bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of AFPGC immune-microenvironment and resistance to immunotherapy.
Authors: Chong Xiaoyi , Lu Jialin , Wang Yakun , Zhang Xiaotian 
Published: July 2024

e16041 Background: Alpha-fetoprotein producing gastric cancer (AFPGC) is a rare subtype GC with high with high morbidity and mortality rates. Even though immunotherapy has become the cornerstone of first-line treatment, our previous results suggest that AFPGC was resistant to immunotherapy, standard regimen remains unclear. It is warranted to explore precision immunotherapy strategies for AFPGC. Methods: A retrospective cohort of 98 patients with gastric cancer receiving mono-immunotherapy was included. Kaplan-Meier survival plots for PFS and OS were generated based on the AFP levels. Log-rank tests were used to compare the survival curves. Chi-square test was used to analyze the differences in the efficacy of immunotherapy between patients with different levels of AFP. AFPGC in vivo models were constructed, and after in vivo administration, RNA-seq, flow cytometry, and Western blot were used to explore and validate the features of the AFPGC microenvironment and explore immunotherapy combination strategies. Results: Retrospectively analysis demonstrated that the response of mono-immunotherapy in AFPGC was inferior to that in non-AFPGC (ORR: 16.7% vs 29.3%; DCR: 33.0% vs 55.4%). The response of the subcutaneous transplant tumor model with AFP overexpression to PD-1 antibody was significantly reduced. Meanwhile, RNA-seq results from the secondary PD-1 antibody resistant model showed that the mRNA level of AFP was significantly upregulated in the resistant model. RNA-seq results from transplant tumors of AFPGC compared to nAFPGC revealed that the differentially expressed genes were significantly enriched in pathways related to neutrophil chemotaxis and angiogenesis. Flow cytometry confirmed that the proportion of neutrophils in AFPGC was significantly higher than that in nAFPGC. SB265610 (neutrophil chemokine receptor inhibitor) combined with PD-1 antibody and apatinib (anti-angiogenesis) plus PD-1 antibody were administrated in animal models. Both of the regimens could release the primary resistance to PD-1 antibody. Based on these preclinical findings, we designed and conducted a clinical study (NCT04609176) to explore the reponse of apatinib combined with PD-1 antibody in AFPGC. Primary endpoints were achieved and will be announced in the near future. Typical case is depicted as follows: A 79 years old male patients diagnosed with low-differentiated adenocarcinoma of GC, AFP: 135220 ng/ml. After fail in chemotherapy, patients were treated with third-line apatinib 250mg po d1-d21, PD-1 monoclonal antibody 200mg d1, q21d for 6 cycles. Patient was evaluated as partial response (PR) for 4 months and AFP sharply decreased to 945 ng/ml. Conclusions: AFPGC is resistant to PD-1 monoclonal antibody. Combined treatment with SB265610 or apatinib can alleviate or reverse the resistance, making it the most promising treatment regimen for AFPGC.
Survival outcomes with curative intent hyperthermic intraperitoneal chemotherapy (HIPEC) for gastric cancer with peritoneal metastasis.
Authors: Joung Bowon , Castillo Dani Ran , Park Daniel , Al-Manaseer Farris , Jeon Won Jin , Yang Chieh , Burke Linnea , Woo Yanghee 
Published: July 2024

e16070 Background: The prognosis of gastric cancer with peritoneal metastasis (GC-PM) remains dismal. Despite the many studies evaluating hyperthermic intraperitoneal chemotherapy and cytoreductive surgery (HIPEC-CRS) for GC-PM in various treatment settings, its curative role in combination with systemic chemotherapy remains unclear. Methods: To determine the survival benefit of CRS-HIPEC in patients with GC-PM, we conducted a systematic review and meta-analysis in accordance with the PRISMA guidelines on primary studies from January 1, 2010 to December 31, 2023. Inclusion criteria were studies involving adults with GC and histologically proven PM who received curative intent gastrectomy, D2 lymphadenectomy, and systemic chemotherapy. Exclusion criteria were studies involving patients with GC without PM involvement and HIPEC utilized strictly for prophylactic purposes. The primary endpoint was overall survival (OS), with a focus on 1-year, 2-year, and 3-year survival outcomes. We performed a random effects meta-analysis of risk ratios using RevMan and assessed heterogeneity using I2. Results: Of 452 studies identified, we included 5 studies and a total of 524 patients with survival outcome of CRS-HIPEC and standard chemotherapy were compared. We observed significantly better OS for patients who received CRS+HIPEC compared to those who received systemic chemotherapy without CRS-HIPEC (odds ratio (OR) 0.50, 95% CI [0.39-0.65], I2= 3%, P < 0.00001). Further analysis demonstrated improved 1-year OS (OR 0.53, 95% CI [0.30-0.93], I2= 45%, p = 0.03), 2-year OS (OR 0.53, 95% CI [0.35-0.81], I2= 0%, p = 0.003), and 3-year OS (0.35, 95% CI [0.14-0.84], I2= 21%, p = 0.02). Low heterogeneity (3%) amongst all the groups suggests that variations within the subgroups did not impact the homogeneity of the dataset. Conclusions: Overall, use of CRS and HIPEC in addition to systemic chemotherapy resulted in statistically significant improvement in OS up to year 3 compared to standard palliative chemotherapy alone in patients with GC-PM. Further studies are warranted to evaluate HIPEC in the curative attempt setting, specifically in combination with emerging targeted therapies.
Exploration of neoadjuvant chemotherapy and post-tumor microenvironment for advanced gastric cancer (GC) or gastroesophageal junction cancer (EGJ).
Authors: Gou Miaomiao , Gao Yunhe , Qiao Zhi , Wang Zhi-Kuan , Liu Yi , Dai Guanghai 
Published: July 2024

e16099 Background: Neoadjuvant chemotherapy (NAC) is still the main strategy for operable local advanced gastric cancer (GC) or gastroesophageal junction cancer (EGJ). Keynote585 and Matterhorn studies had demonstrated the improvement of pathologic complete response rate (PCR), however, the overall survival benefit remains unclear. Little is known why patients’ response differently to NAC in terms of chemotherapy regiment and post neoadjuvant tumor microenvironment (TME). Methods: We retrospectively analyzed the resectable GC or EGJ patients who had been treated with neoadjuvant chemotherapy followed by surgery during 2019.11.26-2023.8.18 in the Chinese PLA general hospital. Patients with complete survival data were enrolled in the final evaluation. The association between clinical features or chemotherapy regiment and outcomes including TGR grade (NCCN criteria) and survival data were explored. Furthermore, tumor-microenvironment by means of multiplex fluorescence staining(mIHC) (CD8, CD68, CD56, PD1, PDL1, PANCK) after SOX neoadjuvant chemotherapy was analyzed. Results: 184 patients were offered neoadjuvant chemotherapy and underwent surgery. Due to follow-up lost, 141 patients with complete survival data were included in this analysis finally. Average age was 61, majority of patients were male. 85 patients received Sox and 33 received Xelox and 12 patients with docetaxel and S1(DS) and 11 patients were administered with triplets (FOLT and DOS). The median cycle of neoadjuvant treatment was 4(range from 1-7). Large proportion of patients were performed Laparoscopic. 31 patients suffered from post surgery complication. Above all, 1-year DFS and 2-year DFS, 3-year DFS rate were 72.6%, 54.8%, 49.0% respectively. 2-year OS and 3-year OS rate were 76.9%, 64.5%. PCR rate was 6.38% (n=9), which is consistent with other previous studies. 9 patients achieved TRG 0 and 26 had TRG 1. There is no statistical difference between triplets and double regiment of NEC for TRG0-1 group (45.5% vs 23.1%, p=0.099). The addition of docetaxel to oxaliplatin based therapy had not improved the TRG0-1 population compared with docetaxel-free regiment (30.4% VS 23.7%, p=0.496). YN0 is a predictor of longer survival in contrast YN+( 1-year DFS, 89.4% vs 62.8%, p=0.000).In the mIHC analyses, the density of CD8 positive and CD8+PD1- in the TGR0-1 group is higher than those cells in the TGR 2-3 group(P<0.05). TGR0-1 group had lower density of PDL1+,CD68+PDL1+ and CD68+PDL1- cells in contrast to TGR 2-3 group(P<0.05).Other multi-dimensional analyses were ongoing to be further disclosure. Conclusions: Neoadjuvant chemotherapy led to nearly 7% PCR rate for patients with local advanced GC. YN0 after NAC is a predictor of longer survival. CD8 positive and CD8+PD1- might be the determinant immune cells for better anticancer-response when exposed to chemotherapy.
A phase 1/2, open-label, multicenter, dose escalation and cohort expansion study of the safety and efficacy of anti-CD70 allogeneic CRISPR-Cas9–engineered T cells (CTX131) in adult patients with relapsed or refractory solid tumors.
Authors: Pal Sumanta Kumar , Reimers Melissa Andrea , Garmezy Benjamin , Xu Wenxin , Hoimes Christopher J. , Weinstein Michael , Cullingford Erika L , Ma Anna , Williams Leah M , Dar Henia , Keegan Alissa , Srour Samer Ali 
Published: July 2024

TPS2676 Background: CD70, a type II transmembrane protein and member of the tumor necrosis factor (TNF) receptor family, demonstrates high expression across multiple malignancies making it an attractive target for chimeric antigen receptor (CAR) T cell therapy. CD70 is expressed in 80% of clear cell renal cell carcinoma (ccRCC) and in 40-60% of cervical carcinoma (CC), esophageal carcinoma (EC), pancreatic adenocarcinoma (PAC), and pleural mesothelioma (PM) (1). CTX131 is a CD70-directed allogeneic CAR T cell investigational product manufactured ex vivo from healthy donor T cells using CRISPR/Cas9 technology. Genetic modifications in CTX131 include targeted insertion of a CD70-directed CAR construct, and targeted disruption of 5 loci: TRAC (to reduce risk of GvHD), B2M (to improve persistence in the allogeneic setting), CD70 (to reduce fratricide and improve anti-tumor function), TGFBR2 (to reduce immunosuppressive effect of TGFB in the tumor microenvironment), and Regnase-1 (to improve functional persistence) (2). Preclinical studies show the combination of TGFBR2 and Regnase-1 disruption in CTX131 works synergistically to enhance anti-tumor activity, inhibit tumor growth in xenograft mouse models, prolong survival, and increase central memory T cell populations (3). Methods: We are conducting a phase 1/2 study in patients (pts) with unresectable or metastatic ccRCC, CC, EC, PAC, and PM. Part 1 is a dose escalation with two separate cohorts, one for ccRCC pts and another for CC, EC, PAC, and PM pts. Part 1 ccRCC cohort began recruiting in 2023. Part 2 is a single-arm expansion of disease-specific cohorts. Key eligibility criteria include at least one prior line of standard treatment, ECOG status 0-1, evaluable disease per RECIST v1.1 (or modified RECIST1.1 for PM), adequate hematologic and organ function, and availability of tumor tissue for CD70 IHC. Key exclusion criteria include prior treatment with CD70-targeting agents and active CNS metastasis. Pts will receive standard lymphodepleting chemotherapy with fludarabine 30 mg/m2 and cyclophosphamide 500 mg/m2 daily x 3 days followed by CTX131 IV infusion at doses ranging from 30-900 million cells in 4 dose level cohorts. Redosing with CTX131 is permitted. For Part 1, the primary endpoint is DLTs with secondary endpoints including ORR, DOR, PFS, and OS. For Phase 2 the primary endpoint is ORR by IRC assessment. The trial is currently open with enrollment ongoing. 1. Flieswasser et. al. 2019. 2. Mai et. al. 2023. 3. Terrett 2023. Clinical trial information: NCT05795595 .
A phase 1, first-in-human study of CUSP06, a cadherin-6 (CDH6) -directed antibody-drug conjugate, in patients with platinum-refractory/resistant ovarian cancer and other advanced solid tumors.
Authors: Spira Alexander I. , Lee Elizabeth Katherine , O'Cearbhaill Roisin Eilish , LoRusso Patricia , Falchook Gerald Steven , Patel Manish R. , Richardson Debra L. , Covino Nicole , Lu Wei , Marreddy Priya , Farrington Daphne L. , Wheler Jennifer J. , Slosberg Eric Daniel , Subbiah Vivek , Meric-Bernstam Funda 
Published: July 2024

TPS3166 Background: Cadherin-6 (CDH6) is a transmembrane glycoprotein involved in cancer metastasis and invasion expressed in various tumor types including ovarian cancer (OC), renal cell carcinoma (RCC), papillary thyroid cancer, cholangiocarcinoma, hepatocellular cancer, glioma, uterine serous carcinoma and non-small cell lung cancer. CUSP06 is an antibody-drug conjugate composed of a human IgG1 monoclonal antibody against CDH6 conjugated with a protease-cleavable linker, T1000, to exatecan, a topoisomerase I inhibitor payload. In preclinical studies, CUSP06 showed CDH6-dependent cell growth inhibition in ovarian cancer cell lines. High CDH6-expressing ovarian and renal CDX and PDX models demonstrated tumor regression after treatment with CUSP06, as did low CDH6-expressing PDX models of other solid tumors. Methods: This is a Phase 1a/1b, open-label, multicenter dose escalation and expansion study to evaluate safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), recommended Phase 2 dose (RP2D), and preliminary efficacy of CUSP06 in patients with platinum-refractory/resistant ovarian cancer (PRROC), advanced RCC and other advanced CDH6-positive solid tumors. Patients with advanced solid tumors previously treated with standard of care systemic therapy, or for whom no standard therapy is available are eligible for enrollment. Prescreening for CDH6 expression will be required for those patients with solid tumors other than PRROC or RCC. CUSP06 will be administered intravenously every 21 days. Phase 1a will follow a standard 3+3 dose escalation design. Phase 1a also includes up to 3 dose enrichment cohorts at doses that have demonstrated safety, each with a maximum of 18 patients, to generate additional safety, PK, PD, and preliminary efficacy data to support an optimized dose for expansion. Phase 1b consists of several dose expansion cohorts including PRROC, RCC, and other CDH6-positive solid tumors, to be enrolled according to Simon's 2-stage design. Mandatory pre- and on-study biopsies in dose expansion cohorts will support a robust exploratory biomarker plan that may include correlation of CDH6 levels with response, and other RNA and protein markers of sensitivity and resistance. The study is currently enrolling in Phase 1a dose-escalation. Clinical trial information: NCT06234423 .
Muon ring and FCC-ee/CEPC based antimuon-electron colliders
Authors: Akturk Dilara , Dagli Burak , Sultansoy Saleh 
Published: July 2024

Abstract
Recently, the construction of an antimuon-electron collider, μTRISTAN, at KEK has been proposed. We argue that the construction of a similar muon ring tangential to FCC-ee and CEPC will give an opportunity to realize antimuon-electron collisions at higher center-of-mass energies. Moreover, the same ring may be used later to realize energy-frontier antimuon-proton colliders based on FCC-pp and SppC. Similarly, the change of the electron ring in the μTRISTAN project into the proton ring will give the opportunity to investigate lepton-hadron collisions at ∼2 TeV center-of-mass energies. In this paper the main parameters of the proposed colliders have been studied. It is shown that sufficiently high luminosities can be achieved for all proposals under consideration.
Relationship Between Serum Thyrotropin Levels and Metabolic Diseases in Older Adults
Authors: Zhai Xiaodan , Li Yongze , Teng Xiaochun , Teng Weiping , Shi Xiaoguang , Shan Zhongyan 
Published: July 2024

Abstract

Context
Subclinical hypothyroidism is associated with metabolic diseases; however, it remains controversial in older individuals.

Objective
This work aimed to investigate the relationship between thyrotropin (TSH) levels and metabolic diseases.

Methods
In this cross-sectional study, sampling was conducted from nationally representative general communities from 31 provinces in mainland China. A total of
6791 older (aged ≥65 years) and 55 303 young participants (aged 18-64 years) were selected after excluding individuals with overt hyperthyroidism or overt hypothyroidism. According to the kit, TSH reference range (0.27-4.2 mU/L) and the age-specific TSH range previously formulated (an upper limit of 8.86 mU/L for older adults and 6.57 mU/L for young adults), the older adults and young adults were separately divided into 4 groups based on their TSH levels. Main outcome measures included anthropometric assessments, serum concentrations of thyroid functions, and various metabolic parameters.

Results
In contrast to young adults, there was no significant increase in the prevalence of any metabolic disorders assessed in the slightly elevated TSH group (TSH 4.21-8.86 mU/L) compared to the euthyroid group (TSH 0.27-4.2 mU/L) among older adults. After adjusting for interference factors, a TSH level higher than 8.86 mU/L was found to be an independent risk factor for low high-density lipoprotein cholesterol (OR, 1.84; 95% CI, 1.14-2.98) and dyslipidemia (OR, 1.49; 95% CI, 1.09-2.04) when compared to the euthyroid group in older adults.

Conclusion
Slightly elevated TSH levels are not associated with an increased risk of metabolic diseases in older adults. Therefore, we recommend raising the upper limit of the TSH range for individuals aged 65 years and older.
Clinical and Genetic Characteristics of Congenital Hyperinsulinism in Norway: A Nationwide Cohort Study
Authors: Velde Christoffer Drabløs , Molnes Janne , Berland Siren , Njølstad Pål Rasmus , Molven Anders 
Published: July 2024

Abstract

Purpose
Congenital hyperinsulinism (CHI) is a rare, monogenic disease characterized by excessive insulin secretion. We aimed to evaluate all probands with suspected CHI in Norway registered over the past 2 decades.

Methods
The study included 98 probands. Clinical data were cumulated from medical records. All probands were screened for variants in the genes ABCC8 and KCNJ11. Other CHI-related genes were Sanger-sequenced as indicated by the patients’ phenotype (n = 75) or analyzed by next-generation sequencing employing a panel of 30 CHI-related genes (n = 23).

Results
Twenty-one probands (21%) received a diagnosis other than CHI, the most common being idiopathic ketotic hypoglycemia (9%) or syndromic hyperinsulinism (4%). In the final cohort of 77 CHI probands, genetic findings were revealed in 46 (60%). ABCC8 variants were most common (n= 40), and 5 novel variants were identified. One proband harbored both the pathogenic GCK variant p.(Ala456Val) and the ABCC8 variant p.(Gly505Cys). Although most ABCC8 variants caused immediate disease onset with severe hypoglycemia and were diazoxide-unresponsive, 8 probands had a heterozygous, apparently dominant variant with milder phenotype. Two probands had pathogenic variants in GLUD1, whereas variants in HADH, HNF4A, KCNJ11, and HK1 were identified in 1 proband each, the latter being noncoding. Neurologic sequelae were reported in 53% of the CHI probands. Of nonsurgically treated probands, 43% had spontaneous resolution. The minimum birth prevalence of CHI in Norway is 1:19,400 live births.

Main Conclusion
Individuals with disease-causing ABCC8 variants dominated our cohort. Patients with known genetic etiology had earlier and more severe disease onset than genetically unsolved patients.
Surgical Strategy for Dumbbell-Shaped Cervical Schwannoma at the Vicinity of the Vertebral Artery: The Utilization of Anatomic Layer
Authors: Park Hangeul , Kim Sum , Kim Young-Rak , Park Sung-Hye , Rhee John M. , Chung Chun Kee , Kim Jun-Hoe , Lee Chang-Hyun , Kim Kyoung-Tae , Kim Chi Heon 
Published: July 2024

BACKGROUND AND OBJECTIVES:
In cases where dumbbell-shaped cervical schwannoma encases the vertebral artery (VA), there is a risk of VA injury during surgery. The objective of this study is to propose a strategy for preserving the VA during the surgical excision of tumors adjacent to the VA through the utilization of anatomic layers.

METHODS:
A retrospective analysis was conducted on 37 patients who underwent surgery for dumbbell-shaped cervical schwannoma with contacting VA from January 2004 to July 2023. The VA encasement group consisted of 12 patients, and the VA nonencasement group included 25 patients.

RESULTS:
The perineurium acted as a protective barrier from direct VA exposure or injury during surgery. However, in the VA encasement group, 1 patient was unable to preserve the perineurium while removing a tumor adjacent to the VA, resulting in VA injury. The patient had the intact dominant VA on the opposite side, and there were no new neurological deficits or infarctions after the surgery. Gross total resection was achieved in 25 patients (67.6%), while residual tumor was confirmed in 12 patients (32.4%). Four patients (33.3% of 12 patients) underwent reoperation because of the regrowth of the residual tumor within the neural foramen. In the case of the 8 patients (66.7% of 12 patients) whose residual tumor was located outside the neural foramen, no regrowth was observed, and there was no recurrence of the tumor within the remaining perineurium after total resection.

CONCLUSION:
In conclusion, when resecting a dumbbell-shaped cervical schwannoma contacting VA, subperineurium dissection prevents VA injury because the perineurium acts as a protective barrier.
Variations in cell plasticity and proliferation underlie distinct modes of regeneration along the antero-posterior axis in the annelid Platynereis
Authors: Bideau Loïc , Velasquillo-Ramirez Zoé , Baduel Loeiza , Basso Marianne , Gilardi-Hebenstreit Pascale , Ribes Vanessa , Vervoort Michel , Gazave Eve 
Published: July 2024

ABSTRACT
The capacity to regenerate lost tissues varies significantly among animals. Some phyla, such as the annelids, display substantial regenerating abilities, although little is known about the cellular mechanisms underlying the process. To precisely determine the origin, plasticity and fate of the cells participating in blastema formation and posterior end regeneration after amputation in the annelid Platynereis dumerilii, we developed specific tools to track different cell populations. Using these tools, we find that regeneration is partly promoted by a population of proliferative gut cells whose regenerative potential varies as a function of their position along the antero-posterior axis of the worm. Gut progenitors from anterior differentiated tissues are lineage restricted, whereas gut progenitors from the less differentiated and more proliferative posterior tissues are much more plastic. However, they are unable to regenerate the stem cells responsible for the growth of the worms. Those stem cells are of local origin, deriving from the cells present in the segment abutting the amputation plane, as are most of the blastema cells. Our results favour a hybrid and flexible cellular model for posterior regeneration in Platynereis relying on different degrees of cell plasticity.