bluuebunny/crossref_metadata_2025 huggingface dataset:
ED-1 PITUITARY TUMORS IN 5TH WHO CLASSIFICATION 2022: WHAT DO YOU MEAN BY PITNET?
Authors: Osamura Robert Y
Published: December 2023

It has been well known that the terminology has been changed from pituitary adenoma(4th WHO) which means benign epithelial tumors to pituitary neuroendocrine tumor(5th WHO 2022). It is apparent that the anterior pituitary cells and derived tumors contain intracytoplasmic neurosecretory granules and belong to neuroendocrine cells, and naturally neuroendocrine tumors. The pancreatic and gastrointestinal neuroendocrine neoplasms(NEN) are composed of well differentiated neuroendocrine tumors(NET) and poorly differentiated neuroendocrine carcinoma(NEC). NETs are potentially malignant(metastatic) tumors and are further graded to G1,G2,G3 by proliferative activities(mitoses or Ki-67 indices) showing correlation with prognosis . PitNET which means pituitary NET is now classified by transcription factors(PIT1,TPIT,SF1) and some tumors show clinical symptoms,(hormone production) invasive growth and rarely metastasize indicating potential malignant behavior. From this broad biological spectrum of PitNET, ICD-O coding /3(primary malignancy) has been proposed(5th WHO CNS, Pediatrics and Endocrine volumes). It has been known that some histological patterns (Sparsely granulated somatotroph PitNET, Crooke cell PitNET and others) are related more aggressive growth of PitNETs, but metastatic behavior is very hard to predict histologically. So in WHO 4th edition, the term pituitary carcinoma was used only after confirming metastasis or remote spread. The metastatic tumors are now called metastatic PitNETs. Five tiered grading by proliferation and invasion has been also proposed(Trouillas). Now we need more updated genomic studies such as single cell RNA sequencing to clarify biologic behavior of the individual PitNET cells to further clarify the their nature. . In my talk, several points of interests regarding PitNETs will be discussed by demonstrating histology and biology of representative cases.
10001-ACT-1 A MULTICENTER EXPLORATORY PHASE II STUDY OF NEOADJUVANT BEVACIZUMAB FOR NEWLY DIAGNOSED MALIGNANT GLIOMA - THE SECOND REPORT
Authors: Tanaka Toshihide , Tamura Ryota , Takei Jun , Morimoto Yukina , Teshigawara Akihiko , Tohmoto Kyoichi , Kuranari Yuki , Imai Ryotaro , Yamamoto Yohei , Hasegawa Yuzuru , Akasaki Yasuharu , Murayama Yuichi , Miyake Keisuke , Sasaki Hikaru
Published: December 2023

BACKGROUND

Preoperative bevacizumab (Bev) is a standard treatment strategy for colorectal cancers, but not malignant gliomas. This multi-institutional phase I/II study was conducted to confirm the safety and explore the clinical utility of preoperative Bev for newly diagnosed glioblastoma (GB).

METHODS

Patients were enrolled based on magnetic resonance imaging (MRI) findings typically suggestive of GB. Preoperative Bev and temozolomide (TMZ) were administered at doses of 10 mg/kg on day 0 and 150 mg/m2 on days 1-5, respectively. Surgical resection was performed between days 21 and 30, inclusive. The initial safety evaluation was performed for the initial 7 cases and efficacy was evaluated in a total of 15 cases by progression-free survival (PFS), changes in tumor volume, Karnofsky Performance Scale (KPS) and Mini-Mental State Examination (MMSE) scores after preoperative therapy.

RESULTS

The study protocol was judged as acceptable. Tumor resection was performed on a mean of day 23.7. Pathological diagnosis was GB, isocitrate dehydrogenase (IDH)-wildtype in 14 cases and GB, IDH-mutant in 1 case, according to the WHO 2016 criteria. Severe adverse events possibly related to preoperative Bev and TMZ were observed in 2 of the 15 patients, as wound infection and postoperative hematoma and thrombocytopenia. KPS and MMSE scores were significantly improved with preoperative therapy. Tumor volume was decreased in all but one case on T1-weighted imaging with contrast-enhancement (T1CE) and in all cases on fluid-attenuated inversion recovery, with mean volume decrease rates of 36.2% and 54.0%, respectively. Tumor volume decrease rate on T1CE and PFS tended to correlate. Median PFS and overall survival were 9.5 months and 16.5 months, respectively.

CONCLUSIONS

Preoperative Bev and TMZ is confirmed to be safe. The strategy might be useful for GB in some patients, not only reducing tumor burden, but also improving patient KPS preoperatively.
10007-ACT-2 FIRST IN HUMAN STUDY OF DSP-0390, AN ORAL EMOPAMIL BINDING PROTEIN (EBP) INHIBITOR, IN RECURRENT HIGH-GRADE GLIOMA (HGG): PRELIMINARY RESULTS
Authors: Arakawa Yoshiki , Goldlust Samuel A , Colman Howard , Reardon David A , Welch Mary R , Yamaguchi Shigeru , Butowski Nicholas A , Li Jian , Iino Shuichi , Song Gregory , Jackman Aimee , Xie Yuran , Wagle Marie-Claire , Lebedinsky Claudia , Narita Yoshitaka
Published: December 2023

BACKGROUND

Cholesterol in the brain is derived wholly from de novo biosynthesis as the blood-brain barrier prevents uptake from the circulation. The overexpression of cholesterol synthesis genes is associated with decreased survival in glioblastoma (GBM), suggesting that gliomas may be sensitive to the inhibition of cholesterol biosynthesis. DSP-0390 is an investigational small molecule that inhibits EBP, a key enzyme in cholesterol biosynthesis. Preclinical studies demonstrated antitumor activity of DSP-0390 in orthotopic xenograft GBM models.

METHODS

This phase I dose escalation study aims to assess the safety, PK, PD, and preliminary antitumor activity of oral DSP-0390 monotherapy for recurrent HGG (NCT05023551). Key eligibility criteria include histologically confirmed grade III or IV glioma (WHO 2016); treatment with ≥1 prior therapy; no treatment options beyond standard of care; KPS ≥70.

RESULTS

As of 9 May 2023, 24 patients (37.5% women) were enrolled across 6 dose levels (20 mg QD to 240 mg QD) with a median age of 51 years (range 24-76) including 17 (70.8 %) with GBM, 3 (12.5%) with anaplastic astrocytoma and 2 (8.3%) with anaplastic oligodendroglioma. Ten patients (41.7%) had IDH mutant tumors. Four patients (16.7%) were on stable dose of corticosteroids at baseline, of which 2 were able to discontinue or dose reduce the corticosteroid while on DSP-0390. There were no reported DLTs. The most common treatment-related TEAEs included grade 1 or 2 nausea (7 patients [29.2%]) and alanine aminotransferase increased (6 patients [25.0%]). Only one grade 3 related AE (dry skin) was noted. Two patients with IDH mutant grade 3 glioma had tumor reduction and remain on DSP-0390 for ≥9 months. Dose dependent changes in PK and PD were observed.

CONCLUSIONS

DSP-0390 has been well tolerated to date with dose escalation ongoing. A dose response relationship was observed between PK and PD biomarkers.
10021-IMT-1 A ROLE OF DENDRITIC CELL IMMUNOTHERAPY AS A MODALITY IN MULTIDISCIPLINARY THERAPY FOR GLIOBLASTOMA
Authors: Akasaki Yasuharu , Takei Jun , Yamamoto Yohei , Tanaka Toshihide , Teshigawara Akihiko , Kamata Yuko , Ohara Keiichiro , Nawate Shohei , Suzuki Tomoya , Yanagisawa Takaaki , Murayama Yuichi
Published: December 2023

We are conducting a clinical study of immunotherapy using tumor-fused dendritic cells (TFDC) as a modality of multidisciplinary treatment for patients with glioblastoma (GBM). In this study, we analyzed the additional effect of TFDC-immunotherapy for standard therapy. Newly diagnose GBM patients who treated at four of Jikei University Hospitals were analyzed in this study. Adjuvant therapy after tumor removal surgery was maintained according to the Supp's regimen. Bevacizumab (10 mg/kg, every 2 weeks) was added when a recurred tumor was confirmed. TFDC vaccine was generated from cultured tumor cells derived from autologous surgical specimen and dendritic cells from peripheral blood, and were subcutaneously administered in the cervical region for 3-14 times. All patients who had not participated in any other immunotherapy-related clinical studies were compared as a control group in a Propensity score matching analysis. The number of analyzed patients was 55 in the immunotherapy group and 35 in the control group. The 2-year survival rate and 5-year survival rate were 20.9% and 0% in the control group, respectively, while the immunotherapy group was 45.7% and 22.7%, respectively. A statistically significant difference in overall survival was observed between them (p=0.0045). There was no difference in the observed adverse events in the two groups. Specific adverse events for TFDC-immunotherapy was not observed. In the biomarker analysis, low HLA-A expression and lack of CCDC88A, KRT4, TACC2, and TONSL mutations in tumor cells were suggested as biomarkers of better prognosis. We are currently analyzing IDH profile in those patients for further analysis. TFDC-immunotherapy should be adopted as one of the modality of multidisciplinary treatments for GBM because it is expected to have some additional effects for standard therapeutic reagents without adversely affecting them. Since there are a certain number of poor responders for this immunotherapy, predictive biomarkers of therapeutic efficacy are awaited.
10111-MPC-11 CLINICAL AND MOLECULAR NEUROPATHOLOGICAL FEATURES OF EPITHELIOID GLIOBLASTOMA
Authors: Adachi Junichi , Shirahata Mitsuaki , Suzuki Tomonari , Mishima Kazuhiko , Sasaki Atshushi , Nishikawa Ryo
Published: December 2023

BACKGROUND

Epithelioid Glioblastoma (E-GBM) has been identified as a pathological subtype of Glioblastoma. It is a rare glioblastoma and is mainly known in case reports, and the details of its clinical features and genetic characteristics are not clear. Here, we retrospecivly studied the results of clinical course and genetic features of E-GBM.

METHODS

Four patients who underwent surgery at our institution and were diagnosed with E-GBM were included in this study. Histological diagnosis was obtained by surgical excision in all cases. We extracted DNA from the resected tissues and analyzed glioma-related genes using various methods such as high resolution melting (HRM), MGMT methylation-specific HRM, digital PCR, and Multiple ligation-dependent probe amplification (MLPA) analysis. Moreover, we assayed methylation EPIC BeadChip arrays for each sample.

RESULTS

E-GBM tended to develop at a slightly younger age than other general glioblastoma. All patients underwent surgical resection followed by radiation therapy and concurrent temozolomide therapy. However, none of the patients were able to transition to temozolomide maintenance therapy due to disease progression, and the overall survival period was 8 to 19 weeks, indicating an extremely poor prognosis. Genetic analysis revealed both TERT promoter mutations and BRAFV600E mutation in all cases. In addition, IDH mutation was not found, and MGMT promoter methylation was unmethylated in all cases. EGFR amplification, CDKN2A/2B homozygous deletion and 1p/19q co-deletion were not found in any cases. Methylation-based classification did not reach E-GBM in all samples.

CONCLUSION

The simultaneous mutations of TERT promoter with BRAFV600E could serve as diagnostic molecular markers for the diagnosis of E-GBM. Standard therapy for glioblastoma was not expected to be effective in treating this tumor. It was considered necessary to introduce new therapeutic strategies such as early administration of BRAF and MEK inhibitors.
10114-GMC-10 EXPERIENCE WITH DIFFERENTIAL NTRK2 FUSION GENE DETECTION IN CANCER MULTI-GENE PANEL TESTING
Authors: Muto Jun , Sugihara Eishi , Tsukamoto Kentaro , Yamada Eiji , Sudo Tamotsu , Saya Hideyuki , Hirose Yuichi
Published: December 2023

INTRODUCTION

NTRK fusion gene-positive CNS tumours are rare and there are only two reports in Japan of the use of entrectinib, both in children; This is third case and the first adult case was experienced; the patient was treated by taking entrectinib. The diagnosis and treatment course are reported here and the problems with current oncopanel testings are discussed.

CASE

Female in her 60s. She came to the hospital on her own with a chief complaint of unstable walk. A mass with a maximum diameter of 8 cm was found in the right temporal occipital lobe. She underwent craniotomy followed by radiotherapy, and in-house panel testing (PleSSision Rapid Neo) detected two BCR-NTRK2 fusion genes. Subsequently, no NTRK gene abnormalities were detected in the foundation-one. Sanger sequencing was performed by ourselves, which could still detect gene mutations, and the patient was submitted to the NCC Onco-Panel at his own expense, where NTRK fusion gene abnormalities could be detected, and after review by the in-house ethics committee, he was started on entrectinib. The tumor showed a shrinking effect and has been stable for eight months.

RESULT

In the in-house panel test, NTRK2 covered Intron8,9,10,11,12 and two BCR-NTRK2 fusion genes were detected, (Exon1-Exon13) and (Exon1-Exon12). Foundation one covered Intron12 and no genetic variants were detected this time. Subsequently, the NCC OncoPanel test covered Intron 9, 10, 12, 13 and 14 and was able to detect fusion gene mutations. Different results were obtained for NTRK2 fusion gene mutations in each panel test, with different detection coverage. The differences in NTRK fusion gene mutations between tests indicate that it is important to reconfirm which panel test to choose.

CONCLUSION

Third case in Japan and first adult case of NTRK fusion gene mutation-positive brain tumor; may need to be addressed in NTRK fusion gene detection, recognizing differences in cancer multi-gene panel testing.
10179-NI-8 CLINICORADIOLOGICAL CHARACTERISTICS OF H3 K27-ALTERED THALAMIC GLIOMAS
Authors: Hayashi Nobuhide , Fukai Junya , Nakatogawa Hirokazu , Kawaji Hiroshi , Okita Yoshiko , Kijima Noriyuki , Shofuda Tomoko , Yoshioka Ema , Kanematsu Daisuke , Katsuma Asako , Sumida Miho , Nakao Naoyuki , Mori Kanji , Kanemura Yonehiro
Published: December 2023

BACKGROUND

Diffuse midline glioma (DMG), H3 K27-altered (CNS WHO grade 4, 2021), exhibits diverse imaging features, and its characteristics have not yet been established.

METHODS

We retrospectively analyzed the imaging features and progression patterns of cases with H3p.K27M mutation in the thalamus, as part of the Kansai Molecular Diagnosis Network for CNS Tumors.

RESULTS

Among the H3p.K27M mutation cases accumulated from May 2007 to July 2022 (total 109 cases), 47 cases were located in the thalamus. The main tumor location was as follows: right side 23 cases, left side 19 cases, bilateral 4 cases and unknown 1 case. The tumor border was well-defined in 18 cases (38.3%), indistinct in 26 cases (55.3%), and uncertain in 3 cases (6.4%). Contrast enhancement was observed in 36 cases (76.6%), necrosis in 29 cases (61.7%), cyst formation in 11 cases (23.4%), peritumoral brain edema in 15 cases (31.9%), ventricular enlargement in 28 cases (59.6%), and evidence of cerebrospinal fluid dissemination on imaging in 8 cases (17.0%). The degree of tumor progression from the main tumor to the surrounding area was scored from 1 to 5 (mean: 3.5, median: 4).

SURVIVAL RESULTS

Among 43 cases with confirmed overall survival (OS) and progression-free survival (PFS), the median OS was 19.2 months (95% CI: 13.2-25.2), and the median PFS was 9.8 months (95% CI: 5.4-14.2). In univariate analysis, favorable prognostic factors were preoperative KPS 80 over(p = 0.007), and tumor progression score of 2 or less (p = 0.01). However, in multivariate analysis, only a tumor progression score of 2 or less remained the sole independent factor (p = 0.03, HR: 3.89, 95% CI: 1.14-13.3).

DISCUSSION AND CONCLUSION

A large-scale prospective study is needed, but in H3 K27M-mutant thalamic gliomas, the extent of tumor progression before surgery may be a prognostic factor.
10181-STMO-9 EFFECT OF INTRAOPERATIVE VENTRICULAR OPENING ON RECURRENCE PATTERNS FOLLOWING BCNU WAFER IMPLANTATION FOR NEWLY DIAGNOSED MALIGNANT GLIOMA
Authors: Yamada Kengo , Matsuda Ryosuke , Maeoka Ryosuke , Yokoyama Shohei , Kotsugi Masashi , Tamura Kentaro , YAMADA Shuichi , Nishimura Fumihiko , Nakagawa Ichiro , Boku Eishu
Published: December 2023

To evaluate the effect of ventricular opening (VO) on recurrence patterns in patients with newly diagnosed malignant glioma treated with bis-chloroethyl-nitrosourea (BCNU) wafer implantation. This single-center retrospective study included 45 patients with newly diagnosed malignant glioma who received BCNU wafer implantation after tumor resection between March 2013 and December 2021. The patients were categorized into two groups based on whether VO occurred during the malignant glioma resection. While 20 patients received VO, 25 did not receive VO. Recurrence patterns classified as local, diffuse, distant, or multifocal and time to recurrence were compared between patients with and without VO. Median survival time was comparable between patients with VO and patients without VO (32 months vs. 26 months, p = 0.95). Recurrence occurred in 28/46 patients (60.8%) in entire cohort. The incidence of recurrence was comparable between patients with VO and patients without VO (12 [60%] vs. 16 [64%], p = 1.0). No significant differences were seen between the two groups in time to recurrence (p = 0.657) or recurrence patterns (p = 0.13). Ventricular opening during surgery with BCNU wafer implantation does not seem to influence the recurrence patterns. Ventricular opening does not induce distant recurrence if appropriate ventricular closure is performed.
10190-MPC-14 ANALYSIS OF GENETIC ABNORMALITIES IN TERTP-WILDTYPE MOLECULAR GBM
Authors: Ogawa Takahiro , Takahashi Yoshinobu , Taniyama Ichita , Yamanaka Takumi , Hashimoto Naoya
Published: December 2023

Glioblastoma (GBM) is frequently linked to TERTp mutations. However, even in cases without these mutations, genetic alterations such as EGFR amplification or chromosome7 amplification/ chromosome10 deletion can lead to GBM diagnosis. In this study, we compared genetic differences between these molecularly characterized GBM (molGBM) cases and GBM cases without these features, focusing on 26 GBM cases lacking IDH and TERTp mutations from January 2016 to February 2022. Using Multiplex Ligation-dependent Probe Amplification (MLPA), we examined copy number changes in key genes (PDGFRA, EGFR, CDKN2A, PTEN, TP53, CDK4, MIR26A2, MDM2, NFKBIA). The thresholds for copy number changes were homozygous deletion (x≤0.4), loss of heterozygosity (LOH) (0.4<x≤0.7), gain (1.3≤x<2.0), amplification (x≥2.0). If PTEN LOH was present, it was considered chromosome10 deletion. Among the 26 cases, three were diagnosed as molGBM: two with EGFR amplification and one with chromosome7 amplification/ chromosome10 deletion. The remaining 23 had pathological GBM diagnoses. Notably, some cases showed amplifications in PDGFRA, CDK4, and MIR26A2, as well as LOH in TP53. In the control group, amplifications in PDGFRA, CDK4, MIR26A2, and LOH in TP53, CDKN2A, and MIR26A2 were observed. The genetic abnormalities observed in the molGBM group were similar to those in the control group. Further studies should clarify the correlation between these genetic abnormalities and the molecular GBM signature and their clinical significance.
10210-STMO-13 CLINICAL AND GENETIC ANALYSIS OF ADULT THALAMIC GLIOMAS - SIGNIFICANCE OF H3K27M AND TERT MUTATIONS
Authors: Tsuzuki Shunsuke , Nitta Masayuki , Muragaki Yoshihiro , Saito Taiichi , Maruyama Takashi , Kouriyama Shunichi , Ro Buntou , Kawamata Takakazu
Published: December 2023

Adult thalamic glioma (ATG) is a rare but deep lesion that is difficult to remove and often refractory to treatment. The diffuse midline glioma (DMG), H3K27M-mutant, newly introduced in the WHO 2016 classification, constitutes part of ATG, but the significance of H3K27M mutations in adult ATG and the prognosis of thalamic DMG are variable and inconsistent among reports. We retrospectively analyzed clinical, pathological, and molecular characteristics of 45 consecutive ATG cases operated on at our institution from 2007 to 2022, and examined outcomes and prognostic factors. The median age was 45 years (range, 18-74), median preoperative KPS was 70% (range, 40-100), median maximum tumor diameter on MRI was 37 mm (range, 22.6-62.6), Gd contrast was present in 31, and bilateral disease was present in 8 patients. 31 patients underwent resection and 14 underwent biopsy. Differences in the surgical approach did not affect OS. WHO G2: 2, G3: 7, and G4: 36, and all IDH wild-type. The mPFS for all patients was 9.5 months and mOS was 26.0 months; G4 consisted of 19 DMG and 17 GBM with mOS of 30.4 months DMG vs. 12.4 months GBM (P=0.012). Analysis of all cases showed a trend toward better prognosis for H3K27M mutation cases (P=0.118), while TERT was significantly worse for the mutation type with 29.2 months for wild type vs. 9.3 months for the mutation type (P=0.026). In univariate analysis, age and TERT mutation status were prognostic factors for OS, and in multivariate analysis, WHO grade was a prognostic factor for OS in addition to these factors. In the past literature of pediatric cases, H3K27M mutation was often reported as a prognostic factor, but in the present study, TERT mutation was the prognostic factor, suggesting that the significance of H3 mutation in thalamic gliomas in adults and children is different.
10221-ML-11 A CASE OF PRIMARY CENTRAL NERVOUS SYSTEM ADULT T CELL LEUKEMIA
Authors: Seiya Yosuke , Sasaki Nobuyoshi , Kobayashi Makoto , Hidaka Rei , Saito Kuniaki , Hibiya Takashi , Yamagishi Yuki , Ikeda Kensuke , Kobayashi Keiichi , Komori Takashi , Nakatomi Hirofumi , Takayama Nobuyuki , Shibahara Junji , Nagane Motoo
Published: December 2023

Adult T cell leukemia (ATL) manifesting only in the central nervous system (CNS) at presentation is rare. We present a case of primary CNS ATL. 54 year old male presenting with multiple enhanced lesions in the cerebrum went under biopsy and was diagnosed as T-cell lymphoma. While systemic workup was negative, human T-cell leukemia virus type 1 (HTLV-1) antibody was found to be seropositive. Southern blotting using peripheral blood DNA revealed positivity for clonal proliferation of HTLV-1 infected cells. He was therefore clinically diagnosed as primary CNS ATL. He received chemotherapy using methotrexate, procarbazine and vincristine (MPV), and gained a complete response unconfirmed (CRu) after completion of four cycles. However, relapse occurred after the fifth cycle of MPV. Salvage treatment using etoposide, cisplatin, cytarabine and prednisone (ESHAP), whole brain radiation therapy, and lenalidomide, were delivered as second, third, and fourth line therapies, but were ineffective and disease continued to progress. He was therefore treated by best supportive care. Primary CNS ATL should be considered in the differential diagnosis of brain tumors. Southern blotting using peripheral blood might be useful for clinical diagnosis in such cases.
10223-ML-12 SYSTEMIC RELAPSE OF PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA
Authors: Miyakita Yasuji , Ohno Makoto , Takahashi Masamichi , Yanagisawa Shunsuke , Narita Yoshitaka
Published: December 2023

PCNSL remains a poor prognosis, with many patients relapsing despite induction high-dose MTX-based chemotherapy and subsequent maintenance therapy. Most recurrences occur in the brain parenchyma, but in rare cases, systemic relapse may occur. We report the clinical and pathological features of the patients with systemic relapse of PCNSL. We examined 165 PCNSLs treated at our hospital since 2005. 102 of the 165 had recurrence, and 11 of these were diagnosed as systemic relapse. The 11 patients at the time of initial diagnosis had 8 males and 3 females, age 49-81 years (median 67), and KPS 50-90 (median 70). The 11 patients at the time of recurrence had age 62-66 years (median 71), KPS 50-100 (median 60), and the sites of recurrence were abdominal lymph nodes in 3 patients, gastrointestinal tract in 3, pleural effusion in 3, and others in 2. The time to systemic relapse ranged from 11.3 to 156.1 months (median 36.4), survival after recurrence ranged from 0.1 to 89 months (median 16.1), and overall survival ranged from 16.5 to 192 months (median 66.5). Tissue sampling at relapse was performed in 9 patients, 8 of whom had DLBCL. Recurrence of PCNSL is often in the brain, and although recurrence outside the CNS occurs in less than 10%, careful follow-up is necessary. Although it has been reported that recurrence in the testes and breast is common, in our case, recurrence in lymph nodes and pleural effusions was common, and genetic histological evaluation, including discussion of the difference from the primary CNS, is considered necessary. Although the prognosis and KPS of PCNSL are poor, there are cases in which a good condition can be maintained with reliable diagnosis and treatment. Detailed clinical information, including genetic analysis at the time of initial onset and at the time of recurrence, is needed.
Ageism Without Anticipation-Blindness
Authors: Andersen Martin Marchman , Nielsen Lasse
Published: December 2023

Ageism is the view that it is of greater moral value to allocate health care resources to younger people than to older people. In medical ethics, it is well-known that standard interpretations of distributive principles such as utilitarianism and egalitarianism imply some form of ageism. At times, ethicists argue as if practical complications are the only or main reason for not abiding to ageism. In this article, we argue that inferences to ageism from such distributive principles tend to commit what we call the anticipation-blindness fallacy: A much too narrow focus on life quality benefits of health care treatments inclines us to overlook the importance of life quality benefits of health care safety, that is the mere trust in and expectation of being treated and cared for as one grows old. This is a key omission because health safety has value for a much larger population and for much longer time. Taking health safety into account therefore has important implications as for how ageist we ought to be.
Imagining the Past of the Present
Authors: Windsor Mark
Published: December 2023

Some objects we value because they afford a felt connection with people, events or places connected with their past. Visiting Canterbury cathedral, you encounter the place where, in 1170, Archbishop Thomas Becket was murdered by four knights of Henry II. Knowing that you are standing in the very place where Becket's blood was spilled gives the past event a sense of tangible reality. One feels ‘in touch with’ the past; history seems to ‘come alive’. In this paper, I propose an explanation for the phenomenology of such experiences in terms of an imaginative activity that represents what an object is historically connected with as part of the object in the present. One imagines of the site of Becket's murder Becket being murdered. According to my account, objects that embody their histories are representations in Kendall Walton's sense: they have the function of serving as props in games of make-believe.
A community-based volunteer service to reduce COVID-19 vaccination inequities in New York City
Authors: Tay Ee Tein , Fernbach Madalyn , Chen Haidee , Ng Charis , Tapia Jade , O’Callaghan Stasha
Published: December 2023

Objectives

We describe our experiences and challenges as community volunteers in assisting individuals in scheduling initial COVID-19 vaccine appointments and highlight disparities and barriers in vaccine access in New York City (NYC).

Methods

Priority for assistance was given to individuals who were eligible for vaccination in NYC and New York State with the following barriers: technological, language, medical, physical and undocumented immigrants. Volunteers in NYC performed outreach and created program to assist in scheduling appointments.

Results

In sum, 2101 requests were received to schedule COVID-19 vaccine appointments from 28 February to 30 April 2021. Vaccinations were successfully scheduled for 1935 (92%) individuals. Challenges in this project included limited community outreach, language barriers, transportation difficulties and safety concerns travelling to vaccination sites. Spanish (40.5%) and Chinese (35.6%) were the primary languages spoken by appointment requesters. Most requests came from residents of Queens (40%) and Brooklyn (27.2%).

Conclusions

The older population, public-facing workers, non-English speakers, undocumented immigrants and the medically complicated population experienced challenges in vaccine appointment access. In-person services and early website access in languages in addition to English may have reduced barriers in appointment navigation. While volunteers faced numerous obstacles when assisting individuals in scheduling vaccine appointments, most found the work fulfilling and rewarding.
Associations of DMARDs with post-acute sequelae of COVID-19 in patients with systemic autoimmune rheumatic diseases: a prospective study
Authors: Venkat Rathnam K , Wang Xiaosong , Patel Naomi J , Kawano Yumeko , Schiff Abigail , Kowalski Emily N , Cook Claire E , Vanni Kathleen M M , Qian Grace , Bade Katarina J , Saavedra Alene , Srivatsan Shruthi , Williams Zachary K , Wallace Zachary S , Sparks Jeffrey A
Published: December 2023

Objective

We investigated the baseline DMARD use and post-acute sequelae of COVID-19 (PASC) risk among patients with systemic autoimmune rheumatic diseases (SARDs).

Methods

Patients with SARDs and confirmed COVID-19 infection at Mass General Brigham completed a survey ≥28 days after a positive PCR/antigen test to prospectively investigate their COVID-19 courses. We investigated DMARD use at COVID-19 onset and PASC risk. PASC was defined as any COVID-19 symptom that persisted for ≥28 days. We used logistic regression to estimate the odds ratios (OR) for PASC by DMARD class. We also used restricted mean survival time to determine the difference in symptom-free days by DMARD class in the 28-day period after infection.

Results

We analysed 510 patients with SARDs and COVID-19 from 11 March 2021 to 17 June 2023; 202 (40%) developed PASC. CD20 inhibitor (CD20i) users had significantly higher odds of developing PASC vs conventional synthetic DMARD (csDMARD) users [adjusted OR (aOR) 2.69 (95% CI 1.23, 5.88)]. IL-12/23, IL-17A or IL-23 inhibitor (IL-12/23i, IL-17Ai, IL-23i) users also had significantly higher odds of PASC [aOR 3.03 (95% CI 1.08, 8.49)]. CD20i users had significantly fewer symptom-free days vs csDMARD users [aOR −4.12 (95% CI −7.29, −0.94)].

Conclusion

CD20i users had significantly higher odds of PASC and fewer symptom-free days over the 28 days following COVID-19 diagnosis compared with csDMARD users. Further research is needed to investigate whether PASC risk in CD20i users may be due to prolonged infection or other immune mechanisms. The association of IL-12/23i, IL-17Ai and IL-23i with PASC calls for additional study.
Which fatigue scale should I use? A Rasch analysis of two fatigue scales in inflammatory conditions
Authors: Bartholomew Emerson J , Medvedev Oleg N , Petrie Keith J , Chalder Trudie
Published: December 2023

Objectives

This study aimed to assess the psychometric properties of two widely used fatigue scales in a sample of patients with inflammatory conditions.

Methods

Rasch analysis was used to examine scale reliability, item bias, unidimensionality and overall fit to the Rasch model. Subtest methodology was utilized to attempt to improve model fit for the Chalder Fatigue Scale (CFQ) and Bristol Rheumatoid Arthritis Fatigue Multidimensional Questionnaire (BRAF-MDQ).

Results

Initial analysis displayed strong reliability (person separation index 0.89–0.96) alongside a lack of item bias in both scales. However, evidence for unidimensionality was not found for either scale. Overall fit to the Rasch model was marginal for the CFQ and misfitting for the BRAF-MDQ. Local dependency was observed as well as significant item misfit for both scales. Subtest modifications resulted in the best model fit for the BRAF-MDQ [χ2(16) = 15.77, P = 0.469] and the CFQ [χ2(25) = 15.49, P = 0.929]. Modifications resulted in improved fit, reductions in measurement error and the production of ordinal-to-interval conversion tables for both scales. Conversion tables apply the benefits of enhanced measurement accuracy, valid comparison of BRAF-MDQ and CFQ scores to other interval-level data, appropriate use in parametric statistics and enhanced precision in clinical cut-off scores—without the need to change administration format.

Conclusion

The BRAF-MDQ and CFQ are valid, reliable tools for fatigue assessment. Psychometric indices and content factors suggest the CFQ is suited to measuring general fatigue, particularly when response burden is a concern, while the BRAF-MDQ should be used in clinical presentations where other symptoms are severe and the impact of fatigue on daily living and emotional and social well-being is of interest.
Entrance surface air kerma to patients during digital radiographic examinations in Tanzania
Authors: Makoba Atumaini , Jusabani Ahmed , Muhogora Wilbroad , Kileo Abdallah , Ndukeki Musa , Makungu Hilda , Maro Haika , Onoka Erick , Ngulimi Miguta , Mammba Huruma , Muhulo Alex , Masoud Ali , Balobegwa Vitus , Ngoye Wilson , Nakembetwa Adam
Published: December 2023

The aim of this study was to determine the entrance surface air kerma (ESAK) in adult patients during digital radiography and to evaluate the optimisation potential in five common X-ray examinations in Tanzania. Based on a sample of 240–610 patients, ESAK was estimated using X-ray tube output measurements, patient information and backscatter factors. The results show that the mean ESAK values were higher or comparable to data from the literature. The diagnostic reference values of ESAK for digital radiography were 0.31 mGy (chest PA), 4 mGy (lumbar spine AP), 5.4 mGy (lumbar spine LAT), 3.8 mGy (abdomen AP) and 2.4 mGy (pelvis AP). For computed radiography, the mean ESAK ranges were 0.44–0.57 mGy (thoracic AP), 3.59–3.72 mGy (lumbar spine AP), 6.16–6.35 mGy (lumbar spine LAT), 3.89–3.44 mGy (abdominal AP) and 2.92–3.47 mGy (pelvic AP). In conclusion, high ESAK variations show the potential for optimising protection in digital radiology.
Job separation and well-being in couples’ perspective in the United Kingdom
Authors: Di Nallo Alessandro
Published: December 2023

The consequences of job uncertainty on well-being are widely known. Yet not all types of job separation might be equally detrimental: the level of expectedness and voluntariness of job ends may shape the consequences on workers and their partners. This article explores the associations of four types of job termination with well-being in a couple’s perspective. Combining two British longitudinal surveys (1991–2021) (N ∼ 13,000 couples), the analyses apply fixed-effects models to estimate deviations of the well-being for workers and partners. Also, the patterns of anticipation and habituation of each episode of job termination are investigated. The results show that events such as dismissals and redundancies—more unanticipated and involuntary—are associated with larger drops in well-being than other more preventable and voluntary causes of job separation. The responses differ between workers and their partners and by gender. Further, anticipation and habituation patterns vary across the types of job separation.
Associations between actigraphy-measured sleep duration, continuity, and timing with mortality in the UK Biobank
Authors: Saint-Maurice Pedro F , Freeman Joshua R , Russ Daniel , Almeida Jonas S , Shams-White Marissa M , Patel Shreya , Wolff-Hughes Dana L , Watts Eleanor L , Loftfield Erikka , Hong Hyokyoung G , Moore Steven C , Matthews Charles E
Published: December 2023

Study Objectives

To examine the associations between sleep duration, continuity, timing, and mortality using actigraphy among adults.

Methods

Data were from a cohort of 88 282 adults (40–69 years) in UK Biobank that wore a wrist-worn triaxial accelerometer for 7 days. Actigraphy data were processed to generate estimates of sleep duration and other sleep characteristics including wake after sleep onset (WASO), number of 5-minute awakenings, and midpoint for sleep onset/wake-up and the least active 5 hours (L5). Data were linked to mortality outcomes with follow-up to October 31, 2021. We implemented Cox models (hazard ratio, confidence intervals [HR, 95% CI]) to quantify sleep associations with mortality. Models were adjusted for demographics, lifestyle factors, and medical conditions.

Results

Over an average of 6.8 years 2973 deaths occurred (1700 cancer, 586 CVD deaths). Overall sleep duration was significantly associated with risk for all-cause (p < 0.01), cancer (p < 0.01), and CVD (p = 0.03) mortality. For example, when compared to sleep durations of 7.0 hrs/d, durations of 5 hrs/d were associated with a 29% higher risk for all-cause mortality (HR: 1.29 [1.09, 1.52]). WASO and number of awakenings were not associated with mortality. Individuals with L5 early or late midpoints (<2:30 or ≥ 3:30) had a ~20% higher risk for all-cause mortality, compared to those with intermediate L5 midpoints (3:00–3:29; p ≤ 0.01; e.g. HR ≥ 3:30: 1.19 [1.07, 1.32]).

Conclusions

Shorter sleep duration and both early and late sleep timing were associated with a higher mortality risk. These findings reinforce the importance of public health efforts to promote healthy sleep patterns in adults.
Interaction between beech and spruce trees in temperate forests affects water use, root water uptake pattern and canopy structure
Authors: Kinzinger Laura , Mach Judith , Haberstroh Simon , Schindler Zoe , Frey Julian , Dubbert Maren , Seeger Stefan , Seifert Thomas , Weiler Markus , Orlowski Natalie , Werner Christiane
Published: December 2023

Beneficial and negative effects of species interactions can strongly influence water fluxes in forest ecosystems. However, little is known about how trees dynamically adjust their water use when growing with interspecific neighbours. Therefore, we investigated the interaction effects between Fagus sylvatica (European beech) and Picea abies (Norway spruce) on water-use strategies and aboveground structural characteristics. We used continuous in situ isotope spectroscopy of xylem and soil water to investigate source water dynamics and root water uptake depths. Picea abies exhibited a reduced sun-exposed crown area in equally mixed compared with spruce-dominated sites, which was further correlated to a reduction in sap flow of −14.5 ± 8.2%. Contrarily, F. sylvatica trees showed +13.3 ± 33.3% higher water fluxes in equally mixed compared with beech-dominated forest sites. Although a significantly higher crown interference by neighbouring trees was observed, no correlation of water fluxes and crown structure was found. High time-resolved xylem δ2H values showed a large plasticity of tree water use (−74.1 to −28.5‰), reflecting the δ2H dynamics of soil and especially precipitation water sources. Fagus sylvatica in equally mixed sites shifted water uptake to deeper soil layers, while uptake of fresh precipitation was faster in beech-dominated sites. Our continuous in situ water stable isotope measurements traced root water uptake dynamics at unprecedented temporal resolution, indicating highly dynamic use of water sources in response to precipitation and to neighbouring species competition. Understanding this plasticity may be highly relevant in the context of increasing water scarcity and precipitation variability under climate change.
Impact of intra-annual wood density fluctuation on tree hydraulic function: insights from a continuous monitoring approach
Authors: Niccoli Francesco , Kabala Jerzy Piotr , Pacheco-Solana Arturo , Battipaglia Giovanna
Published: December 2023

Climate change significantly impacts global forests, leading to tree decline and dieback. To cope with climate change, trees develop several functional traits, such as intra-annual density fluctuations (IADFs) in tree rings. The formation of these traits facilitates trees to optimize resource allocation, allowing them to withstand periods of stress and eventually recover when the conditions become favourable again. This study focuses on a Pinus pinaster Aiton forest in a warm, drought-prone Mediterranean area, comparing two growing seasons with different weather patterns. The innovative continuous monitoring approach used in this study combines high-resolution monitoring of sap flow (SF), analysis of xylogenesis and quantitative wood anatomy. Our results revealed the high plasticity of P. pinaster in water use and wood formation, shedding light on the link between IADFs and tree conductance. Indeed, the capacity to form large cells in autumn (as IADFs) improves the total xylem hydraulic conductivity of this species. For the first time, a continuous SF measurement system captured the dynamics of bimodal SF during the 2022 growing season in conjunction with the bimodal growth pattern observed through xylogenesis monitoring. These results highlight the intricate interplay between environmental conditions, water use, wood formation and tree physiology, providing valuable insights into the acclimation mechanisms employed by P. pinaster to cope with weather fluctuations.
Different EGF‐induced receptor dimer conformations for signaling and internalization
Authors: Haubrich Jordi , Zwier Jurriaan M. , Charrier‐Savournin Fabienne , Prézeau Laurent , Pin Jean‐Philippe
Published: December 2023

The structural basis of the activation and internalization of EGF receptors (EGFR) is still a matter of debate despite the importance of this target in cancer treatment. Whether agonists induce dimer formation or act on preformed dimers remains discussed. Here, we provide direct evidence that EGF‐induced EGFR dimer formation as best illustrated by the very large increase in FRET between snap‐tagged EGFR subunits induced by agonists. We confirm that Erlotinib‐related TK (tyrosine kinase) inhibitors also induce dimer formation despite the inactive state of the binding domain. Surprisingly, TK inhibitors do not inhibit EGF‐induced EGFR internalization despite their ability to fully block EGFR signaling. Only Erlotinib‐related TK inhibitors promoting asymmetric dimers could slow down this process while the lapatinib‐related ones have almost no effect. These results reveal that the conformation of the intracellular TK dimer, rather than the known EGFR signaling, is critical for EGFR internalization. These results also illustrate clear differences in the mode of action of TK inhibitors on the EGFR and open novel possibilities to control EGFR signaling for cancer treatment.
Ablation of placental REST deregulates fetal brain metabolism and impacts gene expression of the offspring brain at the postnatal and adult stages
Authors: Islam Maliha , Samal Ananya , Davis Daniel J. , Behura Susanta K.
Published: December 2023

In this study, the transcriptional repressor REST (Repressor Element 1 Silencing Transcription factor) was ablated in the mouse placenta to investigate molecular and cellular impacts on the offspring brain at different life stages. Ablation of placental REST deregulated several brain metabolites, including glucose and lactate that fuel brain energy, vitamin C (ascorbic acid) that functions in the epigenetic programming of the brain during postnatal development, and glutamate and creatine that help the brain to respond to stress conditions during adult life. Bulk RNA‐seq analysis showed that a lack of placental REST persistently altered multiple transport genes, including those related to oxygen transportation in the offspring brain. While metabolic genes were impacted in the postnatal brain, different stress response genes were activated in the adult brain. DNA methylation was also impacted in the adult brain due to the loss of placental REST, but in a sex‐biased manner. Single‐nuclei RNA‐seq analysis showed that specific cell types of the brain, particularly those of the choroid plexus and ependyma, which play critical roles in producing cerebrospinal fluid and maintaining metabolic homeostasis, were significantly impacted due to the loss of placental REST. These cells showed significant differential expression of genes associated with the metabotropic (G coupled protein) and ionotropic (ligand‐gated ion channel) glutamate receptors, suggesting an impact of ablation of placental REST on the glutamatergic signaling of the offspring brain. The study expands our understanding of placental influences on the offspring brain.
CD30 plays a role in T‐dependent immune response and T cell proliferation
Authors: Cui Dongya , Zhang Yongguang , Chen Liling , Du Hekang , Zheng Baijiao , Huang Miaohui , Li Xinxin , Wei Jianhui , Chen Qi
Published: December 2023

CD30 is a member of the tumor necrosis factor receptor (TNFR) superfamily and expressed in both normal and malignant lymphoid cells. However, the role of CD30 in lymphopoiesis is not known. In this study, we showed CD30 was expressed both in T and B cells, but its deficiency in mice had no effect on T‐ and B‐cell development. In fact, CD30 deficiency attenuated B‐cell response to T‐cell‐dependent antigens. The impaired B cell response in CD30‐deficient mice is caused by the reduction of activation‐induced cytidine deaminase (AID) expression. Moreover, CD30‐deficient mice exhibited decreased TCR‐mediated T cell proliferation and slightly impaired TCR signaling. High‐throughput RNA sequencing analysis revealed that CD30 deficiency led to a decrease of FOXO‐autophagy axis in T cells upon TCR stimulation. Thus, CD30 positively regulates T‐cell‐dependent immune response and T cell proliferation.
Exploring New Graduate Nurses’ Perceptions of Factors Influencing Job Satisfaction and Resignation Ideation During COVID-19
Authors: Urban Regina W. , Porter Marlene T. , Cipher Daisha J.
Published: December 2023

Using an observational design, new graduate nurses’ perceptions of job satisfaction and resignation ideation during COVID-19 were explored. Higher job satisfaction was associated with higher self-confidence, lower stress, and working in first choice of unit. A higher likelihood of resignation ideation was associated with coworker incivility, higher stress, and not working in first choice unit. New graduate nurses need support from nursing professional development practitioners for challenges faced throughout the transition-to-practice year.
Validation of cell-free protein synthesis aboard the International Space Station
Authors: Kocalar Selin , Miller Bess M. , Huang Ally , Gleason Emily , Martin Kathryn , Foley Kevin , Copeland D. Scott , Jewett Michael C. , Saavedra Ezequiel Alvarez , Kraves Sebastian
Published: December 2023

Cell-free protein synthesis (CFPS) is a rapidly maturingin vitrogene expression platform that can be used to transcribe and translate nucleic acids at the point of need, enabling on-demand synthesis of peptide-based vaccines and biotherapeutics, as well as the development of diagnostic tests for environmental contaminants and infectious agents. Unlike traditional cell-based systems, CFPS platforms do not require the maintenance of living cells and can be deployed with minimal equipment; therefore, they hold promise for applications in low-resource contexts, including spaceflight. Here we evaluate the performance of cell-free BioBits® platform aboard the International Space Station by expressing RNA-based aptamers and fluorescent proteins that can serve as biological indicators. We validate two classes of biological sensors that detect either the small molecule DFHBI or a specific RNA sequence. Upon detection of their respective analytes, both biological sensors produce fluorescent readouts that are visually confirmed using a handheld fluorescence viewer and imaged for quantitative analysis. Our findings provide insight into the kinetics of cell-free transcription and translation in a microgravity environment and reveal that both biosensors perform robustly in space. Our findings lay the groundwork for portable, low-cost applications ranging from point-of-care health monitoring to on-demand detection of environmental hazards in low-resource communities both on Earth and beyond.

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