bluuebunny/crossref_metadata_2025 huggingface dataset:
10167-MET-8 CLINICAL CHARACTERISTICS AND TREATMENT STRATEGY OF CANCER CASES PRESENTING WITH CENTRAL NERVOUS SYSTEM SYMPTOMS
Authors: Hirai Nozomi , Saito Norihiko , Koyahara Yuki , Sato Sho , Hiramoto Yu , Fujita Satoshi , Nakayama Haruo , Hayashi Morito , Ito Keisuke , Sakurai Takatoshi , Iwabuchi Satoshi
Published: December 2023

Metastatic brain tumors were previously reported with prognoses of approximately 6 months. The accuracy of diagnostic imaging and advances in drug therapy have improved the treatment outcomes of various types of cancer. On the other hand, patients with advanced cancer who are detected with neurological symptoms caused by metastatic brain tumors usually face difficulty in deciding on a treatment strategy. In this study, we reported the results of cancer patients who were first detected with central nervous system symptoms in the last 10 years and treated at our hospital.There were 14 patients treated at our hospital from 2013 to 2022 with CNS symptoms as the initial symptom. The mean age was 65.5 years, and the most common primary cancer was lung cancer in 11 cases (9 NSCLC and 2 SCLC). The OS examined in the 11 lung cancer cases was 14 months. Among NSCLC, only 2 cases had EGFR mutation and no cases had ALK fusion gene. The mean Lung-molGPA was 0.89 in 9 patients with NSCLC and 0.75 in 2 patients with SCLC, and the expected survival time was 6.9 months and 2.8 months.With advances in drug therapy, median survival for patients with NSCLC brain metastases has been reported to range from 7 months to 2 years for patients with EGFR mutations and 4 years for patients with ALK fusion gene. Thus, it is necessary to consider treatment strategies according to primary tumor, histology, and genetic information, rather than considering metastatic brain tumors as a single entity.The results of this study suggest that aggressive therapeutic intervention may prolong the survival period expected at the time of initial diagnosis, even in cancer patients who are found to have metastatic brain tumors.
10171-MPC-13 IDH-WILDTYPE LOWER-GRADE ASTROCYTOMA
Authors: Takahashi Yoshinobu , Ogawa Takahiro , Taniyama Ichita , Yamanaka Takumi , Tanigawa Seisuke , Takeuchi Hayato , Hashimoto Naoya
Published: December 2023

BACKGROUND AND PURPOSE

In the WHO 2021 classification, glioblastoma is limited to IDH-wildtype and is diagnosed when microvascular proliferation and necrosis are present. Furthermore, even in the presence of morphologically low-grade findings, the diagnosis of glioblastoma is made if there is either EGFR gene amplification, TERT promoter mutation, or +7/-10 chromosome copy number alterations. Therefore, we investigated IDH wild-type lower-grade astrocytoma.

CASES

10 patients were included in this study. Sanger sequencing was performed for TERT promoter mutations, and MLPA was further implemented using probes for EGFR and PTEN genes in TERT wild-type cases. The threshold values for copy number change were homozygous deletion (x≤0.4), loss of heterozygosity (LOH) (0.4<x≤0.7), gain (1.3≤x<2.0), and amplification (x≥2.0). EGFR gain and PTEN LOH were used as surrogate markers for +7/-10 chromosome copy-number alterations.

RESULTS

Seven of these patients were diagnosed with glioblastoma, IDH-wildtype with a TERT promoter mutation. All three did not meet the diagnostic criteria for glioblastoma. All patients received temozolomide combination radiotherapy and maintenance temozolomide therapy. The median survival time of seven glioblastoma, IDH-wildtype patients was 616 days. Two patients who did not meet the diagnostic criteria for glioblastoma survived 510 and 583 days after initial surgery, respectively, and one patient was given the best supportive care policy at 518 days. Genetic analysis of all three cases showed TP53 LOH.

CONCLUSION

It was suggested that tumors with IDH wild-type low-grade astrocytoma that do not meet the diagnostic criteria for glioblastoma may have a poor prognosis. Although TP53 LOH was common, further investigation of specific genetic abnormalities is needed, and the classification and treatment strategy of these disease groups may be a challenge in the future.
10175-GGE-17 MOLECULAR CHARACTERIZATION OF LOW-GRADE DIFFUSELY INFILTRATIVE TUMOR WITH INI1 DEFICIENCY
Authors: Sugino Hirokazu , Nakashima Takuma , Yamamoto Ryo , Sugihara Yuriko , Ishida Joji , Tateishi Kensuke , Kawamura Atsufumi , Narita Yoshitaka , Nobusawa Sumihito , Suzuki Hiromichi
Published: December 2023

Central nervous system low-grade diffusely infiltrative tumor with INI1 deficiency (CNS LGDIT-INI1) is a pathologically low-grade tumor characterized by the infiltrative growth of INI1-deficient tumor cells. Although CNS LGDIT-INI1 is known to progress to an atypical teratoid/rhabdoid (AT/RT)-like tumor, little is yet known about the molecular characteristics distinguishing CNS LGDIT-INI1 from AT/RT. To elucidate the molecular profile of CNS LGDIT-INI1, we performed whole-genome sequencing (WGS), RNA-seq, and DNA methylation array analysis on three cases (1 child and 2 adults) with CNS LGDIT-INI1, including a paired primary-recurrent case. Additionally, 44 publicly available AT/RT cases were analyzed. All the three cases demonstrate homozygous deletions of the SMARCB1 gene, supporting its fundamental role in the tumorigenesis of CNS LGDIT-INI1. The median number of somatic mutations is 1.3/Mb (1.0-2.8) predominantly comprising age-related C-to-T transitions at the CpG site, which is slightly higher than 0.82/Mb in AT/RT, potentially suggesting an association with advanced age of onset. CNS LGDIT-INI1 exhibits a relatively stable genome where broad copy number variations are extremely rare except for the SMARCB1 region, whereas the AT/RT genome shows multiple copy number alterations. Gene set enrichment analysis based on gene expression reveals that CNS LGDIT-INI1 exhibits relatively lower activation in the cell cycle and protein translational activity compared to AT/RT, which is consistent with the low cell proliferation in CNS LGDIT-INI1. The DNA methylation profile of LGDIT resembles that of AT/RT-MYC, suggesting a common cell of origin between CNS LGDIT-INI1 and AT/RT-MYC. In conclusion, CNS LGDIT-INI1 grows based on the loss of SMARCB1, exhibiting a stable genome and low proliferation activity. Considering the similarity of the DNA methylation profile and SMARCB1 deficiency, it is suggested that CNS LGDIT-INI1 may be a precursor of AT/RT.
10195-MET-11 THE PREDICTIVE FACTORS OF EFFICACY OF PEMBROLIZUMAB IN BRAIN METASTASES OF LUNG CANER
Authors: Kawamura Shinji , Otani Ryohei , Yamada Ryoji , Shimizu Sakura
Published: December 2023

The main treatment for metastatic brain tumors is radiation therapy or surgical removal. Since the pembrolizumab, an anti-PD1 monoclonal antibody, was revealed to be effective for brain metastases of lung cancer, it has been used as a therapeutic option. However, the predictive factors of its efficacy have been unclear. If the efficacy of pembrolizumab can be predicted prior to the treatment of metastatic brain tumors, it will have a significant impact on subsequent treatment strategies. In this study, we performed a retrospective analysis of patients with metastatic brain tumors from lung cancer treated with pembrolizumab to investigate predictive factors of pembrolizumab efficacy. From January 2018 to July 2023, 73 patients were treated with pembrolizumab for brain metastases of lung cancer at our institution. Among them, 16 patients who had received pembrolizumab for at least 1 year were included. Median age was 68 years (45-86), 10 were male (63%), and median period of pembrolizumab treatment was 105 months (49-319). Patients with brain metastasis which was well controlled for at least 2 years after starting pembrolizumab were defined as effective, and those who required new treatment were defined as invalid. There were 11 effective cases and 5 invalid cases. We compared clinical characteristics, genetic characteristics of the primary tumor, and imaging characteristics of metastatic brain tumors between the effective and ineffective cases, and identified predictive factors for efficacy of pembrolizumab.
10199-SPDR-2 PERSONALIZED SYNTHETIC LETHALITY INDUCED BY TARGETING ATR-CHK1 IN MEDULLOBLASTOMAS IDENTIFIED BY IMPLEMENTATION OF SLFN11 IMMUNOHISTOCHEMISTRY
Authors: Nakata Satoshi , NAKATA Aki , Yashima Hideaki , Araki Takuya , Murai Junko , Nobusawa Sumihito , Okada Masayasu , Natsumeda Manabu , Tosaka Masahiko
Published: December 2023

Survival in medulloblastoma varies widely between molecular subgroups, and risk-adapted treatment stratification is necessary. Schlafen family member 11 (SLFN11) defines sensitivity to DNA-damaging therapies in a variety of cancers and may be useful in stratifying medulloblastomas. We previously showed that SLFN11 immunohistochemistry identifies poor-prognosis groups that lack expression; however, the additional treatment for these groups has not been fully elucidated. The serine/threonine kinase ATR (ataxia telangiectasia and Rad3-related) binds to single-stranded DNA upon DNA damage competing with SLFN11 and leads to cell cycle arrest and DNA repair process via Chk1 phosphorylation. Although therapeutic effects of ATR/Chk1 inhibitors on SLFN11-deficient cell lines have been reported in other carcinomas, little is known on brain tumors. In the present study, we investigated the effect of ATR/Chk1 inhibition on SLFN11-negative medulloblastomas. ATR knockdown was introduced to the medulloblastoma cell line DAOY and the isogenic SLFN11-knockout line DYB9, and only DYB9 showed increased sensitivity to cisplatin (Prestoblue assay, p < 0.05, t-test). The ATR inhibitor ceralasertib and the Chk1 inhibitor prexasertib also increased cisplatin and camptothecin sensitivity in DYB9 and SLFN11-low Group 3 medulloblastoma D425. Furthermore, combination therapy with cisplatin and prexasertib inhibited the growth of D425 cerebellar tumors (Akaluc IVIS imaging, p < 0.05, t-test) and prolonged survival of the mice (p < 0.05, Log-rank). Combination therapy with irradiation is currently under investigation. Evaluation of SLFN11 expression in medulloblastoma may lead to new treatment strategies, such as reduced radiation dose for the SLFN11-high groups and the combination therapy with ATR/Chk1 inhibitors for the low-expressing groups.
10203-ML-6 TIRABRUTINIB FOR PRIMARY CNS LYMPHOMA: A SINGLE INSTITUTE RETROSPECTIVE ANALYSIS
Authors: Matsutani Tomoo , Hirono Seiichirou , Kobayashi Masayoshi , Higuchi Yoshinori
Published: December 2023

In 2020, Tirabrutinib (TIR) was approved in Japan as a novel treatment for primary CNS lymphoma (PCNSL). However, the position of TIR in relation to the existing therapy, methotrexate (MTX)-based therapy, is still unclear. We are currently using TIR for patients who have insensitivity to MTX, have short-term recurrence after MTX, or have difficulty receiving MTX, with the principle of readministering MTX-based therapy to patients with recurrent disease. The subjects were ten patients treated with TIR at our institute, 6 with multiple relapses, 3 with inability to MTX, and 1 with difficulty in MTX treatment, and the mean number of relapses was 3.8 when Tirabrutinib was used. The mean number of treatments was 104 days, and 7 patients discontinued treatment due to tumor progression, while 3 patients discontinued due to severe skin problems. The median progression-free survival was 99 days, and only one patient was controlled for more than one year. 4 patients received the best supportive care for recurrence after TIR, and one patient received radiotherapy. The four patients in the MTX-based retreatment group had two progressions and two no progressions at the time of the abstract, with a progression-free survival of 133 days, and two patients had CTCAE grade 4 hematologic toxicities that had not occurred with previous therapy. One patient treated surgically died of postoperative pneumocystis pneumonia. Tirabrutinib showed a high early response rate, but the duration of tumor control tended to be shorter than with MTX-based retreatment. This may be due to its use in our institution after multiple relapses and its aggressive administration in MTX-naive patients. It is also important to note that chemotherapy after TIR use is associated with increased hematologic toxicity.
10205-TB-8 ABSENCE OF RNF213 IN MEDULLOBLASTOMA INDUCES STARVATION RESISTANCE VIA GAS6 AND RESULTS IN TUMOR PROGRESSION
Authors: Takahiko Kamata , Mineharu Yohei , Matsui Yasuzumi , Tezuka Toru , Oichi Yuki , Morimoto Takaaki , Tanji Masahiro , Sano Noritaka , Terada Yukinori , Kobayashi Hatasu , Okuda Hiroko , Harada Koji , Koizumi Akio , Arakawa Yoshiki
Published: December 2023

RNF213 gene, initially identified as a disease-causing gene for moyamoya disease, has recently been recognized as a tumor regulator. We investigated the functions of RNF213 in tumorigenicity of medulloblastoma. Knockout of Rnf213 in Ptch1+/- spontaneous medulloblastoma mouse model increased the incidence of SHH type medulloblastoma from 19.8% to 76.5% (p<0.001) at 9 months. Subcutaneous implantation of the tumors showed that depletion of Rnf213 increased tumor formation frequency and tumor size. Unexpectedly, knockout of RNF213 in human Daoy cells decreased tumor growth and invasion in vitro. However, they were resistant to serum starvation and showed higher growth rate when implanted subcutaneously in nude mice. Transcriptome analysis of mouseRnf213-/- cells indicated that downregulation of Igf2 decreased tumor growth and upregulation of Gas6 increased resistance to starvation. In fact, GAS6 was upregulated in serum-free conditions and further upregulated in RNF213-/- cells. Survival advantage in serum starved conditions was lost by GAS6 knock-down in RNF213-/- Daoy cells. In conclusion, the effect of RNF213 depletion was context dependent. Resistance to starvation seems to outweigh growth retardation in normal conditions and is important for tumorigenicity and aggressiveness in vivo.
10206-GGE-21 MOLECULAR LANDSCAPE AND TUMOR EVOLUTION IN ASTROBLASTOMA
Authors: Yamamoto Ryo , Nakashima Takuma , Sugihara Yuriko , Funakoshi Yusuke , Goto Hironori , Ushida Eri , Yamasaki Kai , Yamasaki Fumiyuki , Gomi Akira , Arakawa Yoshiki , Washio Kana , Tateishi Kensuke , Suzuki Tomonari , Saito Ryuta , Narita Yoshitaka , Nobusawa Sumihito , Suzuki Hiromichi
Published: December 2023

Astroblastoma is an extremely rare malignant brain tumor characterized by distinctive gene fusions, including MN1-BEND2 and EWSR1-BEND2 fusions. Despite its indolent nature, frequent local recurrence affects the quality of life for patients. However, there remains a lack of investigation into the genome of astroblastoma. To elucidate the molecular landscape and clonal evolution of astroblastoma, we conducted deep whole-genome sequencing, RNA-seq, and DNA methylation array on 11 cases, including multi-time point samples from 3 cases. Additionally, we integrated publicly available RNA-seq and/or DNA methylation array data from 9 cases. The cohort consists of 13 cases with MN1-BEND2 fusion and 7 cases with EWSR1-BEND2 fusion. Astroblastoma exhibits a relatively silent genome, with median mutation rate is 0.60/Mb (0.22 - 1.09), which is associated with patient age. While EWSR1-BEND2 fusions result from simple translocation, MN1-BEND2 fusions predominantly arise from complex chromosomal rearrangements between chromosome X and 22, frequently involving an additional chromosome, leading to massive oscillation of copy number states in the affected chromosome. Breakpoints in BEND2 within EWSR1-BEND2 fused cases are located near the N-terminus while breakpoints in BEND2 within MN1-BEND2 fused cases cluster in the middle of the gene, suggesting that functional region in BEND2 fusion is distinct based on its partner. Based on DNA methylation, astroblastoma can be divided into three subgroups: MN1-child, MN1-adult, and EWSR1-BEND2 fusion. Gene set enrichment analysis reveals the activation of mitochondrial metabolism in EWSR1-BEND2 fused cases. MN1-adult cases exhibit activation of oxidative stress and DNA replication, whereas MN1-child cases show activation of NOTCH signaling. Multi-time point analysis demonstrates the architecture of clonal evolution. Ionizing radiation appears to be associated with an increase in mutations and deletions, with a radiation-related signature. Our comprehensive analysis provides a detailed view of the genome and evolutionary trajectory of astroblastoma.
10213-GMC-16 A DECADE REVIEW: BEVACIZUMAB'S IMPACT ON GLIOBLASTOMA TREATMENT
Authors: Miyake Keisuke , Yamauchi Yutaka , Fuke Tomono , Tatano Masaki , Ishikawa Momo , Kanda Takahiro , Suzuki Kenta , Fujimori Takeshi , Toyota Yasunori , Ogawa Daisuke , Hatakeyama Tetsuhiro , Okauchi Masanobu , Kawanishi Masahiko
Published: December 2023

OBJECTIVE

This study aims to assess the efficacy of Bevacizumab (Bev) therapy, ten years after its initiation in treating glioblastoma patients at our department.

METHODS

Eighty-four patients treated with Bev from July 2013 to December 2022 were classified into three groups: the initial treatment group given the Stupp regimen with Bev (first-dose group), the group given the Stupp regimen plus Bev followed by tumor resection (neoadjuvant group), and those receiving the Stupp regimen post tumor resection (recurrence group). PET scans were conducted pre- and post- Bev therapy, and variations in Tumor-to-Normal ratio (TNR), Tumor-to-Blood ratio (TBR), and Metabolic Tumor Volume (MTV) were investigated.

RESULTS

The median Progression-Free Survival (PFS) and Overall Survival (OS) rates in the first, neoadjuvant, and recurrence groups were respectively (7.86, 14.27, 4.33) and (12.53, 21.57, 13.23) months. Notably, changes in MET and FMISO MTV in the first-treatment group, MET MTV and FMISO TBR changes in the recurrence group, and MET MTV change in the neoadjuvant group significantly influenced prognosis. In the recurrence group, patients who underwent total resection during initial treatment experienced a prolonged period of 25.9 months from initial treatment to the administration of Bev due to recurrence. Furthermore, cases where the FMISO TBR at recurrence was higher than at the initial treatment observed an extended median OS of 18.63 months upon administering Bev treatment at recurrence.

CONCLUSION

Bev neoadjuvant therapy demonstrated a significant correlation with enhanced PFS and OS outcomes, notably in patients subjected to total resection. In the context of recurrent disease, while the initiation of Bev administration was delayed, a distinct elevation in treatment effectiveness was observed in patients exhibiting an augmented FMISO TBR at the point of recurrence. The observed decreases in MET MTV and FMISO TBR emerge as robust predictors of the efficacy of Bev treatment.
10233-GMC-17 CLINICAL SIGNIFICANCE OF GENETIC ANALYSIS FOR GLIOMA CASES IN OUR INSTITUTE
Authors: Yamaguchi Junya , Ohka Fumiharu , Motomura Kazuya , Kibe Yuji , Shimizu Hiroki , Nishikawa Tomohide , Maeda Sachi , Takido Yuhei , Saito Ryuta
Published: December 2023

The WHO Classification the 5th edition describes that identification of alterations in IDH gene, histone H3 gene, CDKN2A gene, and other genes are quite important for the diagnosis and grading of diffuse gliomas. It is important to efficiently analyze important genetic abnormalities and utilize them in actual clinical practice. In our institute, we have recently performed genetic analysis which is important for the diagnosis of glioma in all patients. Here, we report the results of these analyses. From March 2019 to June 2023, we performed Sanger sequencing for analyses of IDH1/2, H3F3A, TERT promoter, BRAF, and FGFR1 mutation in 235 patients with suspected glioma who underwent biopsy or resection at our hospital and affiliated institutions. In 145 cases, we performed MLPA analyses for detection of 1p/19q codeletion, CDKN2A homozygous deletion (HD), EGFR amplification, and Chromosome 7p gain/10q loss. Sanger sequencing identified 81 TERT promoter mutations, 70 IDH mutations (including 3 IDH2 mutations), 8 BRAF V600E mutations, 4 H3 K27M mutations, 3 H3 G34R/V mutations, and 1 FGFR1 mutation The alterations most frequently identified in MLPA were CDKN2A HD in 26 cases and 1p/19q codeletion in 19 cases. Of the 214 cases in which the pathology diagnosis was neoplastic disease, 85 (39.8%) had no abnormalities in the above genetic analysis. In 32 of these cases, the pathological diagnosis was glioblastoma, IDH-wildtype, while in many other cases, the pathological diagnosis was low-grade glioma. Genetic analysis focusing on important genes for diagnosis according to WHO classification the 5th edition was useful for diagnosis in many cases, but careful consideration is needed for diagnosis in cases without these genetic alterations.
10235-TB-9 TRANSLATIONAL RESEARCH OF BORON NEUTRON CAPTURE THERAPY FOR SPINAL CORD AND SPINE TUMOR IN ANIMAL MODELS
Authors: Fujikawa Yoshiki , Kawabata Shinji , Kayama Ryo , Tsujino Kohei , Kashiwagi Hideki , Fukuo Yusuke , Hiramatsu Ryo , Takata Takushi , Tanaka Hiroki , Suzuki Minoru , Hu Naonori , Miyatake Shin-Ichi , Takami Toshihiro , Wanibuchi Masahiko
Published: December 2023

BACKGROUND

Boron Neutron Capture Therapy (BNCT) is a particle beam therapy that can target at the cellular level. This study evaluated the effectiveness of BNCT on spinal cord gliomas using animal models.

METHODS

F98 rat glioma or 9L rat gliosarcoma cell lines were implanted in rats' spinal cords to create a model. BPA, a boron compound, was administered and the biodistribution compared. Neutron irradiation was performed post-BPA injection, and the effectiveness was evaluated by survival period and hindlimb muscle strength using the Basso-Bresnahan-Beattie (BBB) score.

RESULTS

Significant boron accumulation was observed in tumors. In irradiation experiments, the BNCT group showed suppressed BBB score decrease and a significantly extended survival period compared to other groups. No cases of death or lower limb function decline were observed in the sham-BNCT group.

CONCLUSION

BNCT for spinal cord gliomas was shown to be safe and effective. The spinal cord is an organ at risk in irradiation for spinal cord and spine tumors. As it has a history of being a safety evaluation organ when applying BNCT to the central nervous system, BNCT may be applicable to cases such as recurrence after radiation therapy.
10243-IMT-3 LONG-TERM OUTCOME OF A COCKTAIL WILMS' TUMOR 1 (WT1) VACCINATION USING TWO HLA CLASS I PEPTIDES AND ONE CLASS II PEPTIDE AGAINST RECURRENT MALIGNANT GLIOMAS
Authors: Kagawa Naoki , Oji Yusuke , Hirayama Ryuichi , Kijima Noriyuki , Oka Yoshihiro , Sugiyama Haruo , Kishima Haruhiko
Published: December 2023

PURPOSE

Our clinical trials show the safety and clinical efficacy of Wilms' tumor 1 (WT1) human leukocyte antigen (HLA) class I (Izumoto S et al. J Neurosurg. 2008) and class II (Tsuboi A et al. Cancer Immunol Immunother. 2019) peptide vaccination for recurrent malignant gliomas have been established. We have developed a cocktail vaccine (WT1 trio) containing two class I peptides (HLA-A*24:02 and HLA-A*02:01) and one II class peptide to improve more effective immunological response and improve patient's prognosis. Clinical trial of a cocktail vaccination using WT1 HLA class I and II peptides for recurrent malignant gliomas is planned to verify its safety, clinical efficacy and usefulness of surrogate markers. Patients and

METHODS

Twenty-three patients with recurrent malignant gliomas, which showed WT1-positive in tumor samples and HLA-A*24:02 or HLA-A*02:01-positive in blood sample, were enrolled. These patients (age: 26-72 years old, average: 49.4) included 15 cases of glioblastomas and 8 of anaplastic astrocytomas. Patients received a WT1 trio vaccine intradermally, 7 times at 2-week intervals during 3 months.WT1-DTH and WT1-IgG antibody were regularly measured. Vaccine-related adverse events, best clinical response and the transfer rate of long-term administration of WT1 trio vaccination were estimated.

RESULTS

WT1-DTH positive cases were 12, WT1-IgG antibody positive were in 11. In most patients, WT1 -DTH positiveness coincided with that of WT1-IgG antibody. 9 of 11 cases showed stable disease at 3 months and transferred long-term administration of WT1 trio vaccination. Transfer rate in GBM and AA of long-term administration was 33% and 25%, respectively. Grade1 skin eruption was observed at the injection sites in 15 cases, but no significant adverse events related with vaccination were shown. Conclusion: WT1-DTH and WT1-IgG antibody may be useful surrogate markers. Long-term outcome of WT1 trio vaccination was verified for recurrent malignant gliomas.
10247-ET-8 HHYPOXIA-TARGETING RADIOPHARMACEUTICAL 64CU-ATSM FOR PET MONITORING WITH LOCAL THERAPY IN HIGH-GRADE GLIOMA PATIENT-DERIVED XENOGRAFT MODEL
Authors: Tateishi Kensuke , Hihara Fukiko , Oshima Akito , Yamamoto Tetsuya , Yoshii Yukie
Published: December 2023

High-grade gliomas (HGGs) are highly aggressive brain cancers characterized by the presence of hypoxia within a rapidly-growing tumor mass. Due to invasion to the surrounding brain parenchyma, these tumors commonly recur locally,, and novel local approaches are required. Here, we show a positron emission tomography (PET) integrated local therapy (PETx), to target HGGs. This technique consists of a one-step local theranostic application, followed by PET monitoring, with a hypoxia-targeting radiopharmaceutical64Cu-diacetyl-bis (N4-methylthiosemicarbazone) (64Cu-ATSM). We examined the safety and therapeutic potential of 64Cu-ATSM PETx for HGG patient-derived xenograft (PDX) tumors. PDX models were recapitulated the parent tumor phenotype of high expression of HIF-1 alpha and BNIP3, biomarkers of tissue hypoxia. We confirmed that HIF-1 alpha and BNIP3 were highly upregulated under hypoxia and 64Cu-ATSM was retained with potent cytotoxic effect under hypoxic condition in vitro. We determined that determined the maximum tolerated dose (MTD) to be 3.7 MBq in mouse. PETx using the MTD dose of 64Cu-ATSM indicated high tumor penetration, distribution, and retention of 64Cu-ATSM in PDX tumors, as compared to sham-treated mice. The 64Cu-ATSM PETx promoted DNA double-strand breaks, followed by apoptosis in tumors, and extensively prolonged overall survival with tolerable systemic toxicity. These findings indicate the potential of 64Cu-ATSM PETx to induce high uptake in the hypoxic tumor microenvironment, and strong therapeutic effects in PDX models. These findings establish 64Cu-ATSM PETx as a potential novel theranostic approach to facilitate local control of HGGs.
10252-COT-27 TWO CASES OF OVARIAN HYPERSTIMULATION SYNDROME IN A YOUNG FEMALE PATIENTS WITH GLIOMA WHO UNDERWENT OOCYTE CRYOPRESERVATION.
Authors: Nonoguchi Naosuke , Takai Satoshi , Yagi Ryokichi , Kazuki Rina , Ryu Masae , Umegaki Osamu , Fujita Taisuke , Fukuo Yusuke , Hiramatsu Ryo , Kosaka Takuya , Kameda Masahiro , Furuse Motomasa , Kawabata Shinji , Takami Toshihiro , Wanibuchi Masahiko
Published: December 2023

Young women with malignant gliomas may wish to have their oocytes preserved prior to the start of chemotherapy in order to maintain fertility. In such cases, fertility drugs make it possible to mature and retrieve multiple oocytes in the ovaries. However, the ovaries may overreact and mature many oocytes at once, resulting in adverse symptoms such as abnormal swelling of the ovaries, abdominal discomfort and pain, nausea and vomiting, abdominal distention, fluid retention (edema), and difficulty breathing. This is called ovarian hyperstimulation syndrome (OHSS), in which excessive secretion of estradiol associated with multiple follicle development leads to excessive production of VEGF, which rapidly increases the vascular permeability of systemic organs, resulting in a fluid shift into the third space, which is thought to cause ascites and pulmonary edema. In severe cases, intravascular dehydration and decreased circulating plasma volume can cause hypotension and oliguria, and the increased coagulation capacity associated with hemoconcentration can cause serious thrombotic complications. The severity of OHSS is classified into three levels: mild, moderate, and severe, based on four findings: subjective symptoms, the amount of pleural effusion, the degree of ovarian enlargement (ovarian diameter), and blood test findings. Early detection and appropriate management are essential. We have had two cases of OHSS, one of which was moderate and resolved successfully, while the other became severe, and we had to postpone the start of radiotherapy for a week longer than planned. Severe OHSS is a medical complication that neurosurgeons rarely encounter, and we report this case with a literature review.
10268-NI-13 T2-FLAIR MISMATCH SIGN CORRELATES WITH11C-METHIONINE UPTAKE IN LOWER-GRADE DIFFUSE GLIOMAS
Authors: Ebiko Yusuke , Tamura Kaoru , Hara Shoko , Inaji Motoki , Tanaka Yoji , Nariai Tadashi , Ishii Kenji , Maehara Taketoshi
Published: December 2023

PURPOSE

The T2-FLAIR mismatch sign is recognized as an imaging finding highly suggestive of IDH-mutant astrocytomas. This study was designed to determine whether the T2-FLAIR mismatch sign correlates with uptake of 11C-methionine in lower-grade gliomas.

METHODS

We included 78 histopathologically verified lower-grade gliomas (grade 2: 31 cases, grade 3: 47 cases) in this study. 78 patients underwent 11C-methionine positron emission tomography (MET-PET) scans and magnetic resonance (MR) imaging scans prior to histological diagnosis. The tumor-to-normal ratio (T/N) of 11C-methionine uptake was calculated by dividing the maximum standardized uptake value (SUV) for the tumor by the mean SUV of the normal brain. MR imaging scans were evaluated for the presence of the T2-FLAIR mismatch sign by three independent reviewers. We compared molecular status, the T2-FLAIR mismatch sign and 11C-methionine uptake among patients with different lower-grade glioma molecular types.

RESULTS

The 78 lower-grade gliomas were assigned to one of three molecular groups: Group A (IDH-mutant and 1p/19q non-codeleted, n=22), Group O (IDH-mutant and 1p/19q codeleted, n=20), and Group W (IDH wildtype, n=36). T2-FLAIR mismatch was found in 16 cases (20.5%) that were comprised of 8 (36.4%), 0 (0%), 8 (22.2%) cases in the molecular group A, O and W, respectively. The median T/N ratio of MET-PET in tumors with T2-FLAIR mismatch was 1.50, which was significantly lower than that of tumors without T2-FLAIR mismatch (1.83, p<0.001, Mann-Whitney U test). In the Groups A and W (excluding Group O), the median T/N ratio on MET-PET in groups A and W (but not group O) with T2-FLAIR mismatch was 1.50, which was significantly lower than that of tumors without T2-FLAIR mismatch (1.81, p=0.002, Mann-Whitney U test).

CONCLUSION

The T2-FLAIR mismatch sign correlated with lower 11C-methionine uptake in lower grade gliomas.
10269-ET-10 ARRAYS FOR DELIVERING TUMOR TREATING FIELDS (TTFIELDS) TO THE MOUSE HEAD
Authors: Zbidat Sewar , Blatt Roni , Sellevoll Mariell , Gabay Martin , Schlachet Inbar , Cahal Shay , Davidi Shiri , Tzchori Itai , Enjo Kentaro , Haber Adi , Giladi Moshe , Palti Yoram
Published: December 2023

INTRODUCTION

Tumor Treating Fields (TTFields) therapy is an approved treatment for glioblastoma (GBM), the most common malignant brain tumor. TTFields therapy is delivered continuously by two pairs of arrays placed orthogonally on the skin surrounding the tumor region. Investigational in vivo work in the field of GBM currently utilizes mouse models. To expand the possibility for TTFields-GBM in vivo studies, TTFields arrays for the mouse head are needed. The small dimensions and specific geometries of the mouse head make the development of such arrays challenging.

METHODS

We tested a variety of layouts for the arrays to identify one that will be suited to the geometries of the mouse head, and that will minimally restrict head movement. Efficient treatment delivery requires good adherence to the skin; hence, we investigated different skin attachment adhesive tapes. To validate the ability of the selected arrays to deliver therapeutic field intensity to the desired region, we performed direct fields measurements and simulations.

RESULTS

We employed 2 strategies to overcome the small size and confining geometries of the mouse head: (1) only two of the four arrays were situated on the head – opposing arrays were placed on the mouse torso; (2) the arrays on the head were each divided into two small disks instead of just one large disk. We identified an adhesive tape for securing the arrays to the skin that was thin and transparent, facilitating correct positioning of the arrays on the mouse head. The tape also offered good tackiness, and allowed for easy removal without leaving residual adhesive on the skin, facilitating repeated array placement. The arrays met the requirements for efficient treatment: field intensity ≥ 1 V/cm RMS, current ≥ 50 mA, usage ≥ 75%.

CONCLUSIONS

We were able to develop flexible mouse head arrays, that adheres strongly to the skin, enabling efficient electric field delivery with minimal animal discomfort. These arrays provide means to expand TTFields-GBM treatment research, and will contribute to advance this field.
A LINE-1 mediated deletion resulting in germline retinoblastoma predisposition
Authors: Macke Erica L , Miller Anthony R , Stonerock Eileen , Olshefski Randal , Zajo Kristin , Bedrosian Tracy A , Mardis Elaine R , Akkari Yassmine M N , Cottrell Catherine E , Schieffer Kathleen M
Published: December 2023

Retinoblastoma is an ocular cancer associated with genomic variation in the RB1 gene. In individuals with bilateral retinoblastoma, a germline variant in RB1 is identified in virtually all cases. We describe herein an individual with bilateral retinoblastoma for whom multiple clinical lab assays performed by outside commercial laboratories failed to identify a germline RB1 variant. Paired tumor/normal exome sequencing, long-read whole genome sequencing, and long-read isoform sequencing was performed on a translational research basis ultimately identified a germline likely de novo Long Interspersed Nuclear Element (LINE)-1 mediated deletion resulting in a premature stop of translation of RB1 as the underlying genetic cause of retinoblastoma in this individual. Based on these research findings, the LINE-1 mediated deletion was confirmed via Sanger sequencing in our clinical laboratory, and results were reported in the patient's medical record to allow for appropriate genetic counseling.
Loss of RAS Mutations in Liquid Biopsies of Patients With Multi-Treated Metastatic Colorectal Cancer
Authors: Albuquerque Joana , Neto da Silva Diana , Padrão Teresa , Leal-Costa Luísa , Bizarro Rita , Correia Jorge , Baptista Carlota , Machete Madalena , Prazeres Gil , Margarido Inês , Fernandes Gonçalo , Simões Pedro , Timóteo Teresa , Lopes Fábio , Godinho João , Moreira-Pinto João , Rodrigues Tânia , Faria Ana , Pulido Catarina , Cirnes Luís , Teixeira José A , Passos Coelho José L
Published: December 2023

Background

Liquid biopsy (LB) is a non-invasive tool to evaluate the heterogeneity of tumors. Since RAS mutations (RAS-mut) play a major role in resistance to antiepidermal growth factor receptor inhibitors (EGFR) monoclonal antibodies (Mabs), serial monitoring of RAS-mut with LB may be useful to guide treatment. The main aim of this study was to evaluate the prognostic value of the loss of RAS-mut (NeoRAS-wt) in LB, during the treatment of metastatic colorectal cancer (mCRC).

Methods

A retrospective study was conducted on patients with mCRC between January 2018 and December 2021. RAS-mut were examined in tissue biopsy, at mCRC diagnosis, and with LB, during treatment.

Results

Thirty-nine patients with RAS-mut mCRC were studied. LB was performed after a median of 3 lines (0-7) of systemic treatment including anti-vascular endothelial growth factor (anti-VEGF) Mabs. NeoRAS-wt was detected in 13 patients (33.3%); 9 (69.2%) of them received further treatment with anti-EGFR Mabs with a disease control rate of 44.4%. Median overall survival (OS), from the date of LB testing, was 20 months in the NeoRAS-wt group and 9 months in the persistent RAS-mut group (log-rank 2.985; P = .08), with a 12-month OS of 84.6% and 57.7%, respectively. NeoRAS-wt was identified as a predictor of survival (HR = 0.29; P = .007), with an 11-month improvement in median OS and a 71% decrease in risk of death, in heavily pretreated patients

Conclusions

In conclusion, monitoring clonal evolution in mCRC by LB may provide an additional treatment line for patients with NeoRAS-wt in advanced disease.
Spatial variability in size and lipid content of the marine copepod Calanus finmarchicus across the Northwest Atlantic continental shelves: implications for North Atlantic right whale prey quality
Authors: Helenius Laura K , Head Erica J H , Jekielek Phoebe , Orphanides Christopher D , Pepin Pierre , Perrin Geneviève , Plourde Stéphane , Ringuette Marc , Runge Jeffrey A , Walsh Harvey J , Johnson Catherine L
Published: December 2023

Copepod size and energy content are influenced by regional and seasonal variation in temperature and food conditions, with implications for planktivorous consumers such as the endangered North Atlantic right whale (Eubalaena glacialis). Historical data (1990–2020) on Calanus finmarchicus stage CV copepodite prosome length and oil sac metrics were analyzed to determine the extent of variation in individual body size and estimated lipid and energy content in five regions of the Northwest Atlantic continental shelves [Gulf of Maine (GoM), Scotian Shelf (SS), Gulf of St. Lawrence (GSL), St. Lawrence Estuary (SLE) and Newfoundland Shelf]. Large-scale spatial patterns in size and lipid content were related to latitude, indicating that C. finmarchicus CV in the GSL and SLE were historically larger in body size, and had significantly higher lipid content compared with those in the GoM and the SS. The observed patterns of C. finmarchicus CV size and lipid storage capacity suggest that regional variation in whale prey energy content can play a role in the suitability of current and future whale foraging habitats in the Northwest Atlantic, with the larger lipid-rich individuals in the GSL providing a high-quality diet compared with those in southern areas.
ROS-responsive hydrogels with spatiotemporally sequential delivery of antibacterial and anti-inflammatory drugs for the repair of MRSA-infected wounds
Authors: Qiao Bowen , Wang Jiaxin , Qiao Lipeng , Maleki Aziz , Liang Yongping , Guo Baolin
Published: December 2023

For the treatment of MRSA-infected wounds, the spatiotemporally sequential delivery of antibacterial and anti-inflammatory drugs is a promising strategy. In this study, ROS-responsive HA-PBA/PVA (HPA) hydrogel was prepared by phenylborate ester bond cross-linking between hyaluronic acid-grafted 3-amino phenylboronic acid (HA-PBA) and polyvinyl alcohol (PVA) to achieve spatiotemporally controlled release of two kinds of drug to treat MRSA-infected wound. The hydrophilic antibiotic moxifloxacin (M) was directly loaded in the hydrogel. And hydrophobic curcumin (Cur) with anti-inflammatory function was first mixed with Pluronic F127 (PF) to form Cur-encapsulated PF micelles (Cur-PF), and then loaded into the HPA hydrogel. Due to the different hydrophilic and hydrophobic nature of moxifloxacin and Cur and their different existing forms in the HPA hydrogel, the final HPA/M&Cur-PF hydrogel can achieve different spatiotemporally sequential delivery of the two drugs. In addition, the swelling, degradation, self-healing, antibacterial, anti-inflammatory, antioxidant property, and biocompatibility of hydrogels were tested. Finally, in the MRSA-infected mouse skin wound, the hydrogel-treated group showed faster wound closure, less inflammation and more collagen deposition. Immunofluorescence experiments further confirmed that the hydrogel promoted better repair by reducing inflammation (TNF-α) and promoting vascular (VEGF) regeneration. In conclusion, this HPA/M&Cur-PF hydrogel that can spatiotemporally sequential deliver antibacterial and anti-inflammatory drugs showed great potential for the repair of MRSA-infected skin wounds.
Landscape of immune cells in systematic lupus erythematosus patients with Epstein–Barr virus infection: assessed by single-cell sequencing
Authors: Hu Lingzhen , Tu Jianxin , Gui Jiajun , Fang Mengyuan , Sun Li
Published: December 2023

Objectives

To analyse the immune cell and B-cell receptor (BCR) profiles of patients with SLE, with or without EBV infection, and identify the differences between them.

Methods

We included two patients with SLE and positive detection of EBV infections (SLE-EBV+), four with SLE with negative detection of EBV infections (SLE-EBV–) and two healthy controls. Single-cell RNA sequencing was used to investigate the heterogeneity of cell populations by combining the transcriptomic profiles and BCR repertoires.

Results

A total of 83 478 cells were obtained and divided into 31 subtypes. The proportion of CD8+ proliferation T cells was higher in the SLE-EBV+ group than in the SLE-EBV– group. The IFN-α/β pathways were upregulated in most T cells, monocytes and B cells in the SLE-EBV+ group, compared with the SLE-EBV– group. Moreover, T-cell trajectory indicated CD4+ Tregs may play crucial roles in SLE combined with EBV infection. In the BCR heavy chain, the IGHV3 and IGHV4 gene families were frequently present in all groups. Additionally, IgM was the largest component of five Ig isotypes, but its proportion was significantly decreased in the SLE-EBV+ group.

Conclusion

This study provides a comprehensive characterization of the immune cell profiles and BCR repertoires of patients with SLE, both with and without concurrent EBV infections, contributing to a better understanding of the mechanism underlying the immune response to EBV infection in patients with SLE.
Expert Revision of Key Elements for Clinical-Grade Production and Qualification of Perinatal Derivatives
Authors: Gramignoli Roberto , Hofmann Nicola , Agudo-Barriuso Marta , Antica Mariastefania , Flores Ana I , Girandon Lenart , Kerdjoudj Halima , Navakauskiene Ruta , Schiavi Jessica , Scholz Hanne , Shablii Volodymyr , Lafarge Xavier , Nicolás Francisco J , Gindraux Florelle
Published: December 2023

Perinatal derivatives have been proposed as adjunct therapeutic strategies or innovative treatments. Undoubtedly, perinatal derivatives can offer the opportunity and source material to isolate multipotent stem cells, but both maternal- and fetal-derived tissues can be processed and transformed into engineered tissues or advanced biomedical devices, whose potential remains to be fully elucidated. Promising preclinical and clinical results collected so far clearly foresee an escalation of such novel treatments. Market forecasts predict exponential growth in such advanced medicinal products during the next decade, with a pragmatic innovation for medicine into a more advanced biomedical version, enlarging the portfolio for treating a wide range of congenital and acute conditions. However, all these promising and fascinating therapeutic possibilities cannot gain a solid and recognized role in established medical practice without rigid and harmonized manufacturing strategies. The implementation of strategies according to guidelines and directives compiled by Regulatory Agencies, in conformity to (European) Pharmacopoeia and for Good Manufacturing Practice -conforming production of such products, represent critical steps required to translate perinatal technologies into effective therapeutic approaches. During the past 5 years, a panel of European experts and developers, gathered under the umbrella of the COST Sprint Action, supported by the European Cooperation in Science and Technology action, had the opportunity to revise and summarize experience and recommendations for a fruitful and proficient generation of perinatal biomedical products. In order to facilitate the creation and potential commercialization of perinatal bioengineered and advanced pharmaceutical products and technologies, such a collection of data and recommendations is described and discussed here.
A Randomized, Placebo-Controlled, Phase II Trial of Intravenous Allogeneic Non-HLA Matched, Unrelated Donor, Cord Blood Infusion for Ischemic Stroke
Authors: Laskowitz Daniel T , Troy Jesse , Poehlein Emily , Bennett Ellen R , Shpall Elizabeth J , Wingard John R , Freed Brian , Belagaje Samir R , Khanna Anna , Jones William , Volpi John J , Marrotte Eric , Kurtzberg Joanne
Published: December 2023

Stroke remains a leading cause of death and disability in the US, and time-limited reperfusion strategies remain the only approved treatment options. To address this unmet clinical need, we conducted a phase II randomized clinical trial to determine whether intravenous infusion of banked, non-HLA matched unrelated donor umbilical cord blood (UCB) improved functional outcome after stroke. Participants were randomized 2:1 to UCB or placebo within strata of National Institutes of Health Stroke Scale Score (NIHSS) and study center. Study product was infused 3-10 days following index stroke. The primary endpoint was change in modified Rankin Scale (mRS) from baseline to day 90. Key secondary outcomes included functional independence, NIHSS, the Barthel Index, and assessment of adverse events. The trial was terminated early due to slow accrual and logistical concerns associated with the COVID-19 pandemic, and a total of 73 of a planned 100 participants were included in primary analyses. The median (range) of the change in mRS was 1 point (–2, 3) in UCB and 1 point (-1,4) in Placebo (P = 0.72). A shift analysis comparing the mRS at day 90 utilizing proportional odds modeling showed a common odds ratio of 0.9 (95% CI: 0.4, 2.3) after adjustment for baseline NIHSS and randomization strata. The distribution of adverse events was similar between arms. Although this study did not suggest any safety concerns related to UCB in ischemic stroke, we did not show a clinical benefit in the reduced sample size evaluated.