bluuebunny/crossref_metadata_2025 huggingface dataset:
A novel pathway mutation perturbation score predicts the clinical outcomes of immunotherapy
Authors: Li Xiangmei , He Yalan , Wu Jiashuo , Qiu Jiayue , Li Ji , Wang Qian , Jiang Ying , Han Junwei
Published: September 2022

The link between tumor genetic variations and immunotherapy benefits has been widely recognized. Recent studies suggested that the key biological pathways activated by accumulated genetic mutations may act as an effective biomarker for predicting the efficacy of immune checkpoint inhibitor (ICI) therapy. Here, we developed a novel individual Pathway Mutation Perturbation (iPMP) method that measures the pathway mutation perturbation level by combining evidence of the cumulative effect of mutated genes with the position of mutated genes in the pathways. In iPMP, somatic mutations on a single sample were first mapped to genes in a single pathway to infer the pathway mutation perturbation score (PMPscore), and then, an integrated PMPscore profile was produced, which can be used in place of the original mutation dataset to identify associations with clinical outcomes. To illustrate the effect of iPMP, we applied it to a melanoma cohort treated with ICIs and identified seven significant perturbation pathways, which jointly constructed a pathway-based signature. With the signature, patients were classified into two subgroups with significant distinctive overall survival and objective response rate to immunotherapy. Moreover, the pathway-based signature was consistently validated in two independent melanoma cohorts. We further applied iPMP to two non-small cell lung cancer cohorts and also obtained good performance. Altogether, the iPMP method could be used to identify the significant mutation perturbation pathways for constructing the pathway-based biomarker to predict the clinical outcomes of immunotherapy. The iPMP method has been implemented as a freely available R-based package (https://CRAN.R-project.org/package=PMAPscore).
Comparative Outcomes of Candida auris Bloodstream Infections: A Multicenter Retrospective Case-Control Study
Authors: Simon Samuel P , Li Rosanna , Silver Michael , Andrade Justin , Tharian Biju , Fu Lung , Villanueva Diana , Abascal Daniel Gonzalez , Mayer Ariel , Truong James , Figueroa Nilka , Ghitan Monica , Chapnick Edward , Lin Yu Shia
Published: September 2022

Background

This study was performed to compare clinical characteristics and outcomes between patients with bloodstream infections (BSIs) caused by Candida auris and those with BSIs caused by other Candida spp.

Methods

A multicenter retrospective case-control study was performed at 3 hospitals in Brooklyn, New York, between 2016 and 2020. The analysis included patients ≥18 years of age who had a positive blood culture for any Candida spp. and were treated empirically with an echinocandin. The primary outcome was the 30-day mortality rate. Secondary outcomes were 14-day clinical failure, 90-day mortality rate, 60-day microbiologic recurrence, and in-hospital mortality rate.

Results

A total of 196 patients were included in the final analysis, including 83 patients with candidemia caused by C. auris. After inverse propensity adjustment, C. auris BSI was not associated with increased 30-day (adjusted odds ratio, 1.014 [95% confidence interval, .563–1.828]); P = .96) or 90-day (0.863 [.478–1.558]; P = .62) mortality rates. A higher risk for microbiologic recurrence within 60 days of completion of antifungal therapy was observed in patients with C. auris candidemia (adjusted odds ratio, 4.461 [95% confidence interval, 1.033–19.263]; P = .045).

Conclusions

C. auris BSIs are not associated with a higher mortality risk than BSIs caused by other Candida spp. The rate of microbiologic recurrence was higher in the C. auris group.
Group 2 innate lymphoid cells protect mouse heart from myocardial infarction injury via interleukin 5, eosinophils, and dendritic cells
Authors: Liu Tianxiao , Meng Zhaojie , Liu Jing , Li Jie , Zhang Yuanyuan , Deng Zhiyong , Luo Songyuan , Wang Minjie , Huang Qin , Zhang Shuya , Fendt Pauline , Devouassoux Julie , Li Dazhu , McKenzie Andrew Neil James , Nahrendorf Matthias , Libby Peter , Guo Junli , Shi Guo-Ping
Published: September 2022

Aims

Group 2 innate lymphoid cells (ILC2s) regulate adaptive and innate immunities. In mouse heart, production of myocardial infarction (MI) increased ILC2 accumulation, suggesting a role for ILC2 in cardiac dysfunction post-MI.

Methods and results

We produced MI in ILC2-deficeint Rorafl/flIl7rCre/+ mice and in Icosfl-DTR-fl/+Cd4Cre/+ mice that allowed diphtheria toxin-induced ILC2 depletion. Genetic or induced deficiency of ILC2 in mice exacerbated cardiac dysfunction post-MI injury along with increased myocardial accumulation of neutrophils, CD11b+Ly6Chi monocytes, and CD4+ T cells but deficiency of eosinophils (EOS) and dendritic cells (DC). Post-MI hearts from genetic and induced ILC2-deficient mice contained many more apoptotic cells than those of control mice, and Rorafl/flIl7rCre/+ mice showed thinner and larger infarcts and more collagen-I depositions than the Il7rCre/+ mice only at early time points post-MI. Mechanistic studies revealed elevated blood IL5 in Il7rCre/+ mice at 1, 7, and 28 days post-MI. Such increase was blunted in Rorafl/flIl7rCre/+ mice. Administration of recombinant IL5 reversed EOS losses in Rorafl/flIl7rCre/+ mice, but IL5 did not correct the DC loss in these mice. Adoptive transfer of ILC2, EOS, or DC from wild-type mice, but not ILC2 from Il5−/− mice improved post-MI cardiac functions in Rorafl/flIl7rCre/+ recipient mice. EOS are known to protect cardiomyocytes from apoptosis. Here we showed that DC acted like EOS in blocking cardiomyocyte apoptosis. Yet, ILC2 or IL5 alone did not directly affect cardiomyocyte apoptosis or TGF-β (transforming growth factor-β)-induced cardiac fibroblast Smad signalling.

Conclusion

This study revealed an indirect cardiac reparative role of ILC2 in post-MI hearts via the IL5, EOS, and DC mechanism.
Lobar versus sublobar resection in clinical stage IA primary lung cancer with occult N2 disease
Authors: Liou Douglas Z , Chan Michelle , Bhandari Prasha , Lui Natalie S , Backhus Leah M , Shrager Joseph B , Berry Mark F
Published: September 2022

OBJECTIVES

Sublobar resection is increasingly being utilized for early-stage lung cancers, but optimal management when final pathology shows unsuspected mediastinal nodal disease is unclear. This study tested the hypothesis that lobectomy has improved survival compared to sublobar resection for clinical stage IA tumours with occult N2 disease.

METHODS

The use of sublobar resection and lobectomy for patients in the National Cancer Database who underwent primary surgical resection for clinical stage IA non-small-cell lung cancer with pathologic N2 disease between 2010 and 2017 was evaluated using logistic regression. Survival was assessed with Kaplan–Meier analysis, log-rank test and Cox proportional hazards model.

RESULTS

A total of 2419 patients comprised the study cohort, including 320 sublobar resections (13.2%) and 2099 lobectomies (86.8%). Older age, female sex, smaller tumour size and treatment at an academic facility predicted the use of sublobar resection. Patients undergoing lobectomy had larger tumours (2.40 vs 2.05 cm, P < 0.001) and more lymph nodes examined (11 vs 5, P < 0.001). Adjuvant chemotherapy use was similar between the 2 groups (sublobar 79.4% vs lobectomy 77.4%, P = 0.434). Sublobar resection was not associated with worse survival compared to lobectomy in both univariate (5-year survival 46.6% vs 45.2%, P = 0.319) and multivariable Cox proportional hazards analysis (hazard ratio 0.97, P = 0.789).

CONCLUSIONS

Clinical stage IA non-small-cell lung cancer patients with N2 disease on final pathology have similar long-term survival with either sublobar resection or lobectomy. Patients with occult N2 disease after sublobar resection may not require reoperation for completion lobectomy but should instead proceed to adjuvant chemotherapy.
Aggressive use of prophylactic cerebrospinal fluid drainage to prevent spinal cord ischemia during thoracic endovascular aortic repair is not supportive
Authors: Seike Yoshimasa , Fukuda Tetsuya , Yokawa Koki , Koizumi Shigeki , Masada Kenta , Inoue Yosuke , Matsuda Hitoshi
Published: September 2022

OBJECTIVES

We investigated whether prophylactic preoperative cerebrospinal fluid drainage (CSFD) was effective in preventing spinal cord ischemia (SCI) during thoracic endovascular aortic repair of degenerative descending thoracic aortic aneurysms, excluding dissecting aneurysms.

METHODS

We retrospectively reviewed the medical records of patients who underwent thoracic endovascular aortic repair involving proximal landing zones 3 and 4 between 2009 and 2020.

RESULTS

Eighty-nine patients with preemptive CSFD [68 men; median (range) age, 76.0 (71.0–81.0) years] and 115 patients without CSFD [89 men; median (range) age, 77.0 (74.0–81.5) years] were included in this study. Among them, 59 from each group were matched based on propensity scores to regulate for differences in backgrounds. The incidence rate of SCI was similar: 8/89 (9.0%) in the CSFD group and 6/115 (5.2%) in the non-CSFD group (P = 0.403). Shaggy aorta (odds ratio, 5.13; P = 0.004) and iliac artery access (odds ratio, 5.04; P = 0.005) were identified as positive predictors of SCI. Other clinically important confounders included Adamkiewicz artery coverage (odds ratio, 2.53; P = 0.108) and extensive stent graft coverage (>8 vertebrae) (odds ratio, 1.41; P = 0.541) were not statistically significant. Propensity score matching yielded similar incidence of SCI: 4/59 (6.8%) in the CSFD group and 3/59 (5.1%) in the non-CSFD group (P = 0.697).

CONCLUSIONS

Aggressive use of prophylactic CSFD was not supportive in patients without complex risks of SCI.
The fate of the downstream aorta after total arch replacement
Authors: Ikeno Yuki , Yokawa Koki , Yamanaka Katsuhiro , Inoue Takeshi , Tanaka Hiroshi , Okada Kenji , Okita Yutaka
Published: September 2022

OBJECTIVES

The goal of this study was to evaluate the fate of the downstream aorta following total arch replacement.

METHODS

Between October 1999 and March 2018, a total of 740 patients underwent total arch replacement. After excluding connective tissue disease, previous descending or thoracoabdominal aortic surgery, patients without adequate preoperative images or operative mortality, late outcomes consisting of additional surgery for distal dilation and distal aortic events were evaluated in 623 survivors (240 aortic dissections, including 139 patients with acute dissection and 383 with a non-dissection aneurysm). The mean follow-up was 5.0 ± 4.0 years.

RESULTS

The mean preoperative maximum diameter of the descending aorta was 36.9 ± 8.0 mm. An elephant trunk was inserted in 232 patients, including 183 patients with aortic dissection. Freedom from additional surgery for distal dilation was 88.5% at 5 years and 80.2% at 10 years. Freedom from distal aortic events was 81.9% at 5 years and 70.5% at 10 years. Multivariable regression analysis demonstrated that the preoperative diameter of the descending aorta was a significant risk factor for unfavourable distal aortic events. Computed tomography evaluation demonstrated a significant increase in the descending aortic diameter over time (P < 0.001). Positive aortic remodelling was observed in the proximal descending (P < 0.001) to mid-descending (P < 0.001) aorta exclusively in patients with acute aortic dissection.

CONCLUSIONS

The diameter of the descending aorta increased significantly after total arch replacement, particularly in the distal descending aorta. The preoperative descending aortic diameter portended a significant risk for unfavourable distal aortic events.
Nonidentical function of Upc2A binding sites in the Candida glabrata CDR1 promoter
Authors: Vu Bao Gia , Moye-Rowley William Scott
Published: September 2022

Increased expression of the Candida glabrata CDR1 gene, encoding an ATP-binding cassette membrane transporter, is routinely observed in fluconazole-resistant isolates of this pathogenic yeast. CDR1 transcription has been well-documented to be due to activity of the Zn2Cys6 zinc cluster-containing transcription factor Pdr1. Gain-of-function mutations in the gene encoding this factor are the most commonly observed cause of fluconazole hyper-resistance in clinical isolates. We have recently found that the sterol-responsive transcription factor Upc2A also acts to control CDR1 transcription, providing a direct link between ergosterol biosynthesis and expression of Pdr1 target genes. While this earlier work implicated Upc2A as an activator of CDR1 transcription, our further analyses revealed the presence of a second Upc2A binding site that negatively regulated CDR1 expression. This Upc2A binding site designated a sterol-responsive element (SRE) was found to have significant lower affinity for Upc2A DNA-binding than the previously described SRE. This new SRE was designated SRE2 while the original, positively acting site was named SRE1. A mutant version of SRE2 prevented in vitro DNA-binding by recombinant Upc2A and, when introduced into the CDR1 promoter, caused decreased fluconazole susceptibility and increased CDR1 expression. This negative effect caused by loss of SRE2 was shown to be Pdr1 independent, consistent with the presence of at least one additional activator of CDR1 transcription. The ability of Upc2A to exert either positive or negative effects on gene expression resembles behavior of mammalian nuclear receptor proteins and reveals an unexpectedly complex nature for SRE effects on gene regulation.
Effects of dietary protein content and crystalline amino acid supplementation patterns on growth performance, intestinal histomorphology, and immune response in weaned pigs raised under different sanitary conditions
Authors: Lee Jinyoung , González-Vega Jolie Caroline , Htoo John Kyaw , Yang Chengbo , Nyachoti Charles Martin
Published: September 2022

The aim of this experiment was to investigate the effects of dietary crude protein (CP) contents and crystalline amino acids (CAA) supplementation patterns on growth performance, intestinal histomorphology, and immune response in weaned pigs under clean (CSC) or unclean sanitary conditions (USC). A total of 144 weaned pigs (6.35 ± 0.63 kg body weight) were assigned to 6 treatments in a 3 × 2 factorial arrangement based on CP content and sanitary conditions using a randomized complete block design, giving 8 replicates per treatment with 3 pigs per pen. Pigs were fed one of three diets for 21 d: one high CP (HCP; 22%) and two low CP (LCP; 19%) diets supplemented with 9 indispensable AA or only 6 AA (Lys, Met, Thr, Trp, Val, and Ile) as CAA. The CSC room was washed weekly, whereas the USC room had sow manure spread in the pens and was not washed throughout the experiment. Body weight and feed disappearance were recorded weekly. Blood was sampled from 1 pig per pen weekly, and the same pig was euthanized for jejunal tissues sampling on day 21. Pigs raised under USC had reduced (P < 0.05) average daily gain (ADG) and gain to feed ratio (G:F) in week 2, but contrary results that greater (P < 0.05) ADG and G:F were found in pigs under USC in week 3. Overall, there was an interaction where G:F did not differ between HCP and LCP under CSC, however, LCP decreased (P < 0.05) G:F compared to HCP under USC. Pigs fed the HCP diet had higher (P < 0.05) fecal scores than those fed the LCP diets throughout the experiment. Pigs fed the LCP had higher (P < 0.05) villus height to crypt depth ratio than those fed the HCP. An interaction was observed where goblet cell density in the jejunum was higher (P < 0.05) in pigs fed LCP than HCP under CSC, but no difference was found between HCP and LCP under USC. Different CAA supplementation patterns did not influence both growth performance and histomorphology. Pigs raised under USC had greater (P < 0.05) plasma interleukin (IL)-10 and IL-6 concentrations and reduced (P < 0.05) plasma tumor necrosis factor-alpha concentration. Also, the LCP diets resulted in a greater (P < 0.05) plasma IL-10 concentration. In conclusion, overall growth performance did not differ between HCP and LCP under CSC, but LCP diets reduced G:F under USC. Feeding LCP diets to weaned pigs improved gut morphology under USC and ameliorated systemic inflammation induced by USC, whereas CAA supplementation patterns did not affect growth performance and gut morphology.
How advances in animal efficiency and management have affected beef cattle’s water intensity in the United States: 1991 compared to 2019
Authors: Klopatek Sarah C , Oltjen James W
Published: September 2022

Updating the static model by Beckett and Oltjen (1993), we determined that from 1991 to 2019, U.S. beef cattle blue water consumption per kg of beef decreased by 37.6%. Total water use for the U.S. cattle herd decreased by 29%. As with the 1993 model, blue water use included direct water intake by animals, water applied for irrigation of crops that were consumed by beef cattle, water applied to irrigated pasture, and water used to process animals at marketing. Numbers of cattle, crop production, and irrigation data were used from USDA census and survey data. On 1 January 2019, a total of 31.7-million beef cows and 5.8-million replacement heifers were in U.S. breeding herds, and 26-million animals were fed annually. In total, the U.S. beef cattle herd (feedlot and cull cows) produced 7.7-billion kg of boneless beef, an increase of 10% since 1991. Beef cattle directly consumed 599-billion L of water per year. Feedlot cattle were fed various grain and roughage sources corresponding to the regions in which they were fed. Feeds produced in a state were preferentially used by cattle in that state with that state’s efficiency; any additional feedstuffs required used water at the national efficiency. Irrigation of crop feedstuffs for feedlot cattle required 5,920-billion L of water. Irrigated pasture for beef cattle production required an additional 4,121-billion L of water. Carcass processing required 91-billion L of water. The model estimated that in the U.S. 2,275 L of blue water was needed to produce 1 kg of boneless meat. As with the previous model, the current model was most sensitive to changes in the dressing percentage and the percentage of boneless yield in carcasses of feedlot cattle (62.8 and 65, respectively). In conclusion, with more beef, fewer cows, and lower rates of irrigation, beef cattle’s water intensity has decreased at an annual rate of 1.34% over a 28-yr period.
Invasive type B2 thymoma associated with myasthenia gravis, resection with superior vena cava reconstruction
Authors: Wilde Sawley A , Carroway William P , Hsu Diana S , Banks Kian C , Velotta Jeffrey B
Published: September 2022

After being diagnosed with myasthenia gravis, a 55-year-old male was referred for treatment of an invasive thymoma. Preoperative imaging revealed a thymoma adjacent to the superior vena cava (SVC) with possible invasion of the left innominate vein. After multidisciplinary discussion, he underwent upfront en bloc resection of the tumor with SVC resection and reconstruction. He was discharged after an uncomplicated postoperative course with improvement of his symptoms.
Evolutionary History and Strength of Selection Determine the Rate of Antibiotic Resistance Adaptation
Authors: Cisneros-Mayoral Sandra , Graña-Miraglia Lucía , Pérez-Morales Deyanira , Peña-Miller Rafael , Fuentes-Hernández Ayari
Published: September 2022

Bacterial adaptation to stressful environments often produces evolutionary constraints whereby increases in resistance are associated with reduced fitness in a different environment. The exploitation of this resistance-cost trade-off has been proposed as the basis of rational antimicrobial treatment strategies designed to limit the evolution of drug resistance in bacterial pathogens. Recent theoretical, laboratory, and clinical studies have shown that fluctuating selection can maintain drug efficacy and even restore drug susceptibility, but can also increase the rate of adaptation and promote cross-resistance to other antibiotics. In this paper, we combine mathematical modeling, experimental evolution, and whole-genome sequencing to follow evolutionary trajectories towards β-lactam resistance under fluctuating selective conditions. Our experimental model system consists of eight populations of Escherichia coli K12 evolving in parallel to a serial dilution protocol designed to dynamically control the strength of selection for resistance. We implemented adaptive ramps with mild and strong selection, resulting in evolved populations with similar levels of resistance, but with different evolutionary dynamics and diverging genotypic profiles. We found that mutations that emerged under strong selection are unstable in the absence of selection, in contrast to resistance mutations previously selected in the mild selection regime that were stably maintained in drug-free environments and positively selected for when antibiotics were reintroduced. Altogether, our population dynamics model and the phenotypic and genomic analysis of the evolved populations show that the rate of resistance adaptation is contingent upon the strength of selection, but also on evolutionary constraints imposed by prior drug exposures.
PL01.4.A The relationship between neuronal activity and functional network properties in glioma patients
Authors: Zimmermann M L M , Breedt L C , Centeno E G Z , Kulik S D , Santos F A N , Stam C J , van Lingen M R , Hillebrand A , Douw L
Published: September 2022

Background

Glioma is associated with pathologically high neuronal activity around the tumor, which associates with faster tumor progression in patients. Concurrently, patients with glioma have local and widespread disturbances of the functional brain network as measured with magnetoencephalography (MEG) such as higher network clustering (the extent to which regions connected to a particular area are also connected to each other) and locally altered integrative connectivity (for instance assessed with a centrality measure). How local neuronal activity and nodal network properties relate to each other has yet to be investigated.

Material and Methods

We obtained eyes-closed resting-state MEG in 95 glioma patients before tumor resection and 57 matched healthy controls (HC). Broadband power (BBP, 0.5-48Hz) was used as a proxy for neuronal activity. The local clustering coefficient (CC) and eigenvector centrality (EC) were calculated for the functional network in the lower frequency bands (delta, theta, alpha). We compared averaged nodal network properties and local BBP between peritumoral (regions partially overlapping with the tumor) and contralateral homologue regions in patients and compared these to averaged values in HC. Linear mixed models were used to relate nodal CC and EC to local BBP. Results were corrected for multiple comparisons and deemed significant at alpha 0.05.

Results

The peritumoral area was significantly more active than the non-peritumoral homologue in patients, and showed pathologically higher activity in comparison to HCs. Pathologically high neuronal activity was restricted to the peritumoral areas and not found in the contralateral homologue. However, patients’ functional network was disturbed throughout the brain in terms of pathologically high clustering, but not with regards to centrality. Whereas high activity related to high centrality in HCs and patients alike, high activity seemed to relate to low clustering in homologue regions in patients but not HCs, potentially indicating that lower neuronal activity relates to pathologically high clustering in these patients.

Conclusion

Glioma patients show pathologically high brain activity around the tumor and whole-brain disturbances in local network clustering, while integrative connectivity is preserved. We also find that the relationship between neuronal activity and functional network properties is complex in these patients, further underlining the importance of investigating how local activity may impact global network topology in order to understand how neuron-glioma interactions shape brain functioning.
PL01.6.A Radiomics outperforms semantic features for prediction of response to stereotactic radiosurgery in brain metastases
Authors: Gutsche R , Lohmann P , Hoevels M , Ruess D , Galldiks N , Visser-Vandewalle V , Treuer H , Ruge M I , Kocher M
Published: September 2022

Background

Brain metastases show different patterns of contrast enhancement, potentially reflecting hypoxic and necrotic tumor regions with reduced radiosensitivity. An objective evaluation of these patterns might allow a prediction of response to radiotherapy. We therefore investigated the potential of MRI radiomics in comparison with the visual assessment of semantic features to predict early response to stereotactic radiosurgery in patients with brain metastases.

Material and Methods

In this retrospective study, 150 patients with 308 brain metastases from solid tumors (NSCLC in 53% of patients) treated by stereotactic radiosurgery (single dose of 17-20 Gy) were evaluated. The response of each metastasis (partial or complete remission vs. stabilization or progression) was assessed within 180 days after radiosurgery. Patterns of contrast enhancement in the pre-treatment T1-weighted MR images were either visually classified (homogenous, heterogeneous, necrotic ring-like) or subjected to a radiomics analysis. Random forest models were optimized by cross-validation and evaluated in a hold-out test data set (30% of metastases).

Results

In total, 221/308 metastases (72%) responded to radiosurgery. The optimal radiomics model comprised 10 features and outperformed the model solely based on semantic features in the test data set (AUC, 0.71 vs. 0.56; accuracy, 69% vs. 54%). The diagnostic performance could be further improved by combining semantic and radiomics features resulting in an AUC of 0.74 and an accuracy of 75% in the test data set.

Conclusion

The developed radiomics model allowed prediction of early response to radiosurgery in patients with brain metastases and outperformed the visual assessment of patterns of contrast enhancement.
PL02.3.A Survival and T-cell tumor reactivity in patients treated with nivolumab and bevacizumab for recurrent glioblastoma in the clinical trial CA209-9UP
Authors: Maarup S , Skadborg S , Draghi A , Borch A , Hasselbalch B , Yde C , Svane I , Hadrup S , Christensen I , Law I , Skjoeth-Rasmussen J , Scheie D , Skovgaard Poulsen H , Lassen U
Published: September 2022

Background

Glioblastoma (GBM) is an aggressive brain tumor with a median survival of 14.6 months. We have no standard treatment for relapse and current treatment options have limited effect. Novel treatments are necessary to improve survival and quality of life.

Material and Methods

We present data from; a phase II open label, two-armed clinical trial studying nivolumab and bevacizumab in treatment of recurrent GBM, with progression after Stupp’s regime. Patients were included in two arms depending on the possibility of salvage neurosurgical resection. All patients had biopsies for genome sequencing at primary tumor and recurrence. Both arms received nivolumab and bevacizumab administrated every second week and the surgical arm also received neoadjuvant nivolumab 7 days prior to surgery. Fresh tissue samples were collected for tumor digest, TILs (tumor infiltrating lymphocytes) for phenotype exploration and intracellular staining to test reactivity. Patients were treated until progression, death, or intolerable side effects. Toxicity screens were reported, and follow-up ended in Marts 2022.

Results

Forty-four patients were included from November 2018 to January 2022; 20 in each arm (four screen-failures). Treatment was overall well tolerated. Median (m) age at inclusion was 57,5 years (arm A) and 50,5 years (arm B), and the groups had an even distribution. The surgical and non-surgical arm had an mPFS of 5.95 and 3.83 months respectively, while the mOS was 13.96 months and 6.77 months, respectively. Multivariate analysis was performed by variables such us steroid, MGMT, gender, age at diagnosis, resection extent and arm. Steroid at inclusion was a significant negative predictor of outcome (p = 0.0378). Controls from our GBM registry (N=140), which were treated with neurosurgical resection and then bevazicumab and irinotecan in recurrent setting had an mOS of 8.64 months (log-rank p=0.0181).Furthermore, reactive tumor infiltrating lymphocytes (TIL) were detected in four of the patients who presented with a longer mOS and mPFS of 16.75 months and 9.18 months, while the 16 patients without TIL reactivity had mOS and mPFS of 12.63 months and 5.13 months, respectively (not significant).

Conclusion

We found an increased mOS in patients treated with nivolumab and bevacizumab at recurrence, compared to our controls: 13.96 months and 8.64 months, respectively. Four patients with T-cell reactivity towards tumor cells showed an even longer mPFS and mOS. Though not significant, these results warrant further research evaluation in larger patient cohorts. We are currently investigating proteomics and sequencing data to identify predictive biomarkers.
KS04.6.A Epidemiology of adult meningioma in the Netherlands: a population-based study
Authors: Ho V K Y , Anten M M , Garst A , Bos E M , Snijders T J , Eekers D B P , Seute T
Published: September 2022

Background

Meningiomas are the most common primary tumours of the central nervous system. As the majority of meningiomas are benign, initial management often consists of observation only. Consequently, estimates on meningioma incidence are generally considered too low, with many registries mainly depending on pathology notifications. With additional notification sources, this study provides more complete population-based estimates on the incidence, prevalence, and prognostic impact of meningioma diagnosis in the Netherlands.

Material and Methods

Data on patients diagnosed with meningioma during 2000-2019 were obtained from the Netherlands Cancer Registry (NCR), which was expanded to the Dutch Brain Tumour Registry (DBTR) for meningiomas as of 2016. In addition to histological confirmations, the NCR/DBTR receives case notifications from hospital administrative registrations on cost reimbursement and outpatient care. In addition, a data linkage was performed with a clinical database maintained by one of the Dutch neuro-oncology centres to evaluate local completeness of the NCR/DBTR. Time trends of the age-adjusted incidence rates were evaluated by calculating the estimated annual percentage change (EAPC). Relative survival rates were calculated using the Pohar-Perme estimator.

Results

From 2000 to 2019, a total of 22,605 cases of meningioma were registered; 11,423 (50.5%) were histologically confirmed, while 11,182 (49.5%) had a radiological diagnosis. Over time, incidence increased from 4.7 per 100,000 inhabitants (European Standardized Rate, ESR) to 10.7 (EAPC 4.6%, p<0.01); the incidence of radiological diagnosis increased from 1.2 to 6.9 per 100,000 ESR (EAPC 9.6%, p<0.01). Local data completeness was estimated at 98% for histologically confirmed meningiomas and 87% for radiological diagnoses. On the basis of these incidence estimates, the prevalence of meningioma is estimated at 105/100,000 on January 1st of 2020, with over 17,500 individuals having had a diagnosis of meningioma at that moment. Relative survival rate at 5 years for grade I meningiomas was 94.8% (95%-confidence interval: 94.0%-95.4%), 84.0% (95%CI: 81.0%-86.5%) for grade II meningiomas, and 47.3% (95%CI: 38.2%-55.8%) for grade III meningiomas.

Conclusion

As the incidence estimates in this study may be considered most complete, the results obtained should approximate the true incidence, prevalence, and prognostic impact of meningioma diagnosis in the Netherlands.
JS04.4.A Beyond β-catenin: Genetic alterations ofTP53 andOTX2 and older age indicate increased risk of relapse in WNT medulloblastomas
Authors: Goschzik T , Mynarek M , Doerner E , Spier I , Warmuth-Metz M , Bison B , Obrecht D , Struve N , Kortmann R , Hau P , Aretz S , Rutkowski S , Pietsch T
Published: September 2022

Background

This genetic analysis of WNT-activated medulloblastomas (WNT-MBs) aimed to re-evaluate the prognostic impact of age, TP53 mutations and to identify specific chromosomal aberrations as possible prognostic markers.

Material and Methods

In a cohort of 191 patients with WNT-MBs, mutations in CTNNB1, APC and TP53 were analyzed by Sanger and/or NGS panel sequencing. Chromosomal copy number aberrations were assessed by high-resolution, genome-wide molecular inversion probe technology (MIP), SNP6 array, and/or 850k methylation bead-array hybridization. Association with prognosis was evaluated in 133 patients with follow-up data from the HIT2000 medulloblastoma trial, HIT registries, and the NOA-07 trial.

Results

CTNNB1 mutations were present in 92.2% of the samples. APC mutations were found in 6.8% (13 samples). One CTNNB1 wildtype tumor gained WNT-activation due to a homozygous deletion of FBXW7. Monosomy 6 was present in 78.6%, and more frequent in children compared to adolescents/adults (≥16 years). Adolescents/adults showed worse overall survival (OS; p=0.009) compared to children, but not worse progression-free survival (PFS; p=0.106). With an age cut-off at 18 years, no survival difference was found. Also adolescents alone (16-20 years) had worse OS (p=0.003) compared to children, whereas in patients ≥21 (n=12 adults with PFS/OS data) no tumor progression/relapse occurred. Only one adult died due to therapy-related complications. WNT-MB patients with tumors harboring TP53 mutations (24/133, 18.1%) showed significant worse PFS (p=0.001), which was also found in children and adolescents individually (p=0.004, resp. p=0.017). Gains of the OTX2 locus on chromosome 14q found in 40.2% (35/87) of samples were independent of TP53 mutations and also associated with poor PFS and OS (p=0.034, resp. p=0.016). Individual analyses of OTX2 gains within age groups showed only worse OS in children (p=0.012). Multivariate Cox regression analysis for PFS identified both genetic alterations, but not age, as independent prognostic markers. For OS, multivariate analysis found OTX2 gains and older age as independent prognostic markers.

Conclusion

Our data suggest that adolescent patients with WNT-MB and those patients carrying TP53 mutations or OTX2 gains - independent of age - are at higher risk of relapse. Eligibility of these patients for therapy de-escalation trials needs to be debated.
JS04.5.A Enhancing the activity of anti-CD47 antibody therapy with radiotherapy in preclinical models of medulloblastoma
Authors: Abbas Z , Howlett M , Buck J , Hii H , Kuchibhotla M , Ancliffe M , Whitehouse J , Johns T , Ebert M , Gottardo N , Endersby R
Published: September 2022

Background

Brain cancers are the most common solid cancer in children and the leading cause of cancer-related deaths in children. Medulloblastoma is the most common paediatric brain tumour. Treatment for medulloblastoma involves surgery, craniospinal irradiation (CSI) and chemotherapy. These therapies are extremely damaging to the developing brain and have not changed in decades, resulting in stagnation in the survival outcomes for children with medulloblastoma, and poor quality of life for children who survive their treatment. Immunotherapy has become a focus of novel treatment development. While there are multiple clinical trials aiming to increase immune recognition of medulloblastoma, none have been successful to date. Anti-CD47 is an immune-modulating therapeutic antibody which blocks the anti-phagocytic signal, CD47, expressed by brain cancer cells. Anti-CD47 has shown promising preliminary efficacy in brain cancer models.

Material and Methods

Using a small animal radiotherapy platform, we have developed a preclinical CSI protocol which mimics clinical radiotherapy. Using an orthotopic xenograft model of medulloblastoma, mice were treated with either anti-CD47 antibody therapy, CSI, or the combination of both anti-CD47 and CSI.

Results

CSI was found to deplete adaptive immune cells in the brain, while myeloid cells remained the dominant populations. Anti-CD47 antibody therapy was ineffective as a single agent against a patient derived xenograft model of Group 3 medulloblastoma, and CSI as a monotherapy resulted in temporary tumour regression. We found that the combination of anti-CD47 with CSI resulted in marked and persistent tumour regression.

Conclusion

This preclinical work has shown promising efficacy of anti-CD47 in combination with CSI, which we are currently testing in additional models. Our work is currently employing a range of techniques such as high dimensional flow cytometry and single cell sequencing to elucidate the mechanisms by which radiotherapy enhances the anti-tumour activity of myeloid cells. This work will enable the rational design and translation of optimal combination therapies for medulloblastoma clinical trials.
JS07.4.A Correspondence of glutamine and glycine imaging based on 7T MRSI to amino acid PET
Authors: Hangel G , Rausch I , Furtner J , Roetzer-Pejrimovsky T , Preusser M , Bogner W , Rössler K , Trattnig S , Traub-Weidinger T , Widhalm G
Published: September 2022

Background

New approaches for 7 Tesla magnetic resonance spectroscopic imaging (MRSI) allow the simultaneous imaging of multiple neuro-oncological biomarkers with 3-4 mm resolution in clinically feasible measurement times. Specifically, the amino acids glutamine (Gln) and Glycine (Gly), were previously limited to single voxel detection at lower fields. Both could add to our capabilities to resolve heterogeneous tumour metabolism.

Purpose

To progress the validation of Gln and Gly as neuro-oncological markers by conducting the first comparison to amino acid PET in a cohort of glioma patients.

Material and Methods

In 24 glioma patients (WHO 2021 classification), we quantitatively compared 7T MRSI (3D, 3.4 mm isotropic resolution, 15 min scan time) and routine PET (FET or MET). Within manual tumour segmentations, we defined hotspot volumes of interest (VOI) for the ratios of total choline (tCho, clinical standard reference), Gln, Gly to total N-acetylaspartate (tNAA) and PET tumour-to-brain ratios (TBR), all with a cut-off threshold of 1.6. For these VOIs, we calculated VOI volumes and median ratios as well as Dice similarity coefficients (DSC) and centre of intensity distance (CoI), between MRSI and PET ratios.

Results

We found that Gln and Gly ratios to tNAA had a higher correspondence to PET-based amino acid metabolism than tCho. Our resulting median VOI volumes were 19.08±23.10 cm³ for tCho/tNAA, 33.68±24.60 cm³ for Gln/tNAA, and 22.38±18.49 cm³ for Gly/tNAA compared to 24.33±30.46 cm³ for PET, with correlation coefficients >0.5 for all MRSI hotspot values in relation to PET volumes. Median ratios were 0.52±0.13 for tCho/tNAA, 0.61±0.25 for Gln/tNAA, 0.33±0.15 for Gly/tNAA and 2.11±0.42 for PET. The median DSCs to PET amounted to 0.53±0.36 for tCho/tNAA, 0.66±0.40 for Gln/tNAA, and 0.57±0.36 for Gly/tNAA, while the median CoI distances were 0.56±0.43 cm for tCho/tNAA, 0.39±0.22 cm for Gln/tNAA, and 0.45±0.48 cm for Gly/tNAA.

Conclusion

With this first study that compared high-resolution 3D-MRSI at 7 Tesla to amino acid PET and a quantitative evaluation, we demonstrated that Gln and Gly corresponded better to PET than tCho, which is the main marker used in clinical MR, both within the study and compared to previous literature. Future research is needed to clearly define the benefits of 7T MRSI for neuro-oncology such as the identification of tumour microenvironments or non-invasive determination of molecular-pathologic markers. Gln could be further explored by the application of Gln-based PET tracers to MR-PET. We still see further developments of MRSI methods, such as motion correction or absolute quantification of concentrations instead of ratios, as necessary to obtain such goals.
JS08.6.A A connectivity signature for glioblastoma
Authors: Hoffmann D C , Hai L , Wagener R , Mandelbaum H , Xie R , Hausmann D , Dominguez Azorín D , Weil S , Sievers P , Cebulla G , Ito J , Warnken U , Venkataramani V , Ernst K , Reibold D , Will R , Suvà M L , Herold-Mende C , Sahm F , Winkler F , Schlesner M , Wick W , Kessler T
Published: September 2022

Background

Tumor cell extensions called tumor microtubes (TMs) in glioma resemble neurites during neurodevelopment and connect glioma cells to a network that has considerable relevance for tumor progression and therapy resistance. The determination of interconnectivity in individual tumors has been challenging and the impact of tumor cell connectivity on patient survival remained unresolved so far.

Material and Methods

A connectivity signature was derived by single-cell RNA-sequencing (scRNA-Seq) of highly and lowly connected cells obtained from an SR101 dye transfer xenograft model of primary glioblastoma (GB). The signature was validated in different in vitro models of cell-to-cell connectivity and could be translated to GB clinical specimens.

Results

34 of 40 connectivity genes were related to neurogenesis, neural tube development or glioma progression, including the TM-network-relevant GAP43 gene. Astrocytic-like and mesenchymal-like GB cells had the highest connectivity signature scores in scRNA-Seq data of patient-derived xenografts and patient samples. In 230 human GBs, high connectivity correlated with the mesenchymal expression subtype, TP53 wildtype, and with dismal patient survival. CHI3L1 was identified and validated as a robust molecular marker of connectivity with a functional relevance.

Conclusion

The connectivity signature gives novel insights into brain tumor biology, provides a proof-of-principle that tumor cell connectivity is relevant for patients’ prognosis, and serves as a robust biomarker that can be used for future clinical trials
JS08.7.A Integrative analysis of longitudinal genomic and non-genetic mechanisms of radiotherapy-resistance in glioma
Authors: Kocakavuk E , Varn F S , Johnson K C , Verhaak R G W
Published: September 2022

Background

Radiotherapy (RT) is a mainstay in the treatment of glioma patients, but RT-resistance is common. We have recently identified RT-associated genomic small deletion signatures, marking tumors that have developed resistance. Here, we used longitudinal molecular profiles to explore non-genetic mechanisms of RT-resistance.

Material and Methods

We have analyzed the multi-omic Glioma Longitudinal Analysis (GLASS) dataset, integrating DNA and RNA sequencing datasets from primary and post-treatment gliomas.

Results

We classified tumors as harboring temozolomide-associated hypermutation based on mutational burden increase (HM), and RT-associated signature based on small deletion burden increase (RTscars). By deconvoluting RNA profiles into cell state fractions, we observed an increase of a proliferating stem-like (PSL) cell state in 50% of patients with a RTscars+ signature which was significantly higher than RTscars-/HM- patients (P=8e-04, Fisher’s exact). PSL cell state increase associated with worse overall survival outcomes (P=1.5e-03, log-rank). We observed a significant correlation between the expression change of E2F cell cycle regulator genes (R=0.91, P=6.7e-04, Pearson) and EZH2 (R=0.81, P=8.3e-03) with the increase in the PSL cell state, nominating the E2F/EZH2-pathway as regulator of the PSL cell state. Furthermore, the RTscars signature was associated with an increase in frameshift neoantigens and significantly higher neoantigen burden at recurrence (P=2.4e-02, Kruskal-Wallis). This was accompanied by a significantly higher post-treatment T-cell fraction in RTscars+ tumors (P=8.2e-04, Wilcox), suggesting an increased T-cell infiltration in these patients.

Conclusion

Our analyses revealed a longitudinal increase in the proliferating stem-like cell state associated with RT-resistance and nominates the cell cycle pathway as an actionable target. The RT-associated deletion signature (RTscars) correlated with increased frameshift-neoantigens and T-cell fractions at recurrence, suggesting a potential benefit of a combinatorial immune-targeted therapy in this specific patient population.
JS09.7.A Reirradiation for recurrent high grade glioma (HGG) patients: results of a single arm prospective phase 2 study
Authors: Clerici E , Navarria P , Bellu L , Pessina F , Simonelli M , Marini B , Bianchi S , Scorsetti M
Published: September 2022

Background

Standard of care for recurrent high grade glioma (HGG) is missing. Several treatment options have been investigated including re-irradiation (re-RT). Results are promising but provided by retrospective studies. We designed a single arm prospective phase II study aiming to evaluate efficacy, and toxicity of re-irradiation.

Material and Methods

Adults patients with good performance status, HGG diagnosis reclassified according to the new 2021 fifth edition WHO CNS classification, an interval time (IT) from previous RT ≥ 6 months were included. Outcome was evaluated by MRI imaging at 1 month, and every 3 months thereafter. Toxicities were evaluated in terms of radionecrosis occurrence, and neurocognitive status.

Results

Ninety recurrent HGG patients were treated, 11 oligodendroglioma grade 3, 18 astrocytoma grade 3 and 4, and 61 glioblastoma grade 4. The median age was 54 years, and majority had KPS 90-100. The median IT between first-RT and re-RT was 24 months. Re-surgery has been performed in 56.6%, and chemotherapy in 53.3%. The median follow up time was 64 months; median overall survival (OS) time,1,2,3-year OS rates were 17 months (95%CI 14-19), 66.7%±4.9, 32.6%±5.0, and 22.2 ± 4.7. Prognostic factors impacting on survival were age (p = 0.0154), IT between first RT and re-RT (p = 0.0051), glioma grade (p = 0.0090), and IDH status (p = 0.0001). Radionecrosis grade 2-3 occurred in 9 (10%) patients; neurocognitive functions remained stable until disease progression.

Conclusion

Re-RT proved to be a safe and feasible treatment option with low toxicity. Younger patients with grade 3 IDH mutated gliomas, and a longer IT had the better outcome.