julilili42/papers huggingface dataset:
Prognostic significance of the CP-GEP assay combining clinicopathologic factors and gene expression profiling in patients (pts) with AJCC v8 stage I/II cutaneous melanoma (CM).
2022-06-01

9564 Background: AJCC v8 includes Breslow thickness and ulceration to subdivide stage I and II CM pts into risk groups. In light of the results from adjuvant therapy in stage II CM, it has been discussed that pts’ follow-up and eventually treatment should consider additional markers, namely CP-GEP, to further refine the risk classification provided by the AJCC v8. The aim of this single center study was to clinically validate a prognostic CP-GEP-based risk score for stage I/II CMs combining Breslow, age and the expression of 8 genes SERPINE2, GDF15, ITGB3, CXCL8, LOXL4, TGFBR1, PLAT and MLANA. Methods: All obtainable formalin-fixed paraffin-embedded primaries of stage I/II CMs with negative sentinel lymph node (SLN) from the Central Malignant Melanoma Registry of Germany diagnosed between 2000-2017 and archived in Tuebingen were included. Study hypothesis and protocol were prospectively formulated. Tumors were analyzed blinded to clinical outcome. Quantitative reverse transcription polymerase chain reaction of the 8 genes was performed and combined with age and tumor thickness to define CP-GEP low- vs. high-score groups. Relapse-free survival (RFS), distant metastasis free survival (DMFS) and overall survival (OS) were evaluated using Kaplan-Meier curves. CP-GEP score performance was tested using multivariate Cox regression adjusted for tumor thickness, ulceration and age. Results: We included 543 pts with Stage IA (n=78); IB (n=223); IIA (n= 123); IIB (n=73); IIC (n=46). 43% were females, median Breslow was 1.7mm and 25% of tumors had ulceration. The median follow-up was 78 months (IQR 47-116). 311 (57%) patients had a high-risk CP-GEP score. The 5-y RFS rate was 71% and 92% (HR 4.2; p&lt;0.001), the 5-y DMFS rate was 86% and 96% (HR 4.35; p&lt;0.001) and the 5-y OS was 85% and 95% (HR 3.2; p=0.001), respectively for high and low-risk CP-GEP score. In multivariate Cox regression analysis for RFS including Breslow thickness, ulceration and age, contribution of CP-GEP score remained independently significant (HR 2.75; p=0.0008) compared to age (HR 1.03; p&lt;0.0007), Breslow (HR 1.21; p&lt;0.0001) and ulceration (HR 1.37; p=0.1694). Conclusions: CP-GEP risk score is a non-invasive and independent prognostic model for risk of relapse in stage I/II melanoma validated in this study. It identifies SLN negative pts at high risk of relapse and should be considered for complementing AJCC classification and for inclusion in future clinical trials.[Table: see text]
Prospective identification of prognostic factors for patients with early failure of advanced ovarian cancer who undergo primary cytoreductive surgery followed by chemotherapy: The AGO-OVAR 19/FRAGILE study (NCT02828618).
2022-06-01

5556 Background: Standard treatment for advanced ovarian cancer (aOC) includes primary cytoreductive surgery followed by chemotherapy (PDS &gt; CTX). There is strong evidence that this strategy is accompanied by high risk for early failure in some patients (pts) but prospective multicenter data for this specific question are lacking. Methods: 64 AGO-sites prospectively registered pts with suspected aOC and collected following variables prior to start of therapy: age, Charlson Comorbidity Index (CCI), timed up and go test (TUG), ASA and ECOG performance score, weight, height, estimated ascites, albumin, creatinine, hemoglobin, leucocytes, platelets, CA125, patient reported outcome measures according to EORTC QLQ-C30 and OV28, hospital anxiety and depression score (HADS), physician-assessed suspected FIGO IV stage, abdominal pain requiring treatment, abdominal bloating, dyspnea and required palliative paracentesis (ascites, pleural effusions). Treatment followed according to investigator’s decision. Primary objective was to predict the unfavorable event of death or progression within 10 months after primary diagnosis. We applied univariate and multiple logistic regression with stepwise variable selection after multiple imputation of missing data in order to identify relevant predictors. Results: 223 pts with aOC FIGO IIIB to IVB and PDS were analyzed. Median age was 63 years (range 31-86). 52 (23.3%) pts experienced progression or death within 10 months from time of enrolment. In univariate regression, age (odds ratio (OR) 1.612 per 10 years), ASA (III vs I/II: OR 3.217), TUG (OR 1.087), body height (OR 0.541 per 10cm), ECOG (1 vs 0 OR 2.326, 2-3 vs 0 OR 4.102), estimated ascites ( &gt; 500cc vs. none OR 2.811), paracentesis (OR 1.991), platelets (upper limit of normal (ULN) vs norm or &lt; lower limit of normal (LLN) OR 1.998), albumin ( &lt; LLN vs norm or &gt; ULN OR 2.053), creatinine ( &gt; ULN vs norm OR 3.969) and baseline QoL single-item subscales appetite loss (“very much” vs “not at all” OR 2.611), constipation (“quite a bit” vs “not at all” OR 4.903), and multi-item subscales global health status (OR 0.982 per 1 point) and nausea/vomiting (OR 1.013 per 1 point) were significant (p &lt; 0.05). Multiple logistic regression identified age (OR 1.459 per 10 years), ASA (III vs I/II: OR 2.427), constipation (“quite a bit” vs “not at all” OR 3.786) and global health (OR: 0.985 per 1 point) as independent predictors of progression or death within 10 months after primary diagnosis (p &lt; 0.05). Conclusions: A significant proportion of aOC pts undergoing PDS &gt; CTX are at high-risk for early failure. The finding of independent risk factors including self-ratings of QoL at time of diagnosis should be confirmed and tested against other models to facilitate a more tailored treatment of high-risk pts and design of future trials in aOC. Clinical trial information: NCT02828618.
Encorafenib plus binimetinib in patients with locally advanced, unresectable, or metastatic BRAFV600-mutant melanoma: Updated data from the multicenter, multinational, prospective, non-interventional longitudinal study BERINGMELANOMA.
2022-06-01

9526 Background: For the treatment of advanced BRAF V600 -mutated melanoma, targeted BRAF/MEK-inhibition is a standard of care. Encorafenib + binimetinib (EB) were approved 2018 in the EU and 2019 in Switzerland, based on positive results from COLUMBUS (NCT01909453), median progression-free survival (PFS) 14.9 mo (5-yr PFS: 23%), overall survival (OS) 33.6 mo (5-yr OS: 35%). As data from controlled trials are based on selected populations, BERING MELANOMA investigates EB-use under real-world conditions in a broader population. Methods: BERING MELANOMA (NCT04045691) is an ongoing, multi-national, prospective, longitudinal, non-interventional study. It analyzes the effectiveness (prim. endpoint: 1-yr PFS-rate), QoL and safety of EB-therapy in the unresectable advanced or metastatic setting under real-world conditions, focusing on the first- (1L) and second-line setting including an evaluation of the impact of prognostic factors. The project aims to enroll up to 750 patients (pts) in a total of 80 German, Austrian and Swiss sites (study duration: 8 yrs). So far (10/2019-01/2022), 280 pts have been included. Pts with prior BRAF-/MEK-inhibition (except adjuvant use completed &gt; 6 mo) and &gt; 1 prior therapy line with CPI in the palliative setting were excluded (adjuvant CPI allowed). Results: Here we present the 2nd planned interim snapshot based on the initial 200 enrolled pts (186 treated / 182 evaluable; median FU: 14.2 mo). This analysis set shows a median age of 60.5 yrs (range 20.0-89.0), 45% of pts were female. 87% presented with distant metastases (brain: 30%), with an involvement of ≥3 organ systems in 51% and elevated LDH in 43%. 54% of pts underwent any prior systemic therapy (adjuvant: 30%; 1L CPI palliative: 24%, mainly with ipilimumab + nivolumab). EB was mainly administered in the 1L-setting (60%). Main reasons for EB-selection were: efficacy (44%), physician's preference (34%), QoL (17%). Median estimated EB treatment duration was 11.6 mo (95%CI 8.8-18.6), median relative dose intensity for both drugs: 100%, main reasons EB-discontinuation: PD (55%), toxicity (16%). Treatment adaptations were required in 40% of pts (interruption E 26%, B 29%), toxicity as main reason (E 26%, B 29%). Adverse events were reported in 86% of pts (grade 3/4: 34%), mainly (≥10%, all grades): diarrhea, nausea, fatigue (each 17%), CK increase (16%), GGT increase (11%). No fatal toxicities were observed. Conclusions: This 2nd interim snapshot shows an investigation of EB in a real-world population with advanced disease. Despite the poorer prognosis configuration as compared to the pivotal study, the observed tolerability profile is largely consistent with data derived from COLUMBUS without any new safety signals. The 3rd interim snapshot will be performed after enrollment of 300 pts.
The association of germline HSD3B1 genotype with outcomes in metastatic hormone-sensitive prostate cancer (mHSPC) treated with androgen deprivation therapy (ADT) with or without enzalutamide (ENZA) [ARCHES].
2022-06-01

5022 Background: A common missense-encoding germline polymorphism in HSD3B1(1245A→C) stabilizes the 3βHSD1 enzyme and increases the rate-limiting step for metabolic flux from adrenal precursors to potent androgens. This adrenal-permissive HSD3B1(1245C) allele mechanistically drives more rapid progression after ADT in nonmetastatic and low-volume (LV) mHSPC. It is unknown whether upfront treatment with ENZA could improve these poor outcomes. We sought to determine the association between the HSD3B1 genotype and outcomes in ARCHES, a randomized, placebo (PBO)-controlled, phase 3 global study of ADT with ENZA or PBO in mHSPC. Overall, 31.3% of men on placebo crossed over to ENZA prior to progression. Methods: Germline DNA from 660 men (243 LV and 417 high volume [HV]) in ARCHES was genotyped for HSD3B1. Radiographic progression-free survival (rPFS), prostate-specific antigen (PSA) outcomes, and overall survival (OS) were compared between men who inherited 0 (adrenal restrictive) vs. 1–2 copies of the HSD3B1(1245C) allele (adrenal permissive) using log-rank tests, Kaplan-Meier estimates, and Cox proportional hazards models for hazard ratios (HRs). Results: In ARCHES, 340 and 320 men had the adrenal-restrictive and adrenal-permissive HSD3B1 genotype, respectively. The adrenal-permissive genotype was not associated with worse rPFS, time to PSA progression (TTPP), or OS. Cox model HRs for death in the adrenal-permissive compared with adrenal-restrictive men in the ENZA + ADT and PBO + ADT arms were 1.21 (95% confidence interval [CI] 0.84, 1.74) and 1.48 (95% CI 0.98, 2.25), respectively. Three-year OS was 82% and 73% in men treated with ENZA + ADT with restrictive vs. permissive genotypes, respectively, and 68% and 70% in men treated with PBO + ADT. ENZA significantly improved rPFS, TTPP, and OS, irrespective of genotype. HRs for ENZA + ADT vs. PBO + ADT in models adjusted for genotype were: rPFS, 0.64 (p &lt; 0.001); TTPP, 0.27 (p &lt; 0.001), and OS, 0.62 (p &lt; 0.001). Of OS events in the HSD3B1-genotyped men, 48 (23%) and 163 (77%) deaths occurred in the LV and HV groups, respectively. Conclusions: In men with mHSPC, ENZA improved OS, rPFS, and TTPP over PBO + ADT, irrespective of HSD3B1 genotype. Survival analysis of HSD3B1-genotyped men in this study is largely driven by men with HV disease. The analysis of men with LV disease was limited by the small number of events. Clinical trial information: NCT02677896.
EPEN-09. Multi-omics characterization of the blood-brain barrier in molecular groups of ependymoma
2022-06-01

Abstract BACKGROUND: A major challenge in the treatment of brain tumors is the limited penetration of many drugs through the blood-brain barrier (BBB). BBB characteristics include endothelial cells connected by tight junction proteins (e.g. Claudin5) and expression of efflux transporters (e.g.P-gp) with the physiological role to limit the accumulation of potentially toxic substances in brain tissue. While BBB permeability shows anatomical region-specific characteristics and changes with age, brain tumors can also impact its integrity. To achieve therapeutically relevant drug concentrations in the tumor, characterization of the pathophysiological BBB is fundamental when developing (pre)clinical trials. Our study seeks to increase our understanding of the BBB composition in various molecular groups of ependymoma. RESULTS: Transcriptional BBB characteristics were assessed for primary ependymoma (n=440), cell lines (n=3), mouse models (n=22), and healthy brain controls (n=200). T-distributed stochastic neighbor embedding (tSNE)-based clustering analyses based on most relevant tight junction and efflux transporter gene sets revealed distinct molecular ependymoma group-specific expression patterns. While patient-derived xenografts models (PDX, n=20) showed high similarity with patient tumor samples, in utero electroporation-based (IUE, n=2) mouse models did not fully recapitulate these BBB characteristics. Supratentorial ependymoma with ZFTA fusions revealed a higher transcriptional expression level of important tight junctions (e.g.Claudin5) compared to other groups and normal brain which was confirmed at protein level in respective PDX models by using both western blot and ultra-high content imaging. CONCLUSION: Analyses of important BBB markers revealed significant differences between molecular groups of ependymoma, which may partly explain drug resistance of ependymoma with ZFTA fusion caused by a low BBB permeability. BBB characteristics of corresponding models suggest that IUE and PDX models representing ZFTA fusion-driven tumors cannot equally be used within preclinical drug trials. Findings will be further validated in preclinical studies while molecular BBB characterization will be expanded to other brain tumors.
Concordance and clinical impact of ER, PR, HER2 expression by local and central immunohistochemistry versus RT-PCR in HR+/HER2- early breast cancer (EBC): Results from the ADAPT trial.
2022-06-01

536 Background: We evaluated concordance of ER, PR and HER2 status between local, central, and RT-PCR/mRNA assessments and its clinical impact in the ADAPT trial collective in HR+ HER2- EBC (NCT01779206). Particularly, validity of borderline ER-positivity (expression level 1-10%) has great clinical relevance as treatment concepts between luminal-like and triple negative (TNBC) EBC differ substantially. Methods: Patients (pts) with clinically high-risk HR+/HER2- EBC (ER and/or PR &gt;1%) were initially treated by 3 (+/-1) weeks of endocrine therapy (ET) before surgery or sequential core biopsy (CB) and then allocated to an ET-alone or chemotherapy (ET) trial, depending on risk and endocrine response. OncotypeDX (incl. RT-PCR for ER, PR, HER2) and central IHC for ER, PR, HER2 were performed on the initial 1.CB. ER-low cohort was defined as 1-10% expression by local OR central lab (ASCO-CAP). Cox models were used to estimate hazard ratios. Results: In ADAPT, 5149 pts from 81 centers in Germany with locally ER and/or PR positive (known quantitative levels) EBC were screened 2012-2018. Median follow-up was 59 months. For ER (positive vs. negative), overall concordance measured as agreement (κ) was high between all three assessments: Local vs. central IHC: 99.3% (κ = 0.45), RT-PCR vs. central IHC: 99% (κ = 0.48). Concordance was lower for PR: RT-PCR vs. central IHC: 90.5% (κ = 0.58), local vs. central IHC: 93.1% (κ = 0.56). 3% were centrally found as HER2+ in 1.CB (73% of them were negative by RT-PCR) and/or 2. Sample. Regarding HER2-low status (1+ or 2+ but ISH negative), concordance between local and central IHC was only 53.8% (κ = 0.09). Of all pts, only 2% (n=109; n=85 with both measurements available) had low ER expression (1-10%) by either local or central pathology. Only 9 of them were concordantly identified as ER-low (11%); 8/58 (14%) ER-low by local lab had TNBC by central lab. 17/47 ER-low cases (36.2%) with known post-endocrine Ki67post had Ki67post &lt;10% vs. 59.7% in ER&gt;10%. 41.8% of ER-low cases had RS&lt;25 vs. 76.7% in ER&gt;10%. All cases with ER &lt;10% by both assessments and those with Ki-67≥40% had RS &gt;25. We observed worse iDFS (HR 1.91, p=0.034) in the ER-low group vs. ER&gt;10%. Conclusions: Although we have confirmed high agreement between local and central IHC and RT-PCR for ER, PR, HER2 assessment in locally HR+/HER2- EBC, there are still a few clinically relevant discordances. Regarding HER2-low status, standardization and quality assurance are needed if this becomes clinically relevant. Treatment of the heterogeneous ER-low group as TNBC appears reasonable only if “ER-low” is confirmed by a second assessment and in cases with Ki-67&gt;40%. Preoperative ET response assessment may be helpful if an endocrine-based therapy concept is intended. Clinical trial information: NCT01779206.
GPR15-mediated T cell recruitment during acute viral myocarditis is associated with improved virus elimination and outcome
2022-06-01

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): DZHK Ernst und Berta Grimmke Stiftung Background Myocarditis is an inflammatory disease of the myocardium indicated by mononuclear cell infiltration. It is predominantly caused by infectious agents such as coxsackievirus B3 (CVB3). Especially in young adults, myocarditis is a major source of sudden cardiac arrest. However, its clinical course has a broad spectrum of outcomes, ranging from mild symptoms and complete recovery to cardiac dysfunction and dilated cardiomyopathy. G protein-coupled receptor 15 (GPR15) was identified as a T cell homing receptor in the context of inflammatory intestine and skin diseases. We found Gpr15 to be highly upregulated in the left ventricle (LV) 7 days after CVB3 infection in wild type (WT) mice. Purpose GPR15 has not been described in a cardiac context, yet. Our aim was to investigate the role of GPR15 in recruiting immune cell subsets and later in virus elimination during viral myocarditis. Methods Gpr15 deficient (Gpr15gfp/gfp) and WT mice were infected intraperitoneal with CVB3 to investigate the acute (6 &amp; 7 days post infection(p.i.)) and the subacute phase (16 days p.i.) of myocarditis. To study differentially expressed genes, LV tissue was used for TaqMan analysis and RNA-sequencing. Inflammation and fibrosis were evaluated on histological level. For functional characterization, healthy and diseased mice were hemodynamically characterized 16 days p.i.. Furthermore, in vitro migration assays were used to study the interaction between GPR15 and its ligands in vitro. Results Infected Gpr15gfp/gfp mice exhibited higher upregulation of immune response related genes on mRNA level in the acute phase of myocarditis 7 days p.i.. For instance, Cd8a, a cytotoxic T cell marker, and Foxp3, a regulatory T cell marker, were significantly higher in infected Gpr15gfp/gfp compared to infected WT mice. Bulk RNA-sequencing confirmed that the response to virus did not decline from day 6 to 7 in infected GPR15-deficient mice as observed in infected WT mice. Subsequent gene ontology (GO) term analyses reveled enhanced chemotaxis and cytotoxic T cell-related GO terms in GPR15-deficient mice on day 7. Among investigated T cell subsets, GPR15 was highest expressed on CD8+ T cell. Its deficiency abolished chemotaxis of T cells, especially of cytotoxic T cells, towards GPR15 ligand in vitro. In the subacute phase of myocarditis 16 days p.i., viral persistence was observed in more than 85 % of Gpr15gfp/gfp mice. In contrast, more than 70 % of WT mice with verified viremia cleared the virus successfully. Furthermore, Gpr15gfp/gfp mice demonstrated a decreased cardiac function accompanied by increased fibrosis in comparison to WT mice. Conclusion Our findings indicate that despite the prolonged inflammatory response, scant virus elimination was presumably caused by decelerated recruitment of cytotoxic T cells leading to impaired outcome in the GPR15-deficient mice.
ATRT-12. LIN28A expression correlates with poor prognosis and the MYC subgroup in AT/RTs
2022-06-01

Abstract Atypical teratoid/rhabdoid tumors (AT/RTs) are malignant embryonal tumors of the central nervous system, which mainly affect young children. These tumors are defined by loss of SMARCB1 (or SMARCA4 in rare cases) and can be categorized into three main DNA methylation subgroups (i.e. –MYC, -SHH, -TYR). AT/RTs commonly display heterogeneous expression of LIN28A, an RNA-binding protein, which regulates pluripotency and plays critical roles during embryonic development. The biological impact and clinical significance of LIN28A expression in AT/RTs remains unknown. In this study, we investigated 80 samples of molecularly and clinically characterized AT/RTs for LIN28A expression using immunohistochemistry. Staining signal of tumor tissue was assessed and scored via semi-automated digital image analysis. Global LIN28A expression intensity and heterogeneity were tested for correlation with DNA methylation subtype, tumor localization, as well as patient age, gender and overall survival. LIN28A was found with strongly varying staining patterns and intensities across our cohort of AT/RTs, with significantly elevated expression in the MYC subgroup. Moreover, we identified strong global and focal LIN28A expression as an independent negative prognostic factor in AT/RTs. In summary, we show that AT/RT-MYC tumors display significantly increased LIN28A expression in comparison to the other DNA methylation subgroups, suggesting a subgroup-specific intratumoral role of LIN28A. Furthermore, we demonstrate an impact of LIN28A expression on survival in AT/RTs. Further investigations on the functions of LIN28A in AT/RTs in vitro and in vivo are ongoing and aim to uncover potential therapeutic implications in these tumors.
LGG-56. Surgical management of pre-chiasmatic intraorbital optic nerve gliomas in children after loss of visual function – Resection from bulbus to chiasm
2022-06-01

Abstract INTRODUCTION: Optic pathway gliomas (OPG) in children carry significant morbidity and therapeutic challenges. The subgroup of pre-chiasmatic gliomas manifest with exopthalmus are a subgroup where, after blindness has occurred, an intraorbital and intradural resection is a curative option. We present a two-center cohort using two different surgical approaches and describe indication, technique, and long term surgical outcome. METHODS: A retrospective analysis in both centers was performed to included patients &amp;lt; 18 years at diagnosis with a pre-chiasmatic intra-orbital glioma, in whom a resection from the bulb to the chiasm was performed. RESULTS: 11 patients were included. 4 had NF1. Mean age at surgery was 7.0 years. Interval between diagnosis and surgery was 1-74 (median 10) months. Two had prior chemotherapy, one radiation, one both, one prior intraorbital surgery. In all 5 progression occurred. Indications for surgery were exophthalmos, pain, tumor progression or a combination. 8 patients (Group A) underwent an extradural trans-orbital-roof approach to resect intra-orbital tumour including the optic canal part plus intradural pre-chiasmatic resection. In 3 patients (Group B) a combined supra-orbital mini-craniotomy plus orbital frame osteotomy was used for intraorbital tumour-resection, excluding the optic canal part, plus intradural pre-chiasmatic resection. GTR was achieved in 7/8 of Group A and none had a recurrence (mean-FU 42 month). One residual behind the bulbus showed progression, treated by chemotherapy. All residuals in Group B were remnants of the optic nerve within optic canal remained stable (mean FU 11.8 months). No patient had a chiasmatic functional affection or permanent oculomotor deficits. Two after prior radiotherapy developed slight enophthalmos. CONCLUSION: In these selected patients surgical resection from bulb to chiasm (± removal of optic canal tumor) is safe without long-term sequela and with excellent cosmetic result. Surgery removes immediately exophthalmos and provides an effective long-term tumor control. It should be considered therapy of choice.