WHO Histology Research Articles

MDB-75. MOLECULAR PATHOLOGY, TREATMENT AND PROGNOSIS OF INFANT SONIC HEDGEHOG MEDULLOBLASTOMA: A GLOBAL MULTI-COHORT STUDY

Abstract BACKGROUND Clinical studies in infant medulloblastoma (iMB; <5 years) have, to date, focussed on modestly-sized or national trials cohorts and have not directly compared therapeutic approaches or placed these in the context of dedicated biomarker studies, to inform future treatment strategies. METHODS We assembled a multi-national cohort of molecularly and clinically-annotated iMBs (<5 years at diagnosis; n=646), the largest to date. We investigated molecular pathology, treatments received, and relationships to outcome within this population. RESULTS The SHH group (iMBSHH; n=267, 40%) predominated, encompassing SHH-1 (37.7%, median age 2.0 years), SHH-2 (47.0%, 1.4 years) and SHH-3 (14.4%, 3.0 years) WHO subgroups. MBEN histology was significantly enriched in SHH-2, and SUFU mutation and MYCN amplification in SHH-1 and SHH-3, respectively. Notably, TP53 mutations were identified in all subgroups; in SHH-1 and SHH-2 (each n=3) tumours lacked features typically associated with TP53-mutated SHH-3 (LCA histology and MYCN amplification) and did not have a worse survival. Upfront radiation-sparing treatments were used in 132/267 children and comprised regimens founded on intraventricular methotrexate (IVT-MTX; 54.5%), high-dose (HDCTx; 22.0%) or standard-dose (23.5%) chemotherapy. Across all radio-naive iMBSHH, non-DN/MBEN histology (HR 2.76, CI 1.26-6.01, p=0.011) and SHH-1 (vs SHH-2, HR 2.51, CI 1.25-5.01, p=0.009) conferred worse PFS in univariable analysis; subgroup was the only independently prognostic risk-factor (multivariable analysis; SHH-1 HR 2.65, CI 1.27-5.51, p=0.009). 5-year OS for HDCTx recipients was very favourable in SHH-1 (100%) and SHH-2 (93.3%), and subgroup-dependent for IVT-MTX (SHH-1; 76.4%, SHH-2; 100%, p=0.009). In CSI-treated iMBSHH (n=49), non-DN/MBEN histology (HR 10.23, CI 2.22-47.04, p=0.003) and MYCN amplification (HR 7.35, CI 2.01-26.87, p=0.003) conferred worse PFS. CONCLUSION iMBSHH outcomes in this cohort are dependent upon WHO subgroup, histology and therapy received. These findings provide an evidence-based foundation for selection of cohorts and therapies for prospective assessment in forthcoming iMBSHH clinical trials (e.g. SIOP-CONNECT-YC-MB-LR).

Postoperative radiotherapy results in 192 epithelial thymic tumours patients with 10 years of follow-up

PurposeTo assess the prognostic factors and patterns of failure of patients consecutively treated with surgery and postoperative radiation therapy (PORT) for thymic epithelial tumours (TET). Patients and methodsData from 192 TET patients who were operated and received PORT at a single centre from 1990 to 2019 was retrospectively analysed. ResultsMost patients had thymoma (77 %, B247%), were classified Masaoka-Koga stage III (35 %) or IV (32 %) and had a R0 (75 %) resection. Radiotherapy was delivered at a median dose of 50.4 Gy (range, 42–66 Gy; ≥ 60 Gy in 17 %), 63 (33 %) patients were treated by intensity-modulated radiation therapy and elective nodal radiotherapy was used for 37 %. At a median follow-up of 10.9 years, the 10-year overall survival (OS) and progression-free survival (PFS) rates were 62 % (95 % CI: 54–70 %) and 47 % (95 % CI: 39–55 %), respectively. Locoregional recurrence (LRR) occurred in 72/192 (38 %) patients, distributed as 6 local, 45 regional and 21 both local and regional. LRR were mainly located to the pleura: 66/72 (92 %) and 16/72 (22 %; 16/192 in total, 8 %) were in-field. Distant relapse (DR) were observed in 30 patients (16 %), resulting in 10-year locoregional (LRC) and distant control rates of 58 % (95 % CI: 50–66 %) and 82 % (95 % CI: 77–88 %), respectively. In the multivariate analysis, Masaoka-Koga stage (HR [hazard ratio]: 1.9; p = 0.001), thymic carcinomas/neuroendocrine tumours (TC) (HR: 1.6; p = 0.045) and ECOG PS > 1 (HR: 1.9; p = 0.02) correlated with poorer OS. Higher Masaoka-Koga stage (HR: 2.6; p < 0.001) associated with a decreased LRC but not R1 status (HR: 1.2; p = 0.5) or WHO histology classification. TC (HR: 3.4; p < 0.001) and a younger age (HR: 2.5; p = 0.02) correlated with DR. ConclusionApproximately one-third of the TET in our study experienced a LRR, mainly to the pleura, and 8% in total were in-field. The place of radiotherapy should be better defined in higher risk thymoma patients within prospective randomized studies.

A systematic review and individual participant data meta-analysis of gonadal steroid hormone receptors in meningioma.

The relationship between patient and meningioma characteristics and hormone receptors (HRs) of progesterone, estrogen, and androgen remains poorly defined despite literature suggesting that meningiomas are sensitive to gonadal steroid hormones. Therefore, the authors sought to collect and compare data on this topic by performing a systematic review and meta-analysis of reported studies of HR status in meningiomas. A MEDLINE PubMed literature review conducted for articles published between January 1, 1951, and December 31, 2020, resulted in 634 unduplicated articles concerning meningiomas and HRs. There were 114 articles that met the criteria of detailed detection protocols for progesterone receptor (PR), estrogen receptor (ER), and/or androgen receptor (AR) using immunohistochemistry (IHC) or ligand-binding (LB) assays and simultaneous reporting of HR status with at least one variable among age, sex, histology, location, grade, or recurrence. Between-study heterogeneity and risk of bias were evaluated using graphical and statistical methods. The authors performed a multilevel meta-analysis using random-effects modeling on aggregated data (n = 4447) and individual participant data (n = 1363) with subgroup results summarized as pooled effects. A mixed-effects meta-regression using individual participant data was performed to analyze independently associated variables. The 114 selected articles included data for 5810 patients with 6092 tumors analyzed to determine the expression of three HRs in human meningiomas: PRs, ARs, and ERs. The proportions of HR+ meningiomas were estimated to be 0.76 (95% CI 0.72-0.80) for PR+ and 0.50 (95% CI 0.33-0.66) for AR+ meningiomas. ER+ meningioma detection varied depending on the measurement method used and was 0.06 (95% CI 0.03-0.10) with IHC and 0.11 (95% CI 0.06-0.20) with LB assays. There were associations between age and PR and ER expression that varied between male and female patients. PR+ and AR+ were more common in female patients (OR 1.84, 95% CI 1.47-2.29 for PR and OR 4.16, 95% CI 1.62-10.68 for AR). Additionally, PR+ meningiomas were enriched in skull base locations (OR 1.89, 95% CI 1.03-3.48) and meningothelial histology (OR 1.86, 95% CI 1.23-2.81). A meta-regression showed that PR+ was independently associated with age (OR 1.11 95% CI 1.09-1.13; p < 0.0001) and WHO grade I tumors (OR 8.09, 95% CI 3.55-18.44; p < 0.0001). ER+ was negatively associated with meningothelial histology (OR 0.94, 95% CI 0.86-0.98; p = 0.044) and positively associated with convexity location (OR 1.12, 95% CI 1.05-1.18; p = 0.0003). The association between HRs and meningioma features has been investigated but unexplained for decades. In this study the authors demonstrated that HR status has a strong association with known meningioma features, including WHO grade, age, female sex, histology, and anatomical location. Identifying these independent associations allows for a better understanding of meningioma heterogeneity and provides a foundation for revisiting targeted hormonal therapy in meningioma on the basis of proper patient stratification according to HR status.

Characteristics Predicting Short-Term and Long-Term Health-Related Quality of Life in Patients with Esophageal Cancer After Neoadjuvant Chemoradiotherapy and Esophagectomy

BackgroundEsophagectomy is associated with lasting effect on health-related quality of life (HRQOL). Patients desire detailed information on the expected impact of treatment on their postoperative HRQOL. The aim of the present study is to identify clinicopathological characteristics predictive for changes in short-term and long-term HRQOL after neoadjuvant chemoradiotherapy (nCRT) and surgery.MethodsHRQOL was measured using EORTC-QLQ-C30 and QLQ-OES24 questionnaires prior to nCRT, three, six, nine and twelve months postoperatively and at a minimum of six years postoperatively. Based on previous experience and available literature, several subgroups were predefined for different clinicopathological characteristics: baseline global HRQOL, WHO performance status, histology, tumor stage and tumor location. The primary endpoints of the present study were the change compared to baseline in the HRQOL dimensions physical functioning and eating problems. Secondary endpoints were global HRQOL, fatigue and emotional problems.ResultsIn total, 134 (76%) of 177 patients who received HRQOL questionnaires, responded at baseline. Patients who reported a high baseline global HRQOL had a more severe deterioration in eating problems (+14.5 to + 18.0), global HRQOL (-16.0 to -28.0) and fatigue (+10.5 to +14.9) up to six years postoperatively compared to patients who reported a low baseline global HRQOL. Patients who had stage 2 tumor (UICC 6th edition) had a more severe deterioration in eating problems (+14.6 to +19.0) and global HRQOL (-10.1 to -17.1) than patients who had stage 3 tumor.ConclusionsThe results suggest that patients with locally advanced esophageal cancer in favorable condition at baseline decline more in terms of various HRQOL outcomes.

Utilization of circulating tumor DNA (ctDNA) analysis to detect minimal residual disease post-surgery and disease progression in metastatic thymic tumors.

8598 Background: Thymic epithelial tumors (TETs) are rare and tend to have an indolent disease course. Follow-up consists of physical examinations and routine imaging (CT scans) with no currently available biomarkers to complement surveillance. This study aimed to assess the utility of ctDNA in MRD detection and disease monitoring in TETs. Methods: From Nov 2020 till Feb 2022, ctDNA analysis using a tumor-informed mPCR-NGS (Signatera) assay was performed on 29 patients (pts) with primary (pTETs) or metastatic TETs (mTETs). For pts with early-stage disease, the baseline ctDNA was measured 4-8 w post-surgery and repeated q3m. For mTETs, ctDNA was measured at the first visit, and then q3m with interval CT scan q3-4 m. ctDNA was quantified as mean tumor molecules (MTM)/mL of plasma. All pts had at least one measurement (up to 4). GraphPad was used for statistical analysis. Results: Of 29 pts overall, 9 pts were excluded at the time of analysis for various reasons; a) insufficient specimen (n=5), b) presence of concurrent active cancer (n=2), and c) final report delay (n=2). Of 20 evaluable pts, 7 pts had pTETs and 13 mTETs. The median age was 50 yrs (range, 17-72), and WHO histology distribution of AB=3, B1=5, B2=9, B3=12, TC=3. History of autoimmune disease and second malignancy (not active at the time of obtaining ctDNA) was reported in 33% (n=9) and 40% (n=8) of evaluable pts, respectively. Of 13 metastatic pts, 6 had stage IVA with pleural-only metastasis, 7 pts had Stage IVB with 2 extra-thoracic (liver, adrenal), and 5 with intrathoracic (lung, chest wall, and LNs) involvement. From 7 pTETs, 6 pts had R0 resection with undetectable post-operative ctDNA, while R1 resection with detectable ctDNA was reported (0.47 MTM/mL) in one pt. In mTETs, the mean level of ctDNA in pts with the stable disease was 0.18 MTM/mL (0.1-0.2), pleural-only progression 1.26 MTM/mL (0.1-1.9), and progressive disease (primary and/or pleural) 7.67 MTM/mL(5.04-9.5). Comparing the mean level of ctDNA in clinically stable metastatic pts with those who had progression, pts with pleural-only progression did not have a significantly higher level of ctDNA (p=0.51). In contrast, pts with primary and/or pleural progression had significantly higher levels of ctDNA (p=0.02). The level of ctDNA correlated with tumor size. An increase of 4-6mm in tumor size was associated with an approximate 0.2 MTM/mL increase in ctDNA or making the undetectable status detectable. Conclusions: The ctDNA level correlates well with the tumor volume in mTETs. In pTETs, ctDNA was negative following R0 resection but not in the R1, supporting its potential use as a surrogate biomarker for MRD. This is a pilot study, and the expansion of these data is ongoing to validate the utility of ctDNA testing in these settings. If validated, ctDNA may augment or minimize the routine use of CT scans for disease monitoring in resected and mTETs.

Unradical Surgery for Locally-Advanced Thymoma: Is it time to evolve Perspectives?

ObjectivesNearly-one-third of thymomas are locally-advanced at diagnosis. The traditional dogma that surgery is justified in case a complete resection can be achieved has remained unmovable until today. This study aimed to investigate feasibility and oncologic efficacy of incomplete resection for locally-advanced thymomas in a contest of multimodality therapy. Materials and MethodsA retrospective analysis was conducted using data of prospectively maintained thymomas database in a single high-volume centre. Data on 285 consecutive patients undergoing surgery for stage III and IVa thymomas between 1995 and 2019 were reviewed. Patients who underwent incomplete resection with curative-intent (removal of at least 90% of tumour burden) were included. Long-term outcomes and predictors of cancer-specific survival (CSS) and progression-free survival (PFS) were analyzed. Secondary endpoint was to assess adjuvant therapy efficacy. ResultsThe study included 79 patients, 60 with microscopic residual tumour (76%, R1) and 19 with macroscopic residual disease (24%, R2). Masaoka-Koga stage was: III in 41 patients (52%) and IVa in 38 (48%). Histology was B2-thymomas (n = 31, 39.2%) followed by B3 (n = 27, 34.2%). Five- and 10-years CSS was 88% and 80%. Seventy patients (90%) underwent adjuvant treatment; they showed CSS comparable to radical resected patients (5-years: 89.1% vs 98.9%, respectively; 10-years: 81.8% vs 92.7%, respectively, p = 0.43). The site of residual disease, Masaoka-Koga stage and WHO histology did not affect prognosis. Stepwise multivariable analysis confirmed adjuvant therapy as a favourable CSS prognostic factor (HR, 0.51; 95% CI, 0.33–0.79, p = 0.003). Stratifying by subgroups, R2-patients who received postoperative chemo(radio)therapy (pCRT) showed a significantly better prognosis than R2-patients treated by consolidation radiotherapy alone (10-years CSS: 60%, p < 0.001). ConclusionIn locally-advanced thymomas, whenever a radical surgery cannot be achieved, incomplete resection has proved to be effective in a contest of multimodality strategy, independently of WHO histology, Masaoka-Koga stage and site of residual disease.

DNA methylation provides diagnostic value for meningioma recurrence in clinical practice.

Meningiomas are the most common intracranial tumors. Recent advancements in the genetic profiling of tumors have allowed information including DNA copy number analysis, mutational analysis, and RNA sequencing to be more frequently reported, in turn allowing better characterization of meningiomas. In recent years, analysis of tumor methylomes that reflects both cell-origin methylation signatures and somatically acquired DNA methylation changes has been utilized to better classify meningiomas with great success. We report DNA methylation profiling on meningiomas from 17 patients. Formalin-fixed paraffin-embedded (FFPE) meningioma tumor samples were processed, loaded onto the Infinium Methylation EPIC array, and scanned using the Illumina IScan system. Raw IDAT files were processed through the the CNS tumor classifier developed by the Molecular Neuropathology group at the German Cancer Research Center (DKFZ). Corresponding genomics were captured using targeted sequencing panels. Among the meningioma samples, 13 samples were classified as "benign," two samples as "intermediate," and the remaining three samples (from two patients) as "malignant," based on previously validated classification algorithms. In addition to tumor methylation profiling, we also present information that includes patient demographics, clinical presentations, tumor characteristics (including size and location), surgical approaches, and mutational analysis. The two patients who provided the samples with "malignant" methylation classifications had tumor recurrence, reflecting a more aggressive disease course. In accordance with prior reports, our case series provides support that tumor DNA methylation profiling adds meaningful classification information and may be beneficial to incorporate in clinical practice. Our report also reveals that DNA methylation combined with WHO histology classification can more accurately predict tumor behavior than WHO classification alone.

Brief Report: High Levels of CD47 Expression in Thymic Epithelial Tumors

IntroductionCD47 is a tumor antigen that inhibits phagocytosis leading to immune evasion. Anti-CD47 therapy is a promising new immunotherapy across numerous tumor types, but it has not been tested in thymic epithelial tumors (TETs): thymomas and thymic carcinomas. TETs are rare tumors that are difficult to treat, especially with programmed cell death protein 1/programmed death-ligand 1 checkpoint inhibitors, owing to the excessive rates of immune-related adverse events. This study investigated the levels of CD47 expression in TETs to explore the possibility of anti-CD47 therapy. MethodsA total of 67 thymic tumors (63 thymomas and 4 thymic carcinomas) and 14 benign thymus controls and their clinical data were included. Samples were stained for CD47 expression (rabbit monoclonal antibody SP279, Abcam, Waltham, MA) and scored for both intensity and H-score (intensity multiplied by the percentage of tumor involved). Intensity was defined as follows: 0 = none, 1 = weak, 2 = moderate, and 3 = strong. H-scores ranged from 0 to 300. Samples with an intensity score below 2 or an H-score below 150 were considered CD47low, whereas the rest were CD47high. ResultsCompared with normal thymic tissues, TETs were more frequently CD47 positive and had significantly higher levels of CD47 expression. CD47 was positive in 79.1% of TETs compared with 57.1% of normal thymus. The level of CD47 expression was 16-fold higher in TETs (mean H-score 75.0 versus 4.6, p = 0.003). Multivariate analysis adjusted for age, sex, stage, resection status, and performance status revealed that CD47-high tumors were highly correlated with WHO histology type (p = 0.028). The most frequent CD47high tumors, in contrast to CD47low tumors, were types A (28.6% versus 7.5%) and AB (57.1% versus 13.2%), and the least frequent were B1 (7.1% versus 24.5%), B2 (0% versus 35.8%), B3 (7.1% versus 11.3%), and C (0% versus 7.5%). ConclusionsIn contrast to normal thymus, TETs had significantly higher levels of CD47 expression. Tumor samples with high CD47 expression were mostly WHO types A and AB. This is the first study to explore CD47 expression in thymic cancers and lends support for ongoing investigation of anti-CD47 macrophage checkpoint inhibitor therapy in these tumors.

CD47 expression patterns in thymic epithelial tumors.

8586 Background: Blockade of CD47, an immunoglobulin overexpressed on solid tumor cells that inhibits macrophage phagocytosis, is a promising anti-cancer immunotherapy which has not yet been explored in thymic epithelial tumors (TETs). TETs, including thymomas and thymic carcinomas, are rare tumors with limited immunotherapy treatment options due to the high rates of immune-related adverse effects observed with PD-1/PD-L1 checkpoint inhibitors. This study aimed to examine CD47 protein expression in TETs. Methods: A clinically annotated tissue microarray of 67 TETs consisting of 64 thymomas and 3 thymic carcinomas, as well as 14 thymic controls were included. Each sample with an average of 3 cores was stained for CD47 epithelial expression (rabbit monoclonal antibody SP279, Abcam, USA). Samples were scored for intensity as follows: 0 = none, 1 = weak, 2 = moderate, and 3 = strong. An H-score, defined as intensity x percentage of tumor involved, was also assigned and ranged from 0 to 300. Samples with an intensity score of &lt; 2 or an H-score of &lt; 150 were categorized as CD47low, while the rest as CD47high. Multivariate linear regression analysis accounted for WHO subtype, stage, resection status and presence of paraneoplastic syndrome (Prism 9, Graphpad). Results: Compared to normal thymic tissue, TETs were more frequently CD47 positive and had significantly higher levels of CD47 expression. CD47 was present in 91% of TETs, compared to 64.3% of normal thymus. Importantly, the level of expression was significantly higher in TETs by 16-fold (mean H-score 75.0 vs 4.6, p = 0.003). Among tumors, univariate analyses showed that higher CD47 expression was correlated with a lower stage (p = 0.032) and more complete resection (p = 0.058). A multivariate analysis accounting for these factors showed that CD47 expression by both H-score and intensity were each highly correlated with WHO histology subtype (p = 0.0005; p = 0.0017 respectively) with lower grade subtypes more frequently found in CD47high tumors. The most frequent subtype in CD47high, when compared to CD47low tumors, was AB (61.5% vs 13.7%) and the least frequent was B2 (0% vs 37.3%). Tumors with the highest grade (subtype C, thymic carcinomas) were exclusively CD47low. CD47high tumors were associated with an increased incidence of paraneoplastic syndromes (52.4% vs 12.0%, p = 0.0014). Conclusions: CD47 expression was found in the vast majority of TETs, and in significantly higher levels than normal thymic tissue. Among tumors, those with higher CD47 expression tended to have lower grade and stage, as well as higher frequency of paraneoplastic syndromes. This study is the first to examine CD47 expression in TETs. Given the prevalent expression of CD47 found in TETs and current available CD47 targeted agents, this study lends support for further investigation of this novel therapeutic approach.

The Relationship Between Stimulation Current and Functional Site Localization During Brain Mapping.

Gliomas are often in close proximity to functional regions of the brain; therefore, electrocortical stimulation (ECS) mapping is a common technique utilized during glioma resection to identify functional areas. Stimulation-induced seizure (SIS) remains the most common reason for aborted procedures. Few studies have focused on oncological factors impacting cortical stimulation thresholds. To examine oncological factors thought to impact stimulation threshold in order to understand whether a linear relationship exists between stimulation current and number of functional cortical sites identified. We retrospectively reviewed single-institution prospectively collected brain mapping data of patients with dominant hemisphere gliomas. Comparisons of stimulation threshold were made using t-tests and ANOVAs. Associations between oncologic factors and stimulation threshold were made using multivariate regressions. The association between stimulation current and number of positive sites was made using a Poisson model. Of the 586 patients included in the study, SIS occurred in 3.92% and the rate of SIS events differed by cortical location (frontal 8.5%, insular 1.6%, parietal 1.3%, and temporal 2.8%; P=.009). Stimulation current was lower when mapping frontal cortex (P=.002). Stimulation current was not associated with tumor plus peritumor edema volume, world health organization) (WHO grade, histology, or isocitrate dehydrogenase (IDH) mutation status but was associated with tumor volume within the frontal lobe (P=.018). Stimulation current was not associated with number of positive sites identified during ECS mapping (P=.118). SISs are rare but serious events during ECS mapping. SISs are most common when mapping the frontal lobe. Greater stimulation current is not associated with the identification of more cortical functional sites during glioma surgery.

Clinicogenomic characterization of metastatic thymic epithelial tumors.

8579 Background: Thymic epithelial tumors (TET) are one of the rarest adult malignancies. Overall, patients have favorable survival outcomes, however a small subset develop metastatic disease. Genomic characterization of this very rare, clinically aggressive TET subset is lacking. Herein, we evaluated the clinical and genomic characteristics of metastatic TET (mTET) compared to a large cohort (n = 117) of primary TET (pTET) from The Cancer Genome Atlas (TCGA). Methods: From 2015 to 2020, 52 pts with mTET underwent clinical CLIA-based sequencing using either whole-exome (n = 35), panel-based testing (n = 13) and/or liquid biopsy (n = 22). The specimen was taken from a metastatic organ (n = 34) or relapsed primary mediastinal mass (n = 14); 4 pts had liquid bx only. Data on pTET was derived from the TCGA. Kaplan-Meier and log-rank test was used for assessment of PFS, OS. Results: The median age was 56 yrs in mTET (range 32-74) vs. 60 yrs (range 17-84) in TCGA data. The M/F (%) was 40/60 in mTET and 48/52 in TCGA, respectively. Of note, 13 mTET pts had other types of cancer prior or concurrent with TET diagnosis (4-breast, 2-bladder, 5-other) in which radiotherapy (n = 4) and/or chemotherapy (n = 3) was administered prior to TET diagnosis. In our cohort, 19 pts had stage IVA and 33 pts had stage IVB (most common metastatic site was liver in 17 pts). WHO histologic classification was: A = 1, A/B = 3, B1 = 4, B2 = 10, B3 = 12, TC = 18, TC with neuroendocrine feature = 3, and lymphoepithelial carcinoma = 1. WHO B3 and TC histologies were more common in our cohort of mTET than in the TCGA cohort (63% (33/52) vs. 17% (20/117), respectively). Pts with TC had worse mOS compare to thymoma (109m vs. 163m, HR = 2.78, P = 0.04). The most common genomic alteration in mTET was TP53 (n = 17, 33%) compared to 3% in TCGA. This was followed by CDKN2A (n = 5, 10%), PIK3CA (n = 4, 8%), CDKN2B (n = 3, 6%) and NF1 (n = 3, 6%). All TP53 missense mut functionality was analyzed with polyphen-2 software and 91.6% (22/24) had 98-100% damaging probability. 70% of pts that harbored TP53 muts were TC (41%) or B3 (29%) histology. Clinically actionable genomic alterations targetable with available or investigational agents (e.g. high TMB; gain-of-function mutations in PIK3CA, CDK4, and mTOR; loss-of-function mutations in NF1) were seen in 23% (12/52) of pts. Conclusions: Patients with mTET are associated with more aggressive WHO histology (B3 and TC). Greater frequency of TP53 mutations are observed in mTET compared to pTET. Clinically actionable genomic alterations are frequently seen in mTET suggesting value in the routine sequencing of these patients.

Are the clinical manifestations of CT scan and location associated with World Health Organization histopathological grades of meningioma?: A retrospective study

Introductionmeningioma is the most common intracranial tumor. CT scan is a common method for diagnosis. WHO classified meningioma into 3 histological grades? This study aims to evaluate the relation of different meningioma signs on CT and tumor distribution regard to WHO histological types. MethodsIn this single-center observational retrospective study, authors reviewed data of 75 meningioma patients confirmed by the WHO histological grades (WHO I/II/III) which were underwent CT scans from January 1, 2005 to December 30, 2019 at a teaching hospital, in XXXX. Data collected using patients medical records. Data were analyzed by SPSS 20 and P less than 0.05 was assumed as significant. ResultOur study confirmed that only edema (P = 0.005) and heterogeneity (P = 0.014) had a significant association with malignant histological types. Other signs were not statistically different among WHO histology types (p > 0.05). On the subject of tumor location, atypical/malignant meningioma was significantly more common in parasagittal (P = 0.031) and front-parietal (P = 0.035) regions. Discussionmeningiomas with Edema, heterogeneity on CT, and tumors located in parasagittal and frontoparietal regions are related to malignant histology and should be evaluated and treated more precisely.

The role of postoperative radiotherapy for thymomas: a multicentric retrospective evaluation from three Italian centers and review of the literature.

BackgroundThymoma is a rare mediastinal neoplasia. Surgery is the backbone of the treatment, but the role of postoperative radiotherapy (PORT) remains controversial. We aimed to obtain data on survival and safety in patients treated with PORT in three different Italian institutions.MethodsWe retrospectively analyzed 183 consecutive patients who underwent surgery from 1981 to 2015. According to the Masaoka-Koga staging system, 39.3%, 32.7%, 18.6% and 9.8% patients were in stage I, II, III and IV of disease, respectively. PORT was indicated in 114 patients (62.3%), while 69 subjects underwent surgery alone. Complete resection was obtained in 68 patients who underwent PORT. Adverse events (AEs) were graded according to CTCAE v4.0. We analyzed the recent literature to describe the current reports on PORT for resected thymoma.ResultsMean follow-up was 130 months (range, 3–417 months). Overall survival (OS) at 1-, 5- and 10-year from surgery was 98.3%, 90.2% and 69.7% respectively. One-, 5- and 10-year disease specific survival (DSS) was 98.9%, 92.3% and 89.8% respectively. Disease free survival (DFS) at 1, 5 and 10 years from surgery was 96.7%, 88.3% and 82.8% respectively. Univariate analysis showed that complete resection, cell histology A-AB-B1 and stages I–II were significant predictors of better DSS and DFS. Multivariate analysis showed that sex, R0 margins and WHO histology was independent prognostic factors. Among patients treated with PORT, a trend towards better OS was evident with Masaoka stage I–II (P=0.09). Patients with R0 margins treated with PORT showed better OS and DSS (P=0.05). No differences in DSS for performance status (P=0.70), WHO histology (P=0.19), paraneoplastic syndrome (P=0.23) and surgical procedure (P=0.53) were evident. Patients treated with PORT had a higher level of acute AEs compared to surgery alone, but none of these was graded ≥3.ConclusionsOur results confirmed that patients with incompletely resected thymoma had the worst OS and DSS. High grade acute toxicity was not different between PORT and surgery alone. Other trials reported a significant benefit in OS, DSS and DFS in stage IIb–IV thymoma treated with PORT.

Twelve-month outcome in juvenile proliferative lupus nephritis: results of the German registry study.

Children presenting with proliferative lupus nephritis (LN) are treated with intensified immunosuppressive protocols. Data on renal outcome and treatment toxicity is scare. Twelve-month renal outcome and comorbidity were assessed in 79 predominantly Caucasian children with proliferative LN reported to the Lupus Nephritis Registry of the German Society of Paediatric Nephrology diagnosed between 1997 and 2015. At the time of diagnosis, median age was 13.7 (interquartile range 11.8-15.8) years; 86% showed WHO histology class IV, nephrotic range proteinuria was noted in 55%, and median estimated glomerular filtration rate amounted to 75ml/min/1.73m2. At 12months, the percentage of patients with complete and partial remission was 38% and 41%, respectively. Six percent of patients were non-responders and 15% presented with renal flare. Nephrotic range proteinuria at the time of diagnosis was associated with inferior renal outcome (odds ratio 5.34, 95% confidence interval 1.26-22.62, p = 0.02), whereas all other variables including mode of immune-suppressive treatment (e.g., induction treatment with cyclophosphamide (IVCYC) versus mycophenolate mofetil (MMF)) were not significant correlates. Complications were reported in 80% of patients including glucocorticoid toxicity in 42% (Cushingoid appearance, striae distensae, cataract, or osteonecrosis), leukopenia in 37%, infection in 23%, and menstrual disorder in 20%. Growth impairment, more pronounced in boys than girls, was noted in 78% of patients. In this cohort of juvenile proliferative LN, renal outcome at 12months was good irrespectively if patients received induction treatment with MMF or IVCYC, but glucocorticoid toxicity was very high underscoring the need for corticoid sparing protocols. Graphical abstract.

Follistatin impacts Tumor Angiogenesis and Outcome in Thymic Epithelial Tumors

Tumor angiogenesis is a key factor in the progression of thymic epithelial tumors (TETs). Activin A, a member of the TGFβ family, and its antagonist Follistatin are involved in several human malignancies and angiogenesis. We investigated Activin A and Follistatin in serum and tumor tissue of patients with TETs in relation to microvessel density (MVD), WHO histology classification, tumor stage and outcome. Membranous Activin A expression was detected in all tumor tissues of TETs, while Follistatin staining was found in tumor nuclei and cytoplasm. Patients with TETs presented with significantly higher Activin A and Follistatin serum concentrations compared to healthy volunteers, respectively. Follistatin serum concentrations correlated significantly with tumor stage and decreased to physiologic values after complete tumor resection. Follistatin serum concentrations correlated further with MVD and were associated with significantly worse freedom from recurrence (FFR). Low numbers of immature tumor vessels represented even an independent worse prognostic factor for FFR at multivariable analysis. To conclude, the Activin A - Follistatin axis is involved in the pathogenesis of TETs. Further study of Follistatin and Activin A in TETs is warranted as the molecules may serve as targets to inhibit tumor angiogenesis and tumor progression.

MA20.06 Neutrophil to Lymphocyte Ratio Is an Independent Prognostic Predictor in Thymoma

Thymoma is the most common primary neoplasm of the anterior mediastinum in adults and conventional prognostic factors include Masaoka Stage, WHO histology and completeness of resection. Little is known of preoperative peripheral neutrophil-to-lymphocyte ratio (NLR) as an independent additional discriminator of prognosis. We performed an international multicentre retrospective cohort study (UK Health Research Reference 19/HRA/0440 and EU internal approval reference xxxxxx). We included patients who underwent complete resection for thymoma and data was acquired through patient medical records with follow up data obtained through national database and hospital records. NLR calculated on pre-operation bloods results. From July 1987 to December 2017, 433 patients underwent surgery for thymoma. The majority were male 228(53%) with a mean age (SD) of 55(15) years. The surgical approach was sternotomy in 335 patients (77%), thoracotomy in 23(5%) and VATS in 75(17%). The WHO classification was type A 63(15%), AB 126(29%), B1 98(23%), B2 55(13%) and B3 86(20%) patients. The Masaoka-Koga stage was I in 135(33%) II in 194(47%), III in 54 (13%) and IV in 31(7%) patients. Median (IQR) follow-up time was 86 (30 to 152) months with a 5 and 10-year survival of 88% and 79% respectively. The median NLR was 2.1 (1.5 to 3.1), when split into three groups (NLR < 1.4, NLR between 1.4 and 2.3 and NLR > 2.3), higher NLR was associated with poorer survival (log rank P<0.001) that persisted on Cox regression after adjustment for WHO grade and Masaoka stage with a HR of 1.69 (95% CI 1.20 to 2.39; P=0.002). Pre-operative NLR is a simple, low cost biomarker that can stratify risk of death independent to WHO grade and Masaoka stage in patients undergoing surgery for thymoma.

Does the addition of chemotherapy to neoadjuvant radiotherapy impact survival in high-risk extremity and trunk soft tissue sarcoma?

11054 Background: Large, high-grade extremity/trunk (ET) non-rhabdomyosarcoma soft-tissue sarcoma (STS) is at high risk for distant recurrence and death. The integration of chemotherapy (C) to standard of care neoadjuvant radiotherapy (RT) remains controversial, even for these patients. This study examines the impact of adding C to neoadjuvant RT on overall survival (OS) in high risk ET-STS. Methods: The National Cancer Data Base (NCDB) was queried for patients ≥18 years with high risk (≥5 cm + high grade) non-rhabdomyosarcoma ET-STS (WHO histology) who received neoadjuvant RT and limb sparing surgery from 2006-2014. Patients were next stratified based upon receipt of C (RT and CRT cohorts). Overall survival (OS) for RT vs CRT cohorts was analyzed using the Kaplan-Meier (KM) method, log-rank test, and Cox proportional hazards models. Propensity score-matched analysis (PSM) was employed to account for potential treatment selection bias between cohorts. Results: A total of 848 (71.1%) and 344 (28.9%) patients received RT and CRT, respectively. Patient cohorts were well-balanced except for the CRT cohort having higher rates of treatment in the West (22.1% vs 10.6%) &amp; Midwest (28.3% vs 22.7%), Charlson-Deyo [CD] score 0 vs ≥1 (85.5% vs 79.4%), younger age (≤50) (45.9% vs 21.7%), synovial sarcoma histology (18.9% vs 3.2%), earlier year of diagnosis (2006-2010) (39.5% vs 32.3%), and positive lymphovascular invasion (2.0 vs 1.51%), (p &lt; 0.05 each). The KM 5-year OS was significantly higher in the CRT vs RT cohort: 69.2% vs 58.1% on univariate (p &lt; 0.0001) and multivariate analysis (Hazard Ratio [HR]: 0.66; 95% Confidence Interval [CI]: 0.52-0.85; p = 0.001) even after adjusting for age, race, income, CD score, histology, tumor size, tumor grade, and primary site (lower extremity; upper extremity; trunk). PSM identified evenly matched cohorts of 300 patients each with respect to age, income, CD score, histology, grade, tumor size, and primary site. The addition of neoadjuvant C remained prognostic for OS on PSM (HR: 0.74 [0.56-0.99], p = 0.042). Conclusions: The addition of C to neoadjuvant RT was associated with improved OS in patients with high risk non-rhabdomyosarcoma ET-STS in the NCDB. These hypothesis generating results support prospective evaluation.

Thymectomy for thymoma spanning three decades at Tor Vergata thoracic surgery center

Background: Thymoma is most common primary neoplasm of the anterior mediastinum in the adult population. Surgery remains the cornerstone of the treatment. Methods: In a three decades period [1986–2015] we performed a total of 225 patients for thymoma through open (n=182) or minimally invasive access (n=43) achieving 189 complete resections. Data were reviewed and main prognostic factors considered by Kaplan-Meier and log rank methods. Results: Completeness of resection, Masaoka stage, WHO histology, cell cycle protein expression and preoperative neutrophil to lymphocytes ratio were significant prognosticators. Whereas concomitant myasthenia gravis (MG) and surgical approach were not. Recurrences are slow-growing and deserves always aggressive treatment. Conclusions: Despite the bias due to the long time-span, our analysis allows the evaluation of the whole aspects of this surgery and results are in accordance with those already reported in the literature. New prognostic factors such as cell cycle proteins expression and preoperative neutrophil to lymphocytes ratio resulted significant.

Video-assisted thoracoscopic surgery versus open surgery for Stage I thymic epithelial tumours: a propensity score-matched study.

Video-assisted thoracoscopic surgery (VATS) has been increasingly used in the management of thymic epithelial tumours. However, its oncological efficacy remains to be proved. The purpose of this study is to compare the oncological outcomes following thoracoscopic versus open surgery in the case-matched groups of patients with early-stage thymic tumours from the Chinese Alliance for Research in Thymomas (ChART) retrospective database. Between 1994 and 2012, a total of 1087 patients who underwent surgery for UICC (Union for International Cancer Control) pathological Stage I tumours from the ChART retrospective database were recruited for this study. A propensity score-matched analysis was used to compare the long-term outcomes in patients who received VATS or open surgery. VATS resection was performed in 271 patients (24.9%) and open surgery in 816 patients (75.1%). Before propensity score matching, the VATS group had a smaller tumour size (P = 0.002), lower grade histology (P = 0.034), lower T stage (P < 0.001) and less adjuvant therapy (P < 0.001). Propensity score matching by gender, myasthenia gravis, tumour size, histological classification, pathological T stage, extent of thymectomy, adjuvant radiotherapy and adjuvant chemotherapy identified 110 patients in each group. After matching, there was no significant difference in patient demographics, tumour characteristics or adjuvant therapy. All matched patients had R0 resection. Overall survival, disease-free survival and cumulative incidence of recurrence were only predicted by WHO histology, but not by surgical approach, in both univariable and multivariable analyses. There was no significant difference in the overall survival (85.7% vs 93.1%, P = 0.539), disease-free survival (92.5% vs 91.9%, P = 0.773), cumulative incidence of recurrence (7.1% vs 5.8%, P = 0.522) and improvement rate of myasthenia gravis (83.3% vs 88.2%, P = 0.589) between the 2 groups. This propensity score-matched study suggests that VATS and open surgeries are associated with similar oncological outcomes for Stage I thymic epithelial tumours. Minimally invasive surgery might be an acceptable surgical approach for early-stage thymic malignancies.

Inter-relationship among myasthenia gravis, WHO histology, and Masaoka clinical stage and effect on surgical methods in patients with thymoma: a retrospective cohort study.

The aim of study is to analyze the inter-relationship among WHO histology, myasthenia gravis (MG) and Masaoka stage and to assess the feasibility of thoracoscopic surgery in thymoma patients. Data from 142 consecutive thymoma patients from January 2009 to March 2016 were retrospectively reviewed in our institution. Histological classification and clinical staging were assessed by WHO histology criteria and Masaoka stage. We investigated the clinical characteristics, inter-relationship among WHO histology, MG and Masaoka stage, and compared the feasibility and safety of thoracoscopic thymectomy by comparison of open thymectomy. Among 142 patients, the incidence of MG was 29.6%. Compared with A and AB-type thymomas, a higher prevalence of advance clinical stage was in B1 to C-type thymomas (37/63 vs. 9/43, P<0.001), and there was an increased trend of Masaoka stage from A to C-type thymomas (P<0.001). The incidence of MG was significantly higher in AB, B1 and B2-type thymomas than other type thymomas (23/63 vs. 6/44, P=0.009) and in early Masaoka clinical stage than advanced Masaoka clinical stage (29/80 vs. 12/59, P=0.042). Thoracoscopic surgery could significantly decrease blood loss in patients with (104.06±137.36 vs. 350.91±560.79 mL, P=0.001) or without MG (91.90±77.70 vs. 266.32±292.60 mL, P=0.02), with comparable complications. Additionally, thoracoscopic surgery could achieve an equal effect on the remission of MG with open surgery (7/11 vs. 10/14, P=1.000), and Masaoka stage was significantly associated with the remission of MG after thymectomy. Our study suggests that WHO histology, MG, and Masaoka stage interrelate with one another, and Masaoka stage is an important prognostic factor in remission of MG after thymectomy in thymoma patients. Thoracoscopic thymectomy could achieve an equal efficacy to open thymectomy and should be recommended as a routine surgery for patients with early Masaoka stage.