julilili42/papers huggingface dataset:
MEDB-04. Young children with metastatic medulloblastoma: frequent requirement for radiotherapy in children with non-WNT/non-SHH medulloblastoma despite highly intensified chemotherapy – Results of the MET-HIT2000-BIS4 trial
2022-06-01

Abstract PURPOSE: To assess outcomes and biological parameters of children younger than 4 years with metastatic medulloblastoma treated within the MET-HIT2000-BIS4 trial or outside the protocol. PATIENTS AND METHODS: 48 trial participants received either carboplatin/etoposide (years 2001 to 2005, n=18) or an intensified Head-Start-based induction (years 2006 to 2011, n=30), both groups with intraventricular methotrexate, followed by high-dose chemotherapy (HDCT) and/or craniospinal radiotherapy (CSI). In an extended cohort, data of 58 additional were grouped with trial participant data. RESULTS: Trial participants (n=48): After intensified induction, both response (26/27 vs. 10/17 eligible patients, p=0.003), and progression-free survival (PFS, 5-year-PFS (5y-PFS): 57% vs 28%, p=0.014) was higher after intensified induction. However, CSI- /progression-free survival (CSIfPFS) was low (5-year CSIfPFS 17%). Biological subtype influenced 5y-CSIfPFS with 3% in non-WNT/non-SHH medulloblastoma vs. 58% in SHH-medulloblastoma (p&amp;lt;0.001), independent of induction regimens. Extended cohort (n=48 on trial and n=58 off trial): Non-WNT/non-SHH medulloblastoma (n=74, all treated in analogy to the MET-HIT2000-BIS4 protocol): Most frequent subtypes were II (5y-PFS 0%, 5y-OS 7%, n=21) and IV (5y-PFS 55%, 5y-OS 57%, n=16). 5y-CSIfPFS was only 8% [n=5]. Among patients in CR (n=13) or PR (n=10), who received HDCT but not CSI in primary therapy, only 5 were CSI-free survivors (CR: n=4/PR: n=1; Subtype III: n=1, Subtype IV: n=2, non-WNT/non-SHH by histology: n=2). SHH-medulloblastoma (n=32, treated with MET-HIT2000-BIS4 [n=16] or HIT2000-BIS4/HIT-SKK chemotherapy [with intrventricular methotrexate, without HDCT; n=16]): 5y-PFS (72%) and 5y-CSIfPFS (69%) did not differ according to therapy or SHH-subgroups. Two therapy-related deaths occurred on MET-HIT2000-BIS4 therapy. Relapses were more frequent after HIT-SKK (p=0.083). CONCLUSIONS: Despite maximally intensified chemotherapy, patients with metastatic non-WNT/non-SHH medulloblastoma almost always require craniospinal radiotherapy to survive their disease. In SHH-activated medulloblastoma, HDCT might better control the disease but careful vigilance of toxicity is important.
Comparison of Radiocarbon‐ and Background Location‐Corrections on Soil‐Gas CO 2 Flux‐Based NSZD Rate Measurements at Petroleum Impacted Sites
2022-06-01

Abstract The measurement of contaminant natural source zone depletion (NSZD) rates has become an important tool to manage petroleum contaminated sites. Most NSZD rate measurement methods rely on a balance on the biodegradation by‐products (either carbon or heat). Carbon balance‐based methods stoichiometrically convert measured soil‐gas CO 2 flux related to contaminant degradation to equivalent contaminant mass loses. CO 2 flux‐based methods require separating the fraction of the total CO 2 flux produced by NSZD from the fraction of CO 2 flux produced by natural soil processes (due to modern carbon turnover). Two method corrections are available to distinguish the nature of the measured CO 2 flux: (1) The background location correction subtracts a measurement from an unimpacted location from measurements collected at impacted locations, and (2) a location‐specific radiocarbon ( 14 C) analysis that differentiates the modern and old carbon fractions of each total CO 2 measurement. This work evaluates both correction approaches using 36 measurements at impacted locations from five sites. The 14 C‐corrected data shows that the magnitude and variability of the modern carbon‐related fraction (noise) and the NSZD related fossil fuel signal are similar, suggesting a location‐specific correction is more valid. Only one sparsely vegetated arid site showed close agreement between both corrections ( 14 C‐ and background location). These results highlight the strong effect of the correction method used on NSZD rate measurements, and the importance of considering data quality on the subsequent data management process.
MEDB-45. Functional genomics identifies epigenetic regulators as novel therapeutic targets for sonic hedgehog medulloblastoma
2022-06-01

Abstract Medulloblastoma (MB) is among the most common malignant childhood brain tumors that comprises a group of four molecularly distinct diseases. A significant proportion of these tumors is characterized by aberrant activation of the canonical sonic hedgehog (SHH) signaling pathway. Although small-molecule inhibitors targeting Smoothened (SMO) have proven a promising treatment approach for SHH-MB subgroup, primary or acquired resistance impedes its clinical efficacy. Therefore, novel targeted approaches are urgently needed to improve therapeutic strategies for this tumor entity. Here, we conducted a genome-wide CRISPR/Cas9 knockout screen in a murine and a human SHH-MB cell line, SMB21 and DAOY, respectively, in order to decipher tumor-specific genetic dependencies. Our data demonstrate that SMB21 cells highly depend on positive regulators of the SHH pathway, such as Smo and Gli1 for their survival, as opposed to DAOY cells, suggesting that the latter does not represent a faithful model of SHH-MB. Members of the epigenetic machinery such as Dnmt1 and Smarca5 scored strongly as SMB21-context specific essentialities. Pharmacologically, we show that DNMT1 inhibition is efficacious at clinically relevant concentrations against SMO inhibitor- sensitive, as well as resistant SHH-MB cell lines, indicating novel therapeutic avenues for SHH-MB. By performing RNA sequencing of SMB21 cells, we identified early and late changes in global gene expression induced by DNMT1 inhibition, including decreased expression of mediators of SHH signaling, such as Gli1 and Gli2. Of note, gene set enrichment analysis revealed that DNMT1 inhibition downregulates top gene sets associated with cell cycle progression, corroborating the screening results that Dnmt1 is essential for SMB21 proliferation. Further global DNA methylation profiling in SMB cells will help to define the molecular basis of sensitivity to DNMT1 inhibitors in SHH-MB. Summarizing, our data highlight the potential of inhibitors targeting epigenetic regulators in SMO inhibitor- sensitive and resistant MB for more efficacious treatment options.
A phase 3 study of the subcutaneous programmed cell death protein 1 inhibitor sasanlimab as single agent for patients with bacillus Calmette-Guérin, unresponsiv,e high-risk, non-muscle invasive bladder cancer: CREST Study Cohort B.
2022-06-01

TPS4614 Background: Bacillus Calmette-Guérin (BCG) therapy is the standard of care for high-risk non-muscle invasive bladder cancer (NMIBC) after transurethral resection of bladder tumor. However, disease recurrence or progression is common and patients with BCG-unresponsive disease are unlikely to respond to further BCG therapy. In these patients, the current standard of care is radical cystectomy and bladder-preserving treatment options, limited to intravesical chemotherapy or intravenous pembrolizumab. In a phase 1 study, sasanlimab (PF-06801591), a monoclonal antibody to programmed cell death protein 1 (PD-1), was administered subcutaneously at 300 mg every 4 weeks. Sasanlimab had an acceptable safety profile and showed clinical activity aligned to other anti-PD-1/PD-ligand 1 (PD-L1) agents in patients with advanced urothelial carcinoma and non-small cell lung cancer, while offering the convenience of subcutaneous administration. Therefore, CREST Study Cohort B aims to evaluate sasanlimab administered subcutaneously in patients with BCG-unresponsive NMIBC. Methods: CREST Study Cohort B is a non-randomized, multicenter, multinational, open-label, phase 3 study and will enroll ̃160 patients with histologically confirmed BCG-unresponsive, high-risk, non-muscle invasive transitional cell carcinoma of the bladder urothelium (high-grade Ta or T1 tumor, or carcinoma in situ [CIS]) in 2 separate Cohorts, B1 and B2 (̃110 and ̃50 patients, respectively). Cohort B1 will enroll patients with persistent or recurrent CIS with or without concomitant recurrent high-grade Ta/T1 disease, within 12 months of completing adequate BCG therapy. Cohort B2 will enroll patients with recurrent high-grade Ta/T1 disease within 6 months of completing adequate BCG therapy. All patients will receive subcutaneous sasanlimab as a single agent. Efficacy will be assessed at regular intervals by cystoscopy, urine cytology, biopsy, and imaging. The primary endpoint is complete response (CR) and event-free survival (EFS) for Cohort B1 and B2, respectively. Secondary endpoints include duration of CR (Cohort B1 only), EFS (Cohort B1 only), overall survival, time to cystectomy, safety, health-related quality of life, pharmacokinetic parameters, PD-L1 expression, and incidence of anti-drug antibodies. Recruitment of patients in CREST Study Cohort B will be opened in Canada and the United States of America, with other sites in Asia, Australia, and Europe. Clinical trial information: NCT04165317.
Colorectal submucosa thickness in specimens obtained by EMR versus ESD: a retrospective pilot study
2022-06-01

Abstract Accurate histopathology is the mainstay for reliable classification of resected early colorectal cancer lesions in terms of potential risk of lymph node metastasis. In particular, thickness of resected submucosa is important in cases of submucosal invasive cancer. Nevertheless, little is known about the quality and thickness of submucosal tissue obtained using different endoscopic resection techniques. In this small pilot study, we performed morphometric analysis of submucosal thickness in specimens obtained from right-sided colorectal lesions using endoscopic mucosal resection (EMR) versus endoscopic submucosal resection (ESD). Comparative measurements showed significant differences in submucosal area ≥ 1000 μm and minimum submucosal thickness per tissue section analyzed (EMR vs. ESD: 91.2 % ± 6.6 vs. 47.1 % ± 10.6, P = 0.018; 933.7 μm ± 125.1 vs. 319.0 μm ± 123.6, P = 0.009). In contrast, no significant differences were observed in variation coefficient and mean maximum submucosal thickness. Thus, unexpectedly, in this small retrospective pilot study, specimens obtained using EMR had a better preserved submucosal layer than those obtained using ESD – possibly due to the different methods of specimen acquisition. The findings should be kept in mind when attempting to resect lesions suspicious for submucosal invasive cancer.
P1448: LONG-TERM SURVIVORS AFTER FAILURE OF CAR-T CELL THERAPY FOR R/R LARGE B-CELL LYMPHOMA (LBCL): A GLA/DRST STUDY
2022-06-01

Background: Information on the long-term outcome of patients who relapse or progress after CD19-directed CAR-T therapy with axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) for >2L treatment of LBCL is still limited. Aims: The purpose of this study was to investigate characteristics, relapse patterns and management strategies in patients with LBCL surviving one year or longer after having failed a preceding standard of care CAR-T therapy. Methods: The study sample consisted of all patients who had a relapse/progression event in a prior GLA/DRST real world analysis (Bethge et al, ASH 2022 #3822). Baseline patient, disease, and treatment data were collected from MED-A cellular therapy forms. Centers were approached to provide additional treatment and follow-up information for each patient with a documented event. Results: Altogether, relapse/progression (REL) after CAR-T therapy was reported for 214 of 356 patients (60%) of the original study. For 143 of 214 patients (67%) a full dataset as needed for the purpose of this study was available. OS at 12 months post REL of these 143 patients was 22% with no significant difference between axi-cel and tisa-cel failures (Figure). 26 of 143 patients (18%) survived 12 months or longer from REL, 109 (76%) died within the first year after REL, and 8 patients (6%) were alive but had not reached the 12-month landmark. Patients surviving and not surviving 12 months post REL, respectively, were comparable for age, gender, IPI at lymphodepletion, PS, prior HCT, and 1st salvage regimens used. However, long-term survivors had less often bridging failure prior to CAR-T therapy, met less often ineligibility criteria for ZUMA1, had less often REL within the first 30d and more often beyond 100d post CAR-T therapy, and had more often received alloHCT for consolidation of treatment responses post REL (Table). 12-month OS post REL of the 40 patients who proceeded to alloHCT was 34% (19-39%). Table. - Survival ≥12mo <12mo P n 26 109 Median age 56 (20-79) 57 (21-83) n.s. Male 15 (71%) 73 (65%) n.s. IPI high/high-i @ LD 11 (42%) 62 (57%) n.s. LDH >N @ LD 12 (46%) 68 (62%) n.s. ZUMA1 ineligible 19 (73%) 104 (95%) 0.0019 Bridging responders / no bridging 15 (58%) 28 (27%) 0.0047 ECOG ≥2 @ LD 1/24 (4%) 17/103 (17%) n.s. ≥3 Treatment lines 24 (92%) 76 (70%) 0.023 Prior SCT 7 (27%) 34 (31%) n.s. Tisa-cel 15 (58%) 71 (65%) n.s REL after CAR-T ≤30d 1 (4%) 26 (24%) 0.027 REL after CAR-T >100d 12 (46%) 22 (20%) 0.011 alloHCT performed 13 (50%) 26 (24%) 0.015 1st salvage Pola-based 9 (35%) 30 (28%) n.s. 1st salvage CPi-based 4 (15%) 8 (7%) n.s. 1st salvage Lena-based 1 (4%) 7 (6%) n.s. Image:Summary/Conclusion: Long-term survival after failure of CAR-T therapy for LBCL is possible in about 20% of the patients. Predictors of a favorable survival post REL are good-risk pre CAR-T features and a long interval between CAR-T therapy and REL. AlloHCT can successfully consolidate salvage treatment responses in a sizable proportion of patients and may improve outcome of CAR-T failure.
Russia’s War And The Future Of European Order
2022-06-01

Russia’s war in Ukraine fundamentally challenges the post-Cold War international order. Yet the scenario of a renewed Cold War must be balanced by alternative visions of European order. This contribution reassesses the concepts of interdependence, socialization, normative power, and international society taken from international relations theory to develop some general lessons for European order and concrete pointers toward alternative policy paths. Such an order needs to build on a more honest engagement, serious great power management mirrored by societal linkages, and creative thinking about joint institutions and regional overlaps.
A RAS-independent biomarker panel pedicts response to MEK-inhibitors in colorectal cancer.
2022-06-01

e15524 Background: Biomarker discovery and development are essential for stratifying cancer patients in order to improve treatment outcomes. In colorectal cancer (CRC), mutations in the TGF-β/BMP pathway, especially in the SMAD4 gene have been correlated with decreased overall survival and are suspected to modulate drug sensitivity on the cellular level, hence SMAD4 mutations are worthwile targets for novel targeted therapy aproaches. Methods: In the present study, we uncover the mechanistic role of a loss-of-function mutation in SMAD4 in syngeneic patient-derived organoids (PDOs). CRISPR-engineered SMAD4 R361H PDOs were subjected to a comparative drug screening, RNA-Sequencing and multiplex protein profiling analysis (DigiWest®). We have confirmed the response towards MEK inhibition of the initial model in an additional set of 62 PDOs with known mutational status. Results: We show that acquisition of SMAD4 loss-of-function mutations renders PDOs sensitive to MEK-inhibitors. Further, an activation of the TGF-β/BMP signaling pathway, specifically of the BMP branch was observed in SMAD4 wt PDOs; indicating that BMP signaling is likely responsible for the resistance towards MEK inhibition. It is plausible that functional loss of SMAD4 and thus loss of BMP signaling renders SMAD4 mutated tumors more sensitive to MEK-inhibitors. By looking at additional genes involved in TGF-β/BMP signaling that are frequently mutated in CRC, we identified the novel gene mutational SFAB-signature ( SMAD4, FBXW7, ARID1A, or BMPR2), when at least one pathogenic mutation is present in these genes. The frequency of SFAB in CRC patient cohort (TCGA, n = 594) was comparable to the frequency of SFAB in our PDOs. For PDOs with SFAB-signature, we found up to 95% and 70% significant positive prediction for cobimetinib and selumetinib, respectively and also up to 70% positive prediction for trametinib. Thus, the SFAB-signature predicts response to MEK inhibition in PDOs with a very high confidence. We further investigated whether the RAS status of CRC PDOs does predict sensitivity to MEK inhibition. The RAS status alone and in combination with SFAB-signature failed to yield better prediction sensitivity to MEK-inhibitors. Conclusions: The present study is a significant step forward to more personalized treatment regimens for CRC patients by early inclusion of MEK-inhibitors. The SFAB-signature should be put to clinical testing as a RAS-independent biomarker for stratification of patients providing a valuable alternative treatment option against CRC, thus ensuring that all patients receive effective and specific therapies as early as possible.
The validity of clinicians’ diagnoses: Is it bread and butter?
2022-06-01

Major depression has become one of the most frequent diagnoses in Germany. It is also quite prominent in cases referred for medicolegal assessment in insurance, compensation or disability claims. This report evaluates the validity of clinicians’ diagnoses of major depression in a sample of claimants. In 2015, n = 127 consecutive cases were examined for medicolegal assessment. All had been diagnosed with major depression by clinicians. All testees underwent a psychiatric interview, a physical examination, they answered questionnaires for depressive symptoms according to DSM-5, embitterment disorder, post-concussion syndrome (PCS) and unspecific somatic complaints. Performance and symptom validity tests were administered. Only 31% of the sample fulfilled the diagnostic criteria for DSM-5 major depression according to self-report, while none did so according to psychiatric assessment. Negative response bias was found in 64% of cases, feigned neurologic symptoms in 22%. Symptom exaggeration was indiscriminate rather than depression-specific. By self-report (i.e. symptom endorsement in questionnaires), 64% of the participants qualified for embitterment disorder and 93% for PCS. In conclusion, clinicians’ diagnoses of depression seem frequently erroneous. The reasons are improper assessment of the diagnostic criteria, confusion of depression with bereavement or embitterment and a failure to assess for response bias. Disclosure No significant relationships.
An investigation of depression and inflammation as potential mediators linking adverse childhood experiences with cognitive decline in adulthood: results from a prospective cohort study
2022-06-01

Introduction Adverse childhood experiences (ACEs) have been associated with numerous health consequences in adulthood including cognitive decline. However, the underlying mechanisms implicated remain unclear. Objectives In this study, depressive symptoms and systemic inflammation were investigated as potential independent mediators of the association between ACEs and cognitive decline. Methods Participants were adults aged 50+ from the English Longitudinal Study of Ageing (N = 3,029; 54.8% female). Measures included self-reported ACEs at wave 3 (2006-2007), C-reactive protein (CRP) and depressive symptoms at wave 4 (2008-2009), and cognitive function at waves 3 and 7 (2014-2015). Mediation analyses examined the direct associations between ACEs and cognitive function at wave 7 and the indirect associations via depressive symptoms and CRP at wave 4 and were conducted using ordinary least squares regression models with the SPSS PROCESS macro. In Step 1, models were adjusted for sociodemographic factors and baseline cognitive function. Models in Step 2 were additionally adjusted for obesity and health behaviours (n = 1,874). Results Cumulative ACEs exposure was shown to positively predict later-life depressive symptoms, which in turn predicted cognitive decline. ACEs were also shown to positively predict systemic inflammation as measured by CRP. However, CRP did not mediate the association between ACEs and cognitive decline. Conclusions These findings suggest that ACEs are related to cognitive decline partly via depressive symptoms and corroborate prior research linking ACEs with adult systemic inflammation. Efforts towards screening for, preventing, and mitigating the effects of ACEs may therefore represent an important avenue for improving health outcomes in later life. Disclosure No significant relationships.
P922: HEALTH-RELATED QUALITY OF LIFE WITH TECLISTAMAB, A B-CELL MATURATION ANTIGEN X CD3 BISPECIFIC ANTIBODY, IN PATIENTS WITH RELAPSED/REFRACTORY MULTIPLE MYELOMA FROM MAJESTEC-1
2022-06-01

Background: Because patients with multiple myeloma (MM) have impaired health-related quality of life (HRQoL), it is important that patient-reported outcomes (PROs) are assessed in addition to clinical outcomes. Teclistamab (JNJ-64007957) is a B-cell maturation antigen (BCMA) x CD3 bispecific antibody designed to mediate T cell-induced lysis of BCMA-expressing MM cells. In the phase 1/2 MajesTEC-1 trial, initial results from the pivotal cohort (patients who received ≥3 prior lines of therapy [LOT], including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 antibody) showed that teclistamab was well tolerated with encouraging efficacy. Aims: We report PROs of the pivotal cohort from MajesTEC-1. Methods: MajesTEC-1 included patients aged ≥18 years with documented relapsed/refractory multiple myeloma (RRMM) as per the International Myeloma Working Group diagnostic criteria, progressive/measurable disease, and previous exposure to ≥3 prior LOT. Patients who had received prior anti-BCMA treatment were ineligible. Patients were given weekly subcutaneous teclistamab at the recommended phase 2 dose (1.5 mg/kg with step-up doses of 0.06 and 0.3 mg/kg). PRO assessments were performed at screening and at every even treatment cycle; results for cycles 2-8 are reported here. HRQoL was assessed by EORTC QLQ-C30 (range: 0–100; with higher scores indicating better global health status [GHS] but greater symptom severity [symptom scales]) and EuroQol 5-dimensional descriptive system (using the visual analog scale [VAS] with “0” indicating worst imaginable health state and “100” indicating best imaginable health state). Mixed-effects model with repeated measures was used to determine treatment effect. Meaningful improvement was defined as the proportion of patients with a change of ≥10 points. Kaplan-Meier estimate was used to determine time to worsening. Results: The analysis included 110 patients, with median follow-up duration of 7.8 months. The PRO compliance rates were high at baseline (85–90%) and through treatment cycles 2–8 (80–94%). Overall HRQoL was improved with teclistamab, as shown by improved GHS scores (cycle 2–8) and reduced pain (-4.2 [cycle 2] to -15.1 [cycle 8]; Table), with no overall changes in physical functioning and fatigue. Meaningful improvements from baseline to cycle 8 were observed in GHS (50% of patients), physical function (35%), pain (65%), and fatigue (73%). Meaningful improvement in overall health (VAS) was also observed in 50% of patients. Median time to improvement from baseline was ~1.5 months with longer time to improvement seen for nausea/vomiting and fatigue. Across all symptoms, median time to worsening ranged from 2 months to not estimable. Image:Summary/Conclusion: Teclistamab provided rapid, clinically meaningful improvements in HRQoL in patients with RRMM, which are consistent with clinical outcomes in MajesTEC-1.