bluuebunny/crossref_metadata_2025_split huggingface dataset:
10024- TB-2 COMBINATION THERAPY OF NOVEL MDM4 INHIBITOR CEP-1347 AND IONIZING RADIATION FOR MALIGNANT BRAIN TUMORS
Authors: Mitobe Yuta , Nakamura Kazuki , Sonoda Yukihiko , Kitanaka Chifumi 
Published: November 2024

Abstract
Radiation therapy represents the cornerstone treatment for malignant brain tumors, the majority of which express wild-type p53. Identification of drugs that promote ionizing-radiation (IR) induced activation of p53, therefore, is expected to help increase the efficacy of radiation therapy for these tumors. The growth inhibitory effects of CEP-1347, a known inhibitor of MDM4 expression, on malignant brain tumor cell lines expressing wild-type p53 were examined, alone or in combination with IR, by dye exclusion and/or colony formation assays. The effects of CEP-1347 on the p53 pathway, alone or in combination with IR, were examined by RT-PCR and Western blot analyses. The combination of CEP-1347 and IR activated p53 in malignant brain tumor cells and inhibited their growth more effectively than either alone. Mechanistically, CEP-1347 and IR each reduced MDM4 expression, but their combination did not result in further reduction. Instead, CEP-1347 promoted IR-induced Chk2 phosphorylation and increased p53 expression in concert with IR in a Chk2-dependent manner. Our findings show that CEP-1347 is capable of promoting Chk2-mediated p53 activation by IR besides inhibiting the expression of MDM4 and thus identify CEP-1347 as a promising radiosensitizer for malignant brain tumors expressing wild-type p53.
10166- ACT-9 TRANSLATING BASIC RESEARCH ON AD-REIC FOR RECURRENT GLIOBLASTOMA INTO AN INVESTIGATOR-INITIATED CLINICAL TRIAL
Authors: Otani Yoshihiro , Kurozumi Kazuhiko , Ishida Joji , Fujii Kentaro , Sasaki Tatsuya , Shimazu Yosuke , Oka Tetsuo , Hattori Yasuhiko , Tan Hironobu , Kumon Hiromi , Tanaka Shota 
Published: November 2024

Abstract
Glioblastoma is the most aggressive type of brain tumor, and the development of new treatments is urgently needed. A viral gene therapy incorporating the tumor suppressor gene REIC/Dkk-3 discovered at Okayama University was conducted from basic research to investigator-initiated clinical trials. Here, we present the results from basic research to clinical application.In 2014, we confirmed the antitumor effects of the first-generation Ad-REIC product, Ad-CAG-REIC, in both in vitro and in vivo experiments using human glioblastoma cells (Gene Ther, 2014). Subsequently, we developed the second-generation formulation, Ad-SGE-REIC, which enhances the expression of the REIC/Dkk-3 gene. Ad-SGE-REIC induced stronger endoplasmic reticulum stress and higher levels of cell death. In addition, Ad-SGE-REIC demonstrated a more potent antitumor effect than Ad-CAG-REIC in both immunodeficient models using human glioblastoma cells and immunocompetent models using mouse glioblastoma cells. Significant infiltration of CD8-positive and CD11c-positive cells were observed, suggesting immunogenic cell death (Sci Rep, 2016). Furthermore, the combination of Ad-SGE-REIC with Bevacizumab enhanced the therapeutic effect (PLoS One, 2022).Based on these results, we initiated a Phase 1/2a investigator-initiated clinical trial (jRCT2063190013, Future Oncol, 2020) for recurrent malignant glioma in 2019, supported by the AMED Translational Research Program Seeds C, and completed patient enrollment in 2022. We are currently evaluating the safety and efficacy of this trial. Additionally, since 2023, under the AMED P-PROMOTE, we have been exploring biomarkers for Ad-REIC. Ad-SGE-REIC has the potential to be a novel treatment for recurrent glioblastoma.
10178- ACT-11 A PHASE 1 STUDY OF LOMUSTINE MONOTHERAPY AND COMBINATION THERAPY WITH PROCARBAZINE, LOMUSTINE, AND VINCRISTINE IN JAPANESE PATIENTS WITH GLIOMA (LOMG)
Authors: Arakawa Yoshiki , Makino Yasuhide , Yamamoto Etsuko , Takeuchi Yasuhide , Takada Shigeki , Sano Noritaka , Tanji Masahiro , Mineharu Yohei , Yonezawa Atsushi 
Published: November 2024

Abstract
In the development of treatments for glioma, international clinical trials have demonstrated the efficacy of carmustine (BCNU), lomustine (CCNU), and methyl-CCNU against glioma. In Japan, nimustine (ACNU) has been developed and is used as a treatment for glioma. Internationally, compared to BCNU, the combination therapy of procarbazine, lomustine (CCNU), and vincristine (PCV therapy) has been confirmed to extend the survival period for glioma Grade 2/3, and numerous clinical trial results using PCV therapy have been accumulated. As a result, PCV therapy has become the standard treatment for Grade 2/3 oligodendroglioma and Grade 2 astrocytoma worldwide. However, lomustine is not approved in Japan, making it impossible to implement the standard treatment used overseas. Therefore, in 2019, the Japan Society for Neuro-Oncology submitted a request for the domestic development of lomustine to the ‘Meeting for the Evaluation of Unapproved Drugs and Indications with High Medical Needs.’ As a result of deliberation, it was determined in 2022 that clinical trial results involving Japanese subjects were necessary. Consequently, this physician-led trial was planned as a Phase I trial of lomustine, and the trial began in 2023. This report provides an overview and background of this clinical trial.
10312- ACT-20 A GLOBAL, RANDOMIZED, DOUBLE-BLINDED, PHASE 3 STUDY OF VORASIDENIB VERSUS PLACEBO IN PATIENTS WITH ADULT-TYPE DIFFUSE GLIOMA WITH AN IDH1/2 MUTATION (INDIGO): JAPAN SUBGROUP ANALYSIS
Authors: Arakawa Yoshiki , Mellinghoff Ingo K , van den Bent Martin J , Narita Yoshitaka , Mukasa Akitake , Saito Ryuta , Hirose Yuichi , Sugiyama Kazuhiko , Hashimoto Naoya , Tanaka Shota , Zhao Dan , Pandya Susan , Steelman Lori , Hassan Islam , Wen Patrick Y , Cloughesy Timothy F 
Published: November 2024

Abstract

INTRODUCTION
The Phase 3 INDIGO study (NCT04164901) evaluated vorasidenib, an oral, brain-penetrant, dual inhibitor of mutated isocitrate dehydrogenase 1/2 (mIDH1/2), in patients with mIDH1/2 diffuse glioma. The primary endpoint of progression-free survival (PFS) per blinded independent review committee (BIRC) and key secondary endpoint of time to next intervention (TTNI) were met in the second interim analysis. In March 2023, the study was unblinded following committee recommendation. We present results for patients from Japan.

METHODS
Patients with grade 2 mIDH1/2 oligodendroglioma or astrocytoma were enrolled (aged ≥12 years; Karnofsky Performance Status, ≥80; measurable non-enhancing disease; surgery as only prior treatment; no immediate need of chemoradiotherapy). Patients were randomized 1:1 to vorasidenib 40 mg or placebo daily in 28-day cycles.

RESULTS
In Japan, nine patients were randomized to placebo and seven to vorasidenib. At unblinding, all patients receiving placebo crossed over to vorasidenib. Study unblinding occurred in close succession to enrollment in Japan resulting in a short duration of placebo exposure. The Japan subgroup included all patients who received ≥1 dose of vorasidenib (n=16; median age, 44.0 years; oligodendroglioma, 10; astrocytoma: 6). As of March 2024, mean (SD) duration of vorasidenib exposure was 10.2 (3.0) months and 81.3% remained on treatment. No progression events per BIRC or deaths occurred. Median PFS and TTNI were not estimable: one patient received anticancer therapy and no other TTNI events occurred. All-grade adverse events occurring in &gt;20% patients were increased alanine transferase (68.8%, Grade≥3: 25.0%), increased aspartate aminotransferase (56.3%; Grade≥3: 18.8%) and increased gamma-glutamyltransferase (31.3%, Grade≥3: 6.3%).

CONCLUSIONS
Vorasidenib is an effective targeted therapy for patients with mIDH1/2 diffuse glioma in this Japanese patient population. Findings are consistent with the statistically significant and clinically meaningful benefit of vorasidenib in the overall INDIGO study population.
10019- MPC-4 IN-HOUSE MOLECULAR DIAGNOSIS FOR THE ERA OF MOLECULAR STRATIFIED THERAPY OF GLIOMAS
Authors: Hata Nobuhiro , Fudaba Hirotaka , Momii Yasutomo , Anan Mitsuhiro , Fujiki Minoru 
Published: November 2024

Abstract

OBJECTIVE
Molecular diagnostics has become increasingly diverse since its formal adoption at WHO 2016 and then WHO 2021. In addition, with the forthcoming approval of molecular targeted therapies for IDH and BRAF, there is a need to explore molecular diagnostic systems that are compatible with clinical practice. While it is desirable to establish molecular diagnostic systems that can be completed within an institution for rapid post-diagnosis treatment, optimization of analytical methods with consideration of cost and simplicity is an important issue. We investigated the optimization of such molecular diagnostics at our institution.

METHODS
The author established an institutional molecular diagnostic system by combining MGMT methylation analysis by MS-PCR in addition to HRM analysis for point mutations of IDH1/2, BRAF, and H3, TERT promoter mutation analysis by Sanger sequencing, and MLPA using two different probe sets at a previous institution. After transferring to the current facility, we attempt to optimize molecular diagnostics within the facility with limited research funding.

RESULTS
The HRM system is low-cost, technically simple, and can detect stable results for IDH1/2, BRAF, and H3 mutations in a short time, and was easy to implement at the new facility. In addition, the newly developed MLPA probe set enabled single-step combined analysis of IDH, TERT, and MLPA methylation without bisulfite treatment. Given the usefulness of TERT as a molecular marker for glioblastoma and a surrogate marker for 1p19q, these two assays alone are now generally sufficient for the in-house molecular diagnosis of diffuse glioma in adults.

CONCLUSION
HRM and MLPA were suitable for the establishment of a sustainable molecular diagnostic system. Since the establishment of treatment strategies based on molecular diagnosis has become essential in recent years, and the optimization of an in-house molecular diagnosis system is desirable, so we will continue to study this issue.
10150- MPC-14 THE COMPARISON BETWEEN HISTOLOGICAL DIAGNOSIS, GENOME-WIDE DNA METHYLATION PROFILING AND INTEGRATED DIAGNOSIS FOR PEDIATRIC LOW-GRADE GLIOMA
Authors: Inoue Yohei , Yoshihiro Otani , Ishida Joji , Miyahira Akira , Yuko Hibiya , Matsushita Yuko , Satomi Kaishi , Fukuoka Kohei , Yamasaki Kai , Nakano Yoshiko , Yoshioka Takako , Hirato Junko , Tanaka Shota , Ichimura Koichi 
Published: November 2024

Abstract

INTRODUCTION
Genome-wide DNA methylation profiling is performed for pediatric low-grade glioma (pLGG) with diagnostic challenge. We compared histological diagnosis, DNA methylation profiling and integrated diagnosis for pLGG.

METHODS
We analyzed histology, molecular findings, DNA methylation profiling and integrated diagnosis of pLGG that were registered to the central diagnosis of Japan Children’s Cancer Group from March 2018 to June 2024 and underwent genome-wide DNA methylation profiling.

RESULTS
Fifty-eight cases were enrolled. Thirty-seven cases (64%) had calibrated scores of 0.84 or higher (match), and 21 cases (36%) had the scores below 0.84 (no match). Definitive diagnoses based on integrated diagnoses were achieved in 22 cases (59%) among the match cases, in 6 cases among the no match cases and in total 28 cases (48%). Tumor types of the 28 cases with definitive diagnoses were pilocytic astrocytoma (PA) in 16 cases, diffuse low-grade glioma, MAPK pathway-altered in 2 cases, subependymal giant cell astrocytoma in 2 cases, dysembryoplastic neuroepithelial tumour in 2 cases, and others in 6 cases. All 6 cases with definitive diagnoses among the no match cases were PA. Discrepancies between histological diagnosis and methylation class were observed in total 34 cases (match 17 cases, no match 17 cases). Among the 34 cases, definitive diagnoses were achieved in 8 cases (match 6 cases, no match 2 cases) and all the diagnoses supported the histological diagnoses. Twenty-one cases of the 34 cases were histologically diagnosed with unspecific tumor types like low-grade glioma or classified to MC Control tissue in DNA methylation profiling.

DISCUSSION/CONCLUSION
Genome-wide DNA methylation profiling was useful for pLGG matched to specific methylation class. Sixteen percents of the match cases showed discrepancy between histological diagnoses and methylation class, but supported histological diagnoses as definitive diagnoses, indicating the importance of integrated diagnosis.
10171- MPC-16 SCREENING OF NTRK FUSION IN JAPANESE CENTRAL NERVOUS SYSTEM TUMORS
Authors: Saito Tsuyoshi , Ura Ayako , Ashizawa Karin , Hayashi Takuo , Yao Takashi 
Published: November 2024

Abstract
NTRK fusions have been reported to be rare in cancers across various organs, except for certain types of tumors. NTRK fusion positive tumors are reported to be highly sensitive to TRK inhibitors such as Larotrectinib and Entrectinib. It is very important to identify patients who may have benefit from these inhibitors. In central nerve system (CNS) tumors, especially gliomas, the frequency of NTRK fusions has been reported to be approximately 2%, however, the frequency of NTRK fusions in CNS tumors of Japanese patients is unknown. Pan-trk IHC is useful to identify NTRK fusion tumors, however, the physiological expression of trks in neural tissues hamper the identification of CNS tumors with NTRK fusion by IHC. In this study, we employed quantitative PCR (qPCR)-based screening system of NTRK fusions in CNS tumors by evaluating the imbalanced expression of NTRK1-3. We performed Real-time qPCR for NTRK1, NTRK2 and NTRK3 in 390 cases of Japanese CNS tumors. Primers and probes were designed to recognize each 5’-side and 3’-side of NTRK1-3. Cases with imbalanced expression for either NTRK1-3 were further analyzed using NanoString gene expression assay containing probes for each 5’-side and 3’-side of NTRK1-3. Cases showing imbalanced expression were sent for target RNA sequences. We found a glioblastoma (GB) case (1%) with CKD5RAP2(ex22)-NTRK2(ex14) in-frame fusion among 96 consecutive Japanese GBs, and another GB with BCR(ex1)-NTRK2(ex10) out-of-frame fusion. NTRK fusion positive rate of glioblastoma in this study was similar to that of previous studies (1.1-2.6%). Imbalanced gene expression-based screening was considered to be useful to detect NTRK fusion in CNS tumors.
10016- NI-2 RADIOMICS ANALYSIS OF NON-ENHANCING LESIONS AFTER BEVACIZUMAB ADMINISTRATION IN RECURRENT GLIOBLASTOMA
Authors: Sanada Takahiro , Sato Hirotaka , Shimizu Takeshi , Saito Masato , Mitsui Nobuyuki , Hiroshima Satoru , Tanino Mishie , Kinoshita Manabu 
Published: November 2024

Abstract

INTRODUCTION
Identifying non-enhancing lesions (nCETs) in glioblastomas within the high-intensity area on T2/FLAIR is challenging. Bevacizumab (BEV) administration can reduce the size of contrast-enhancing lesions (CETs), which may correspond to the nCET. Elucidating these imaging features could enable visualization of non-enhancing lesions in glioblastomas. The current study aimed to investigate imaging features useful for identifying nCET by performing radiomic analysis on areas where CETs were transformed into nCET after BEV administration.

MATERIALS AND METHODS
The study included 25 patients with recurrent glioblastoma in which contrast-enhancing lesions on contrast-enhancing T1-weighted images shrank after BEV administration at the Asahikawa Medical University Hospital. FLAIR images, T2-weighted images, and ADC images were linearly transformed to the standard brain coordinate system with recommended signal correction. Regions of interest were defined as non-contrast T2/FLAIR areas (T2FL-H) before BEV administration (Pre-BEV) and reduced contrast enhancement areas (nCET) after BEV administration (Post-BEV). A total of 147 image features were extracted from Pre-BEV FLAIR images, T2-weighted images, and ADC images with T2FL-H and Post-BEV with nCET. The relationship between each imaging feature and T2FL-H or nCET was investigated.

RESULTS
Univariate analysis showed 81 statistically significant imaging features (p&lt;0.05). FLAIR_GLRLMRln_SD exhibited the highest ability to discriminate between T2FL-H and nCET (n=40, AUC=0.9825, p&lt;0.0001). An ideal cut-off for detecting nCET was FLAIR_GLRLMRln_SD &lt; 332.4-354.0, with a sensitivity of 95% and specificity of 95%.

CONCLUSION
FLAIR_GLRLMRln_SD was able to most accurately identify areas where the contrast effect disappeared after BEV administration. It may be possible to accurately detect the nCET in glioblastomas by applying this image feature.
10122- NI-9 DEEP-LEARNING-BASED RECONSTRUCTION OF DIFFUSION WEIGHTED IMAGES OF MALIGNANT BRAIN TUMORS.
Authors: Sakaguchi Yusuke , Takahashi Satoshi , Ishiguro Naoaki , Suzuki Yuichi , Takami Hirokazu , Takahashi Masamichi , Takayanagi Shunsaku , Miyake Mototaka , Nomura Masashi , Kitagawa Yosuke , Tanaka Shota , Narita Yoshitaka , Saito Nobuhito , Hamamoto Ryuji 
Published: November 2024

Abstract

BACKGROUND
Diffusion Kurtosis Imaging (DKI) is increasingly used to diagnose malignant brain tumors by assessing non-Gaussian diffusion of water molecules, reflecting tissue microstructure. It aids in preoperative molecular classification and infiltration identification. However, its time-consuming process and complex analysis, requiring Diffusion Weighted Images (DWI) at b=0 and at least two distinct non-zero b-values across 15 axes, hinder its clinical adoption. This study aims to simplify this by using deep learning to reconstruct DWI (b=2000) from DWI (b=0, 1000).

MATERIALS & METHODS
We analyzed 157 malignant brain tumor cases from the University of Tokyo Hospital (2016-2023) using the ResViT model for reconstructing high-accuracy medical images, performing 5-fold cross-validation on 282,600 DWI sets. The reconstructed images were evaluated with the Structural Similarity Index Measure (SSIM) and Peak Signal-to-Noise Ratio (PSNR).

RESULTS
Reconstructed images showed SSIM and PSNR values of 0.956±0.007 and 31.46±1.05, respectively.

DISCUSSION
The deep learning-reconstructed DWI (b=2000) images were comparable to prior studies, suggesting potential for reduced DKI imaging time.
10137- ML-3 HIGH-DOSE CHEMOTHERAPY AND AUTOLOGOUS STEM-CELL TRANSPLANTATION (HDC-ASCT) FOR THE PATIENTS WITH PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA (PCNSL)
Authors: Miyakita Yasuji , Yanagisawa Shunsuke , Ohno Makoto , Takeda Wataru , Fukuda Takahiro , Narita Yoshitaka 
Published: November 2024

Abstract
High-dose chemotherapy and autologous stem-cell transplantation (HDC-ASCT) for the patient with primary central nervous system lymphoma (PCNSL) has been used as treatment at relapse or as consolidation therapy. We report on the efficacy, safety, and future issues of HDC-ASCT. Sixteen patients with PCNSL (12 males and 4 females) underwent HDC-ASCT, ranging in age from 45 to 66 years (median 60 years) and KPS from 60 to 100 (median 90) at the time of HDC-ASCT. HDC-ASCT was performed at the time of consolidation therapy (without radiation) in 11 patients, at first recurrence in 3 (including 1 without radiation), and at second recurrence in 2. The main medical care was provided by the Department of Neurosurgery and Neuro-Oncology (NSNO) from PCNSL diagnosis to just before transplantation, HDC-ASCT by the Department of Hematopoietic Stem Cell Transplantation (HSCT), and after discharge by the Department of NSNO. The conditioning regimen consisted of busulfan 3.2mg/kg/day for 4 days and thiotepa 5mg/kg/day for the 2 following days, followed by ASCT. The observation period after HDC-ASCT ranged from 4.1 to 63.5 months (median 16.1 months), and the hospitalization period for HDC-ASCT ranged from 23 to 42 days (median 33 days), with no serious complications. All patients have returned to society and there have been no deaths to date, but one patient died and one patient relapsed afterwards. HDC-ASCT in PCNSL is an important option to improve outcomes. Sixteen patients who underwent HDC-ASCT at our hospital had good outcomes with no serious side effects. Therefore, it is important to have sufficient cooperation and communication among the departments from the biopsy of tumor diagnosis to the post-transplantation period, and it is essential to be fully aware of the roles of each department in the treatment.
10206- ML-10 CLINICAL SIGNIFICANCE OF CEREBROSPINAL FLUID IL-6 AND IL-10 IN PATIENTS WITH CENTRAL NERVOUS SYSTEM MALIGNANT LYMPHOMA
Authors: Sasayama Takashi , Yamanishi Syunsuke , Nagashima Hiroaki , Ikeuchi Yusuke , Tanaka Kazuhiro , Nishihara Masamitsu 
Published: November 2024

Abstract

INTRODUCTION
In primary central nervous system lymphoma (PCNSL), various cytokines and chemokines are known to be elevated in cerebrospinal fluid (CSF). In this study, we investigated the relationship between CSF IL-10 and IL-6 concentrations and prognosis.

METHODS
The patients with PCNSL who underwent treatment with MTX from 2008 to 2024 were analyzed. IL-10, IL-6, b2-microglobulin (MG), and sIL-2 receptor (sIL-2R) were measured preoperatively. we analyzed the relationship between CSF concentration d each cytokines and overall survival (OS) or progression-free survival (PFS).

RESULTS
A total of 67 patients (38 males, 29 females) were included, with an average age of 66 years and an average KPS of 72. Thirty-six patients received MTX + RT therapy, and 31 patients received R-MPV therapy. CSF IL-10, IL-6, b2-MG, and sIL-2R levels were 505&plusmn2133pg/ml, 20.5&plusmn40.4pg/ml, 4059&plusmn:1730ug/l, and 377&plusmn621U/ml, respectively. When the cutoff value for IL-6 was set at 8pg/ml, the PFS was significantly longer in the high CSF IL-6 group than in the low CSF group (p=0.026). When the cutoff value for IL-10 was set at 80pg/ml, the high CSF IL-10 group tended to have a longer PFS than the low CSF group (p=0.06). Multivariate analysis of PFS revealed that CSF IL-6 (p=0.0003), CD10 expression (p=0.0078), and pretreatment KPS (p=0.026) were significant prognostic factors. Multivariate analysis of OS revealed that CSF IL-6 (p=0.015), CD10 expression (p=0.043), and treatment (p=0.046) were significant prognostic factors, with CSF IL-6 being a significant prognostic factor for both OS and PFS.

CONCLUSION
Patients with high CSF IL-6 concentrations had significantly longer survival times, but CSF IL-10 was not. IL-6 is a proinflammatory cytokine with diverse effects, and PCNSL with high IL-6 levels may be more responsive to treatment.
10286- ML-16 RMPV REMISSION INDUCTION/MAINTENANCE THERAPY FOR ELDERLY PATIENTS WITH CENTRAL NERVOUS SYSTEM LYMPHOMA
Authors: Ehara Takuro , Shirahata Mitsuaki , Suzuki Tomonari , Takayanagi Syunsaku , Mishima Kazuhiko 
Published: November 2024

Abstract

OBJECTIVE
To evaluate the outcomes of RMPV (rituximab, methotrexate, procarbazine, vincristine) remission induction and maintenance therapy without whole brain irradiation for elderly patients with CNS lymphoma.

METHODS
CNS lymphoma patients aged 65 years or older who started treatment at our institution between November 2016 and November 2023 were included. Eight cycles of RMPV therapy were given every 2-4 weeks as remission induction, and in patients who reached remission, RMPV therapy was continued every 8 weeks for 2 years as maintenance therapy. Drug doses were reduced according to the adverse events according to the protocol. The endpoints were overall survival (OS), progression-free survival (PFS), adverse events (AE), Karnofsky Performance Status (KPS), Mini-Mental State Examination (MMSE), Best response.

RESULTS
43 patients (38 primary CNS lymphoma, 5 secondary CNS lymphoma), median age 73 years (66-84), median PFS 19.5 months, median OS 51.2 months, median KPS before treatment 60 (40-80), median after remission 80 (40-100), MMSE averaged 18 (8-27) before treatment and 25 (13-30) after treatment, and the best response was complete response in 31 patients (72.1%). AEs requiring reduction or discontinuation of treatment were drug eruption in 6 patients, renal dysfunction in 4, peripheral neuropathy in 7, hemopenia in 7, depression in 1, gastrointestinal bleeding in 1, and severe infection in 3.