tbuckley/cabot-search huggingface dataset:
Clinical outcomes in salivary adenoid cystic carcinoma.
Authors: Prarthana Dalal, Sarah Dermody, Collin Brummel, Chad Brenner, Keith Casper, Steven B. Chinn, Kelly M Malloy, Michelle Lynn Mierzwa, Molly Heft Neal, Mark Prince, Jennifer Lobo Shah, Andrew Shuman, Chaz Stucken, Matthew Spector, Francis P. Worden, Paul Swiecicki
Journal: Journal of Clinical Oncology (2024)

6102 Background: Adenoid cystic carcinoma (ACC) is a rare salivary gland malignancy with a paucity of clinical outcome data. As such, evidence supporting and informing current guidelines remains limited. Methods: Inclusion criteria stipulated adults with adenoid cystic carcinoma treated at the University of Michigan between 1988 and 2019 with complete records (n=102). Clinical variables including demographics, disease stage, and treatment modality were abstracted. Pathologic variables analyzed included tumor grade, perineural invasion, lymphovascular invasion, and surgical margin status. Multivariate analyses were performed with disease recurrence calculated with Kaplan-Meier methodology as the primary outcome. Results: Mean age at diagnosis was 59 years; stage I and II disease accounted for 35 (38%) patients. Initial treatment was most commonly surgery with adjuvant radiation (77%). Median follow-up was 3 years. Distant metastatic disease developed in 34 (33%) patients. Most common sites included lung (68%), bone (21%), and brain (21%). Median time to distant metastases was 46 months with median overall survival of 58 months. Patients with locoregional recurrence experienced median survival of 91 months. Multivariate analysis adjusted for grade, perineural invasion, and surgical margin status (Table). Grade 3 tumors with predominantly solid histologic pattern pose higher risk of recurrence compared to grade 1 tubular histologic patterns as a reference (HR 3.69, 95% CI 1.15-11.88, p=0.028). Conclusions: Survival among patients with adenoid cystic carcinoma after locoregional recurrence is significantly better compared to those experiencing distant metastasis. Furthermore, tumor grade is most predictive of recurrence. Additionally, distant metastases may emerge over the course of many years. These data from one of the largest retrospective databases to date may inform the development of disease-specific surveillance guidelines and novel salvage treatment paradigms. [Table: see text]
Real-world analysis of inetetamab combined with pyrotinib plus chemotherapy for the treatment of HER2-positive advanced breast cancer: A multi-center retrospective study.
Authors: Huanhuan Zhou, Zhanhong Chen, Chao Deng, LU Gan, Fan Li, Xuefeng Xu, YanMan Fang, Xiaowei Qi, Wei Gang Bian, Zeshun Yu, Xiaojia Wang
Journal: Journal of Clinical Oncology (2024)

e13012 Background: Inetetamab combined with tyrosine kinase inhibitors exhibited stronger antitumor effects than inetetamab alone. At present, there was few studies on the efficacy and safety of inetetamab combined with pyrotinib in the treatment of advanced breast cancer (ABC) patients. The study aims to investigate the efficacy and safety of inetetamab combined with pyrotinib plus chemotherapy for HER2-positive ABC patients. Methods: We retrospectively investigated the medical records of eligible women who aged 18 years or older with pathologically confirmed HER2-positive recurrent or metastatic invasive breast cancer, and received at least two cycles of inetetamab combined with pyrotinib plus chemotherapy treatment regimens in multicenters in China between July 2020 and December 2022. The primary endpoint was progression-free survival (PFS) estimated by the Kaplan-Meier method. The secondary endpoints were the objective response rate (ORR), disease control rate (DCR), and safety. Cox regression model was used to identify predictive factors for PFS. Results: A total of 99 patients were included. Overall patient's median PFS was 12.3 (95% CI: 10.9-13.6) months. Of 99 evaluable patients, 53 (53.5%) patients achieved objective response, including 9 (9.1%) complete response and 44 (44.4%) partial response. The remaining 45 patients achieved stable disease as the best response, thus, the DCR was 99.0%. Patients who received Inetetamab combined with pyrotinib plus chemotherapy as first-line treatment (15.0 months [95% CI: 13.6-15.8]) provided longer median PFS than that as second-line treatment (10.3 months [95% CI:9.6-10.9], p&lt;0.001). Furtherly, the Cox multivariate regression analysis indicated that patients who received inetetamab combined with pyrotinib plus albumin-bound paclitaxel for first-line treatment achieved longer median PFS. Grade 1-2 diarrhea (59.6%), vomiting (29.3%) and nausea (28.3%), hand-foot syndrome (23.2%) were the top four most common adverse events (AEs). The most common grade ≥3 AEs were leukopenia (19.2%), diarrhea (18.2%), myelosuppression (7.1%) and neutromenia (4.0%). Conclusions: The first-line treatment of inetetamab combined with pyrotinib plus chemotherapy was an effective and safe treatment for HER2-positive ABC patients. Inetetamab combined with pyrotinib plus albumin-bound paclitaxel might be the most effective combination therapies. All AEs were controllable and tolerable.
Comprehensive electroacupuncture treatments reduce serum inflammatory factors and relieve pain symptoms in patients with lumbar disc herniation—a systematic review and network meta-analysis
Authors: Ran Hu, Zihuai Xu, Menghan Dang, Xiangqi Shao, Jianru Sun, Fan Liu, Li Zhang, Guokai Liu
Journal: International Journal of Surgery (2024)

Hu, Ran BS; Xu, Zihuai MS; Dang, Menghan BS; Shao, Xiangqi BS; Sun, Jianru MS; Liu, Fan MD; Zhang, Li MD; Liu, Guokai MD Author Information
Unraveling the synergistic mechanisms of pyrotinib in combination with trastuzumab: Insights from the PHILA trial.
Authors: Shuning Liu, Bo Lan, Lixi Li, Haili Qian, Fei Ma
Journal: Journal of Clinical Oncology (2024)

e13015 Background: There are many options for the treatment of advanced HER2-positive breast cancer. The results of PHILA study suggest that pyrotinib, trastuzumab and docetaxel may be considered as a potential first line treatment for patients with untreated HER2-positive metastatic breast cancer. We aimed to investigate the synergistic mechanisms of pyrotinib plus trastuzumab and compare them to trastuzumab plus pertuzumab, providing further insights for the PHILA trial. Methods: The efficacy of combination treatments was detected by cell vitality assay, Western blot and immunohistochemistry. The relevant mechanism was examined by flow cytometry and co-immunoprecipitation. Cell-derived xenografts and TUBO tumor model were utilized to evaluate the anti-tumor activity of rational combinations. Next-generation sequencing of circulating tumor DNA from a cohort of 18 patients in the PHILA trial was performed to evaluate molecular alterations associated with clinical response. Results: We demonstrated that pyrotinib plus trastuzumab superiorly inhibited cell growth than trastuzumab plus pertuzumab in models of HER2-dependent breast cancer. In addition to inhibiting HER family phosphorylation, pyrotinib plus trastuzumab synergistically reduced membrane HER2 levels by inducing receptor ubiquitination and internalization via HSP90 dissociation, which resulted in a comprehensive blockade of HER signaling pathway. Moreover, TUBO tumor model was utilized to further confirm the synergistic effects of pyrotinib and anti-neu antibody on HER2 signaling cascade. In both treatment groups of PHILA study, patients with aberrant mutations in HER2 signaling cascade showed a significantly shorter median progression-free survival compared to individuals with wild-type pathway. Correspondingly, in models of HCC1954 breast cancer cell harboring PIK3CA H1047R mutation, we did not observe a synergy between pyrotinib and trastuzumab. Conclusions: Pyrotinib and trastuzumab synergistically achieve the comprehensive blockade of HER signaling pathway in HER2-dependent breast cancer. Patients with advanced HER2-positive breast cancer, who are addicted to HER2 signaling cascade, could be considered for pyrotinib in combination with trastuzumab and docetaxel as an alternative first line treatment.
Efficacy and safety of inetetamab-containing regimens in patients with HER2-positive metastatic breast cancer in first-line/second-line setting.
Authors: Yuxin Mu, Yanchun Meng, Jian Zhang
Journal: Journal of Clinical Oncology (2024)

e13013 Background: Inetetamab is a novel recombinant humanized anti-human epidermal growth factor receptor-2 (HER-2) monoclonal antibody. This real-world retrospective study assessed the efficacy and safety of inetetamab-based combination regimens in first-line/second-line treatment of HER2-positive metastatic breast cancer (MBC). Methods: This study retrospectively recruited HER2-positive MBC patients who received inetetamab-based combination regimens from June 2020 to May 2023. The outcomes included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and disease control rate (DCR). Results: A total of 329 patients were enrolled and included in the efficacy analysis. The most frequently used treatment strategy was inetetamab plus pyrotinib-contained regimens (205/329, 62.3%). Patients treated with first-line regimens benefited the most, with a median PFS of 14.5 versus (vs.) 10.0 months (first-line- vs. second-line combination therapy of inetetamab, pyrotinib and chemotherapy, p &lt;0.001), 18.0 vs. 17.0 months (first-line- vs. second-line combination therapy of inetetamab, pertuzumab and chemotherapy, p=0.096), and 14.0 vs. not applicable months (first-line- vs. second-line inetetamab plus chemotherapy, p=0.229). The complete response (CR) was observed in 14 (4.3%) patients. The ORR was 54.4% (95%CI, 49.0%-59.7%), and the DCR was 99.4% (95%CI, 97.8%-99.8%). Diarrhea (39.2%) and white blood cell count decreased (33.0%) were the most common adverse events (AEs). The grade 3 and higher AEs were observed in 29.5% of the whole study cohort. Conclusions: Inetetamab-based combinations therapy demonstrated promising clinical activity and a manageable safety profile in patients with HER2-positive MBC, especially in the first-line setting.
Single-cell chromatin accessibility and transposable element landscapes reveal shared features of tissue-residing immune cells
Authors: Malte Simon, Philipp Stüve, Lisa Schmidleithner, Sebastian Bittner, Niklas Beumer, Nicholas Strieder, Christian Schmidl, Asmita Pant, Claudia Gebhard, Andreas Eigenberger, Michael Rehli, Lukas Prantl, Thomas Hehlgans, Benedikt Brors, Charles D. Imbusch, Michael Delacher, Markus Feuerer
Journal: Immunity (2024)

Tissue adaptation is required for regulatory T (Treg) cell function within organs. Whether this program shares aspects with other tissue-localized immune populations is unclear. Here, we analyzed single-cell chromatin accessibility data, including the transposable element (TE) landscape of CD45
Astrocytic autophagy plasticity modulates Aβ clearance and cognitive function in Alzheimer’s disease
Authors: Suhyun Kim, Heejung Chun, Yunha Kim, Yeyun Kim, Uiyeol Park, Jiyeon Chu, Mridula Bhalla, Seung-Hye Choi, Ali Yousefian-Jazi, Sojung Kim, Seung Jae Hyeon, Seungchan Kim, Yeonseo Kim, Yeon Ha Ju, Seung Eun Lee, Hyunbeom Lee, Kyungeun Lee, Soo-Jin Oh, Eun Mi Hwang, Junghee Lee, C. Justin Lee, Hoon Ryu
Journal: Molecular Neurodegeneration (2024)

Abstract Background Astrocytes, one of the most resilient cells in the brain, transform into reactive astrocytes in response to toxic proteins such as amyloid beta (Aβ) in Alzheimer’s disease (AD). However, reactive astrocyte-mediated non-cell autonomous neuropathological mechanism is not fully understood yet. We aimed our study to find out whether Aβ-induced proteotoxic stress affects the expression of autophagy genes and the modulation of autophagic flux in astrocytes, and if yes, how Aβ-induced autophagy-associated genes are involved Aβ clearance in astrocytes of animal model of AD. Methods Whole RNA sequencing (RNA-seq) was performed to detect gene expression patterns in Aβ-treated human astrocytes in a time-dependent manner. To verify the role of astrocytic autophagy in an AD mouse model, we developed AAVs expressing shRNAs for MAP1LC3B/LC3B (LC3B) and Sequestosome1 ( SQSTM1) based on AAV-R-CREon vector, which is a Cre recombinase-dependent gene-silencing system. Also, the effect of astrocyte-specific overexpression of LC3B on the neuropathology in AD (APP/PS1) mice was determined. Neuropathological alterations of AD mice with astrocytic autophagy dysfunction were observed by confocal microscopy and transmission electron microscope (TEM). Behavioral changes of mice were examined through novel object recognition test (NOR) and novel object place recognition test (NOPR). Results Here, we show that astrocytes, unlike neurons, undergo plastic changes in autophagic processes to remove Aβ. Aβ transiently induces expression of LC3B gene and turns on a prolonged transcription of SQSTM1 gene. The Aβ-induced astrocytic autophagy accelerates urea cycle and putrescine degradation pathway. Pharmacological inhibition of autophagy exacerbates mitochondrial dysfunction and oxidative stress in astrocytes. Astrocyte-specific knockdown of LC3B and SQSTM1 significantly increases Aβ plaque formation and GFAP-positive astrocytes in APP/PS1 mice, along with a significant reduction of neuronal marker and cognitive function. In contrast, astrocyte-specific overexpression of LC3B reduced Aβ aggregates in the brain of APP/PS1 mice. An increase of LC3B and SQSTM1 protein is found in astrocytes of the hippocampus in AD patients. Conclusions Taken together, our data indicates that Aβ-induced astrocytic autophagic plasticity is an important cellular event to modulate Aβ clearance and maintain cognitive function in AD mice.
A phase 1 clinical trial of DB-020 intratympanic injections administered prior to high-dose cisplatin chemotherapy to reduce ototoxicity.
Authors: Benedict J. Panizza, Stephen John O'Leary, Christopher David Hart, Chandra Sai Diwakarla, Catherine Barnett, Pablo Lapuerta, John Lee, Shane Raines, Tera Quigley, Heather M Wolff, John Keilty, Rahul Ladwa, Sandro V Porceddu, Margaret McGrath, Nagashree Seetharamu, Tsien Fua, Danny Rischin
Journal: Journal of Clinical Oncology (2024)

6100 Background: Hearing loss (HL) as a result of cisplatin (CP) chemotherapy is common. DB-020 is a formulation of sodium thiosulfate for intratympanic (IT) injection being developed to reduce CP ototoxicity. This phase 1 study was designed to evaluate safety and tolerability of repeated IT injections of DB-020 and compare CP-induced hearing changes with DB-020 vs placebo. Methods: Patients scheduled for at least three cycles of CP and cumulative exposure of ≥280 mg/m 2 were randomized to blinded, bilateral, IT injection with DB-020 (12% or 25%) in one ear and placebo in the other ear, once every 3 or 4 weeks, ≤3 hours before receiving CP. Patients naïve to CP with moderate or severe HL at baseline were excluded. Ototoxicity was defined by American Speech-Language-Hearing criteria: ≥20 dB threshold increase at any one test frequency, or ≥10 dB threshold increase in any two adjacent frequencies, or loss of response at three consecutive frequencies where responses were previously obtained. Severe ototoxicity was defined as ≥20 dB threshold increase in any two adjacent frequencies. Pre-specified analyses evaluated safety, ototoxicity (with McNemar’s test using the last observation carried forward), and average threshold shifts (from air conduction audiometry, analyzed with a mixed model with repeated measures). This is the final analysis of the data set following the interim analysis presented in 2023. Results: Twenty-two patients were randomized with a mean age of 55 years (86% male; 100% white). Pre-DB-020 treatment, mean cumulative CP dose was 255 mg/m 2 , and 95% had head and neck cancers; 5% had lung cancer. Twenty patients had both baseline and follow-up audiometry, and 18/20 had baseline audiograms within 5 dB of the median threshold for age-matched controls. Free CP systemic levels (overall mean cumulative CP dose was 254.7 mg/m 2 ) were similar to reference values. Acute or temporary ear pain (18/22 patients, 82%), and tinnitus (11/22 patients, 50%) were common. Ear pain was more common in DB-020 treated ears, and tinnitus in placebo treated ears. No persistent tympanic perforations, no serious adverse events in the ear and labyrinth disorders category, and no deaths were reported. Ototoxicity was significantly more common and severe in placebo treated ears. Conclusions: In this initial clinical trial experience, there was no significant safety signal, and DB-020 IT injections showed a meaningful reduction in CP-induced ototoxicity. Clinical trial information: NCT04262336 . [Table: see text]
Ketamine alleviates NMDA receptor hypofunction through synaptic trapping
Authors: Frédéric Villéga, Alexandra Fernandes, Julie Jézéquel, Floriane Uyttersprot, Nathan Benac, Sarra Zenagui, Laurine Bastardo, Hélène Gréa, Delphine Bouchet, Léa Villetelle, Olivier Nicole, Véronique Rogemond, Jérôme Honnorat, Julien P. Dupuis, Laurent Groc
Journal: Neuron (2024)

Activity-dependent modulations of N-methyl-D-aspartate glutamate receptor (NMDAR) trapping at synapses regulate excitatory neurotransmission and shape cognitive functions. Although NMDAR synaptic destabilization has been associated with severe neurological and psychiatric conditions, tuning NMDAR synaptic trapping to assess its clinical relevance for the treatment of brain conditions remains a challenge. Here, we report that ketamine (KET) and other clinically relevant NMDAR open channel blockers (OCBs) promote interactions between NMDAR and PDZ-domain-containing scaffolding proteins and enhance NMDAR trapping at synapses. We further show that KET-elicited trapping enhancement compensates for depletion in synaptic receptors triggered by autoantibodies from patients with anti-NMDAR encephalitis. Preventing synaptic depletion mitigates impairments in NMDAR-mediated CaMKII signaling and alleviates anxiety- and sensorimotor-gating-related behavioral deficits provoked by autoantibodies. Altogether, these findings reveal an unexpected dimension of OCB action and stress the potential of targeting receptor anchoring in NMDAR-related synaptopathies.
Intraosseous versus intravenous vascular access in upper extremity among adults with out-of-hospital cardiac arrest: cluster randomised clinical trial (VICTOR trial)
Authors: Ying-Chih Ko, Hao-Yang Lin, Edward Pei-Chuan Huang, An-Fu Lee, Ming-Ju Hsieh, Chih-Wei Yang, Bin-Chou Lee, Yao-Cheng Wang, Wen-Shuo Yang, Yu-Chun Chien, Jen-Tang Sun, Matthew Huei-Ming Ma, Wen-Chu Chiang
Journal: BMJ (2024)

To compare the effectiveness of intraosseous versus intravenous vascular access in the treatment of adult patients with out-of-hospital cardiac arrest.
Efficacy and safety of disitamab vedotin (RC48) in HER2-expressing breast cancer: A multicenter retrospective study.
Authors: Can Yang, Jianying Chang, Taolang Li, Yuncong Liu, Hanqun Zhang, Xiaoqing Luo, Yang Xiang, Cui Zhang, Yisidan Huang, Jing Hou, Guanghui Wang, Yong Li
Journal: Journal of Clinical Oncology (2024)

e13011 Background: RC48 is an Antibody-Drug Conjugate (ADC) that integrates a humanized monoclonal antibody targeting human epidermal growth factor receptor 2 (HER2) linked to the microtubule inhibitor monomethyl auristatin E (MMAE). This study reports real-world data using RC48 monotherapy in HER2-expressing advanced breast cancer (ABC). Methods: The study reviewed patients with HER2-expressing ABC who received RC48 monotherapy at three hospitals in China between September 2021 and June 2022. The electronic medical record was used to collect the clinical characteristics of the patient and to evaluate the antitumor activity and safety. The primary outcome was real-world progression-free survival (rwPFS). Results: A total of 15 patients were included, of whom 9(60%) were HER2-positive and 6(40%) had HER2 low expression (IHC 1+ or IHC 2+/ISH-).11 patients (73.3%) had visceral metastases, 40% of patients (6/15) had central nervous system (CNS) metastases at baseline. 6 patients (40%) had ≥3 metastatic lesions, and 13(86.7%) of patients received RC48 as third-line treatment or higher. Progression-free survival (PFS), overall survival (OS), and response can be assessed in all patients. The median follow-up was 10 months and the median rwPFS was 8.0 months (95% CI, 4.897-11.103), while the median OS was not reached. Objective response rate (ORR) and disease control rate (DCR) were 46.7% and 80% respectively. Partial response (PR) was achieved in 46.7% of the patients (7/15). patients with HER2-positive and HER2 low expression, the median rwPFS was 8.77 and 4.63 months, respectively (HR = 0.49,95% Cl, 0.13-1.80, P = 0.196), and in 6 patients with CNS metastases, the median rwPFS was 7.5 months (95% CI, 2.82-18.28). The most common treatment-related adverse events (TRAEs) were elevated transaminase (33.3%) and Leukopenia (33.3%), most of which were grade 1-2, No serious adverse events related to treatment were observed. Conclusions: The novel HER2-targeted ADC, RC48, demonstrated promising preliminary antitumor activity in patients with HER2-expressing ABC, patient with brain metastases could also benefit, with tolerable toxicities.
Improved outcome of COVID-19 over time in patients treated with CAR T-cell therapy: Update of the European COVID-19 multicenter study on behalf of the European Society for Blood and Marrow Transplantation (EBMT) Infectious Diseases Working Party (IDWP) and the European Hematology Association (EHA) Lymphoma Group
Authors: Anne Mea Spanjaart, Per Ljungman, Gloria Tridello, Juana Schwartz, Nuria Martinez-Cibrián, Pere Barba, Mi Kwon, Lucia Lopez-Corral, Joaquin Martinez-Lopez, Christelle Ferra, Roberta Di Blasi, Hervé Ghesquieres, Pim Mutsaers, Friso Calkoen, Margot Jak, Jaap van Doesum, Joost S P Vermaat, Marjolein van der Poel, Johan Maertens, Massimiliano Gambella, Elisabetta Metafuni, Fabio Ciceri, Riccardo Saccardi, Emma Nicholson, Eleni Tholouli, Collin Matthew, Victoria Potter, Adrian Bloor, Caroline Besley, Claire Roddie, Keith Wilson, Arnon Nagler, Antonio Campos, Soeren Lykke Petersen, Frantisek Folber, Peter Bader, Jurgen Finke, Nicolaus Kroger, Nina Knelange, Rafael de La Camara, Marie José Kersten, Stephan Mielke
Journal: Leukemia (2024)

Abstract COVID-19 has been associated with high mortality in patients treated with Chimeric Antigen Receptor (CAR) T-cell therapy for hematologic malignancies. Here, we investigated whether the outcome has improved over time with the primary objective of assessing COVID-19-attributable mortality in the Omicron period of 2022 compared to previous years. Data for this multicenter study were collected using the MED-A and COVID-19 report forms developed by the EBMT. One-hundred-eighty patients were included in the analysis, 39 diagnosed in 2020, 35 in 2021 and 106 in 2022. The median age was 58.9 years (min-max: 5.2–78.4). There was a successive decrease in COVID-19-related mortality over time (2020: 43.6%, 2021: 22.9%, 2022: 7.5%) and in multivariate analysis year of infection was the strongest predictor of survival ( p = 0.0001). Comparing 2022 with 2020–2021, significantly fewer patients had lower respiratory symptoms (21.7% vs 37.8%, p = 0.01), needed oxygen support (25.5% vs 43.2%, p = 0.01), or were admitted to ICU (5.7% vs 33.8%, p = 0.0001). Although COVID-19-related mortality has decreased over time, CAR T-cell recipients remain at higher risk for complications than the general population. Consequently, vigilant monitoring for COVID-19 in patients undergoing B-cell-targeting CAR T-cell treatment is continuously recommended ensuring optimal prevention of infection and advanced state-of-the art treatment when needed.