
Study Cohort ◽  
Time To Death ◽  
Stage 4 ◽  
Stage 1

Abstract BACKGROUND: Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with poor prognosis. The aim of this study was to characterize patients diagnosed with ACC at a single center between 2014-2019. METHODS: We retrospectively reviewed data regarding demographics, tumor characteristics and functionality, treatment and survival. RESULTS: The study cohort included 27 subjects (56% females), followed for 27±10.6 months. The mean age at diagnosis was 49.4±9 years. Co-morbidities at presentation included hypertension (63%), diabetes mellitus (22%) and dyslipidemia (26%). 74.1% of tumors were functioning – of which 85% were cortisol-secreting and 15% androgen-secreting. Aldosterone was secreted additionally in 15%. ENSAT stage at diagnosis was stage 1 in 15%, stage 2 in 35%, stage 3 in 12% and stage 4 in 38%. Eighty-nine % of patients underwent surgery. Treatment with mitotane was initiated in 82% of patients, reaching a mean maximal dose of 3.3 ±0.4 grams/day. Chemotherapy and/or radiation were given in 37% and 22%, respectively. Several patients (14.8%) had a second primary cancer, diagnosed before ACC in 75%. Progression was observed in 48% of patients, with a progression-free survival of 8.3±6.6 months. Thirty-five % of patients died during follow up, time to death was 12.8±0.4 months. Twenty two % of patients survived over 30 months after diagnosis. KI67 above 20% or stage above 2 negatively affected survival. CONCLUSIONS: ACC remains a rare disease with a poor prognosis. However, it is a heterogeneous disease, with some patients achieving survival of over 30 months after diagnosis. Further characterization of this population may improve our understanding of the biology and treatment of this rare disease.

scholarly journals Effectiveness of Guided Writing in Teaching Composition

2015 ◽  
Vol 4 ◽  
pp. 18-25
Author(s):  
Dipendra Kumar Khatri
Keyword(s):  
Data Collection ◽  
Secondary School ◽  
Sample Population ◽  
Guided Writing ◽  
Post Test ◽  
Teaching Composition ◽  
The Individual ◽  
Individual Scores ◽  
Experimental Group ◽  
Practical Teaching

This article summarizes the study conducted to find out the effectiveness of guided writing in teaching composition. Fifty-two students of grade nine studying at Khelnechour Secondary School, Surkhet were the sample population of this research. The researcher requested one of the teachers to involve in the practical teaching for carrying out the research. The tests (pre-test and post test) were the major tools for data collection. The students were ranked from the first to the fifty-second position based on the results of the pre-test. They were divided into two groups based on odd-even ranking of the individual scores. Then, experimental group was taught through guided writing activities whereas controlled group was taught without guided writing activities. Each groups attended thirty lessons. Then the post-test was administered. The results of these two tests (Pre and Post) were compared and found that guided writing activities were more effective in teaching composition. Journal of NELTA Surkhet Vol.4 2014: 18-25

scholarly journals Immunotherapy in Adrenocortical Carcinoma: Predictors of Response, Efficacy, Safety, and Mechanisms of Resistance

Biomedicines ◽  
2021 ◽  
Vol 9 (3) ◽  
pp. 304
Author(s):  
Marta Araujo-Castro ◽  
Eider Pascual-Corrales ◽  
Javier Molina-Cerrillo ◽  
Teresa Alonso-Gordoa
Keyword(s):  
Adrenocortical Carcinoma ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Progression Free Survival ◽  
Mechanisms Of Resistance ◽  
Response Efficacy ◽  
Predictors Of Response ◽  
Primary Endpoints ◽  
Tumor Mutational Burden

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with limited treatment options in the advanced stages. Immunotherapy offers hope for altering the orthodox management of cancer, and its role in advanced ACC has been investigated in different studies. With the aim clarifying the role of immunotherapy in ACC we performed a comprehensive review about this topic focusing on the predictors of response, efficacy, safety, and the mechanisms of resistance. Five clinical trials with four immune checkpoint inhibitors (pembrolizumab, avelumab, nivolumab, and ipilimumab) have investigated the role of immunotherapy in advanced ACC. Despite, the different primary endpoints used in these studies, the reported rates of overall response rate and progression free survival were generally poor. Three main potential markers of response to immunotherapy in ACC have been described: Expression of PD-1 and PD-L1, microsatellite instability and tumor mutational burden. However, none of them has been validated in prospective studies. Several mechanisms of ACC immunoevasion may be responsible of immunotherapy failure, and a greater knowledge of these mechanisms might lead to the development of new strategies to overcome the immunotherapy resistance. In conclusion, although currently the role of immunotherapy is limited, the identification of immunological markers of response and the implementation of strategies to avoid immunotherapy resistance could improve the efficacy of this therapy.

Palbociclib (P) in patients (pts) with soft tissue sarcoma (STS) with CDK4 amplification: Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 11565-11565
Author(s):  
Scott Schuetze ◽  
Michael Rothe ◽  
Pam K. Mangat ◽  
Liz Garrett-Mayer ◽  
Funda Meric-Bernstam ◽  
...  
Keyword(s):  
Treatment Options ◽  
Objective Response ◽  
Progression Free Survival ◽  
Complete Response ◽  
Stage Design ◽  
Secondary Endpoints ◽  
Grade 3 ◽  
Ecog Ps ◽  
Stage 1 ◽  
Anti Tumor Activity

11565 Background: TAPUR is a phase II basket study evaluating anti-tumor activity of commercially available targeted agents in pts with advanced cancers with genomic alterations. Results in a cohort of STS pts with CDK4 amplification treated with P are reported. Methods: Eligible pts had advanced STS, no standard treatment options, measurable disease, ECOG PS 0-2, and adequate organ function. Genomic testing was performed in CLIA-certified, CAP-accredited site selected labs. Pts received P at 125 mg orally once daily for 21 days, followed by 7 days off until disease progression. Pts matched to P had CDK4 amplification and no RB mutations. Simon 2-stage design tested the null disease control (DC) - defined as partial (PR), complete response (CR) or stable disease at 16+ weeks (SD 16+) - rate of 15% vs. 35% (power = 0.85; α = 0.10). If ≥2 of 10 pts in stage 1 have DC, 18 more pts are enrolled. If ≥7 of 28 pts have DC, the null DC rate is rejected. Secondary endpoints are progression-free survival (PFS), overall survival (OS) and safety. Results: 29 pts (66% male) with STS with CDK4 amplification were enrolled from July 2016 to Nov 2019. 1 pt was not evaluable and excluded from efficacy analyses. Demographics and outcomes are summarized in Table. One pt with partial response (PR) and 12 pts with SD16+ were observed for DC and objective response (OR) rates of 48% (95% CI: 31%, 62%) and 3.7% (95% CI: 0.1%, 19%), respectively, and the null DC rate of 15% was rejected (p<0.001). 9/13 pts with DC continued on treatment for >32 weeks. 14 pts had at least one grade 3-4 AE at least possibly related to P with the most common being low WBC/platelets. Other grade 3 AEs included increased alanine aminotransferase, anemia, and fatigue. Conclusions: Monotherapy P demonstrated anti-tumor activity in heavily pre-treated pts with STS with CDK4 amplification. Additional study is warranted to confirm the efficacy of P in pts with STS with CDK4 amplification. Clinical trial information: NCT02693535. [Table: see text]

Combination of mitotane and locoregional treatments in low-volume metastatic adrenocortical carcinoma

2021 ◽  
Author(s):  
Alice Boileve ◽  
Elise Mathy ◽  
Charles Roux ◽  
Matthieu Faron ◽  
Julien Hadoux ◽  
...  
Keyword(s):  
Adrenocortical Carcinoma ◽  
Stage Iv ◽  
Retrospective Chart Review ◽  
Progression Free Survival ◽  
Complete Response ◽  
Tumor Burden ◽  
Interquartile Range ◽  
First Line ◽  
Chemotherapy Administration ◽  
Metastatic Sites

Abstract Purpose European and French guidelines for ENSAT stage IV low tumor burden or indolent adrenocortical carcinoma (ACC) recommend combination of mitotane and locoregional treatments (LRT) in first-line. Nevertheless, the benefit of LRT combination with mitotane has never been evaluated in this selected group of patients. Methods A retrospective chart review was performed from 2003-2018 of patients with stage IV ACC with ≤2 tumoral organs who received mitotane in our center. Primary endpoint was the delay between mitotane initiation and first systemic chemotherapy. Secondary endpoints were progression-free survival (PFS) and overall survival (OS) from mitotane initiation. Adjusted analyses were performed on the main prognostic factors. Results Out of 79 included patients, 48 (61%) patients were female and median age at stage IVA diagnosis was 49.8 years (interquartile-range:38.8-60.0). Metastatic sites were mainly lungs (76%) and liver (48%). Fifty-eight (73%) patients received LRT including adrenal bed radiotherapy (14 patients, 18%), surgery (37 patients, 47%) and/or interventional radiology n(35,44%). Median time between mitotane initiation and first chemotherapy administration was 9 months (Interquartile-range:4-18). Median PFS1 (first tumor-progression) was 6.0 months (CI95%:4.5-8.6). Median OS was 46 months (CI95%:41-68). PFS1, PFS2 and OS were statistically longer in the mitotane plus LRT group compared to the mitotane-only group (Hazard ratio (HR)=0.39 (CI95%:0.22-0.68), HR=0.35 (CI95%:0.20-0.63) and HR=0.27 (CI95%:0.14-0.50) respectively). Ten (13%) patients achieved complete response, all from mitotane plus LRT group. Conclusion Our results endorse European and French guidelines for stage IV ACC with ≤2 tumor-organs and favor the combination of mitotane and LRT as first-line treatment. For the first time, a significant number of complete responses were observed. Prospective studies are expected to confirm these findings.

An individualised treatment algorithm for tumour stage 1 glottic squamous cell carcinoma

2013 ◽  
Vol 127 (11) ◽  
pp. 1127-1133 ◽  
Author(s):  
U Aydil ◽  
M Akmansu ◽  
Y Kizil ◽  
Ö Yazici ◽  
S Üstün ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Survival Rates ◽  
Treatment Algorithm ◽  
Tumour Stage ◽  
Treatment Groups ◽  
Laryngeal Preservation ◽  
Stage 1 ◽  
Individualised Treatment

AbstractObjective:To report and discuss the outcome of a treatment algorithm for patients with tumour stage 1 glottic squamous cell carcinoma.Method:A retrospective outcome analysis study was performed using data from a tertiary referral centre.Results:Sixty-nine patients were treated with radiotherapy and 26 with surgery, in accordance with the treatment algorithm. Five-year overall survival rates were the same for both treatment groups (92 per cent). Five-year disease-specific survival rates were 100 per cent for surgery, 98 per cent for radiotherapy and 99 per cent overall. The overall 5-year laryngeal preservation rate was 89.1 per cent, being 95.7 per cent for surgery patients and 86.7 per cent for radiotherapy patients (p = 0.502). There was no significant association between laryngeal preservation rates and age (p = 0.779), anterior commissure involvement (p = 0.081), tumour stage (1a or 1b) (p = 0.266) or treatment modality (surgery or radiotherapy; p = 0.220). There was no significant difference in local recurrence rates between the two treatment groups (19.3 per cent for radiotherapy vs 10.0 per cent for surgery; p = 0.220). The overall 5-year regional recurrence rate was 1.2 per cent.Conclusion:Tumour stage 1 glottic carcinoma can be managed with different treatment modalities, following an individualised treatment algorithm, with results comparable to published outcomes.

scholarly journals Development of a Machine Learning Model for Optimal Applicator Selection in High-Dose-Rate Cervical Brachytherapy

2021 ◽  
Vol 11 ◽  
Author(s):  
Kailyn Stenhouse ◽  
Michael Roumeliotis ◽  
Robyn Banerjee ◽  
Svetlana Yanushkevich ◽  
Philip McGeachy
Keyword(s):  
Machine Learning ◽  
Feature Selection ◽  
Dose Rate ◽  
High Dose Rate ◽  
Gradient Boosting ◽  
Classification Algorithms ◽  
High Dose ◽  
Discriminative Performance ◽  
The Individual ◽  
Voting Model

PurposeTo develop and validate a preliminary machine learning (ML) model aiding in the selection of intracavitary (IC) versus hybrid interstitial (IS) applicators for high-dose-rate (HDR) cervical brachytherapy.MethodsFrom a dataset of 233 treatments using IC or IS applicators, a set of geometric features of the structure set were extracted, including the volumes of OARs (bladder, rectum, sigmoid colon) and HR-CTV, proximity of OARs to the HR-CTV, mean and maximum lateral and vertical HR-CTV extent, and offset of the HR-CTV centre-of-mass from the applicator tandem axis. Feature selection using an ANOVA F-test and mutual information removed uninformative features from this set. Twelve classification algorithms were trained and tested over 100 iterations to determine the highest performing individual models through nested 5-fold cross-validation. Three models with the highest accuracy were combined using soft voting to form the final model. This model was trained and tested over 1,000 iterations, during which the relative importance of each feature in the applicator selection process was determined.ResultsFeature selection indicated that the mean and maximum lateral and vertical extent, volume, and axis offset of the HR-CTV were the most informative features and were thus provided to the ML models. Relative feature importances indicated that the HR-CTV volume and mean lateral extent were most important for applicator selection. From the comparison of the individual classification algorithms, it was found that the highest performing algorithms were tree-based ensemble methods – AdaBoost Classifier (ABC), Gradient Boosting Classifier (GBC), and Random Forest Classifier (RFC). The accuracy of the individual models was compared to the voting model for 100 iterations (ABC = 91.6 ± 3.1%, GBC = 90.4 ± 4.1%, RFC = 89.5 ± 4.0%, Voting Model = 92.2 ± 1.8%) and the voting model was found to have superior accuracy. Over the final 1,000 evaluation iterations, the final voting model demonstrated a high predictive accuracy (91.5 ± 0.9%) and F1 Score (90.6 ± 1.1%).ConclusionThe presented model demonstrates high discriminative performance, highlighting the potential for utilization in informing applicator selection prospectively following further clinical validation.

scholarly journals WHEN BIAS KILLS THE VARIANCE: CENTRAL LIMIT THEOREMS FOR DEA AND FDH EFFICIENCY SCORES

2014 ◽  
Vol 31 (2) ◽  
pp. 394-422 ◽  
Author(s):  
Alois Kneip ◽  
Léopold Simar ◽  
Paul W. Wilson
Keyword(s):  
Central Limit ◽  
Limit Theorems ◽  
Central Limit Theorems ◽  
Data Envelopment ◽  
Free Disposal Hull ◽  
Average Efficiency ◽  
Free Disposal ◽  
Monte Carlo Experiments ◽  
The Individual ◽  
Individual Scores

Data envelopment analysis (DEA) and free disposal hull (FDH) estimators are widely used to estimate efficiencies of production units. In applications, both efficiency scores for individual units as well as average efficiency scores are typically reported. While several bootstrap methods have been developed for making inference about the efficiencies of individual units, until now no methods have existed for making inference about mean efficiency levels. This paper shows that standard central limit theorems do not apply in the case of means of DEA or FDH efficiency scores due to the bias of the individual scores, which is of larger order than either the variance or covariances among individual scores. The main difficulty comes from the fact that such statistics depend on efficiency estimators evaluated at random points. Here, new central limit theorems are developed for means of DEA and FDH scores, and their efficacy for inference about mean efficiency levels is examined via Monte Carlo experiments.

Tumor-associated immune cells and progression-free survival in advanced endometrial cancer (EC), results from the PHAEDRA trial (ANZGOG 1601).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 5584-5584
Author(s):  
Deborah Smith ◽  
Kristy Robledo ◽  
Sonia Yip ◽  
Michelle Cummins ◽  
Peey-Sei Kok ◽  
...  
Keyword(s):  
Immune Cells ◽  
Predictive Value ◽  
Tumor Response ◽  
External Validation ◽  
Prognostic Significance ◽  
Progression Free Survival ◽  
Immune Biomarkers ◽  
Formalin Fixed Paraffin ◽  
Formalin Fixed Paraffin Embedded ◽  
The Individual

5584 Background: Activity of durvalumab in patients with deficient mismatch repair (dMMR) advanced endometrial carcinoma (EC) was confirmed in the PHAEDRA trial (ANZGOG 1601). This study investigated the association between immune biomarkers and clinical outcomes in PHAEDRA. Methods: Formalin-fixed paraffin embedded sections immunohistochemically stained for PD-L1 using the Ventana platform, were with matched H&E slides scored independently by two pathologists according to the Ventana PD-L1 (SP263) algorithm for urothelial carcinoma (UC). Immune biomarkers assessed were PD-L1 staining of tumor cells (TCP) and immune cells (IC), and presence of tumor-associated immune cells (ICP). Results: Sixty-seven of the 71 patients had sufficient tumor for PD-L1 testing. AUC were 0.667, 0.726 and 0.644 for TCP, ICP and IC, respectively for predicting tumor response. Optimal cutpoints were TCP≥1%, ICP≥10% and IC≥35%. ICP≥10% achieved the highest sensitivity (53%) and specificity (82%) of the individual cutpoints. The optimal cutpoint algorithm was able to identify patients who would not respond, (sensitivity 88%, negative predictive value 92%), but had low specificity (48%) and positive predictive value (37%). Differences in PFS were found using ICP≥10% (logrank p = 0.01), compared to TCP (p = 0.25), IC (p = 0.48) and the UC algorithm (p = 0.08) (Figure 1). PFS was shorter in patients with pMMR than dMMR after adjusting for ICP (HR 2.99, 95%CI: 1.61-5.57, p < 0.001). Adjustment for MMR reduced the prognostic significance of ICP≥10% for PFS (HR 0.59, 95% CI: 0.28-1.23, p = 0.16). For OS, differences were seen for the UC algorithm (p = 0.02), but not ICP (p = 0.07), TCP (p = 0.18) or IC (p = 0.23). Similarly to PFS, adjustment for MMR reduced the prognostic significance of the UC algorithm for OS (HR: 0.53, 95% CI: 0.25-1.12, p = 0.10). Conclusions: In this exploratory analysis, ICP was more closely associated with tumor response and PFS than TCP or IC. ICP alone was better than the UC algorithm for predicting PFS. The optimum cutpoint algorithm was promising for identifying non-responders, but requires external validation. Clinical trial information: ACTRN12617000106336.

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