[Effect of preoperative immune checkpoint inhibitors on reducing residual lymph node metastases in patients with gastric cancer: a retrospective study].

Objective: To investigate the effect of immune checkpoint inhibitors on reducing residual lymph node metastasis in patients with gastric cancer. Methods: The cohort of this retrospective study comprised patients from Nanfang Hospital of Southern Medical University and the First Affiliated Hospital of Xiamen University who had undergone systemic treatment prior to gastrectomy with D2 lymphadenectomy and had achieved Grade 1 primary tumor regression (TRG1) from January 2014 to December 2023. After exclusion of patients who had undergone preoperative radiotherapy, data of 58 patients (Nanfang Hospital: 46; First Affiliated Hospital of Xiamen University: 12) were analyzed. These patients were allocated to preoperative chemotherapy (Chemotherapy group, N=36 cases) and preoperative immunotherapy plus chemotherapy groups (Immunotherapy group, N=22 cases). There were no significant differences between these groups in sex, age, body mass index, diabetes, tumor location, pathological type, Lauren classification, tumor differentiation, pretreatment depth of invasion by primary tumor, pretreatment lymph node stage, pretreatment clinical stage, mismatch repair protein status, number of preoperative treatment cycles, or duration of preoperative treatment (all P>0.05). The primary outcome measure was postoperative lymph node downstaging. Secondary outcomes included postoperative depth of invasion by tumor, number of lymph nodes examined, and factors affecting residual lymph node metastasis status. Results: Lymph node downstaging was achieved significantly more often in the Immunotherapy group than the Chemotherapy group (pN0: 90.9% [20/22] vs. 61.1% [22/36]; pN1: 4.5% [1/22] vs. 36.1% [13/36]; pN2: 4.5% [1/22) vs. 0; pN3: 0 vs. 2.8% [1/36], Z=-2.315, P=0.021). There were no significant difference between the two groups in number of lymph nodes examined (40.5±16.3 vs. 40.8±17.5, t=0.076, P=0.940) or postoperative depth of invasion by primary tumor (pT1a: 50.0% [11/22] vs. 30.6% [11/36]; pT1b: 13.6% [3/22] vs. 19.4% [7/36]; pT2: 13.6% [3/22] vs. 13.9% [5/36]; pT3: 13.6% [3/22] vs. 25.0% [9/36]; pT4a: 9.1% [2/22] vs. 11.1% [4/36], Z=-1.331, P=0.183). Univariate analysis revealed that both preoperative treatment regimens were associated with residual lymph node metastasis status in patients whose primary tumor regression was TRG1 (χ2=6.070, P=0.014). Multivariate analysis incorporated the following factors: pretreatment depth of invasion by primary tumor, pretreatment lymph node stage, pretreatment clinical stage, number of preoperative treatment cycles, and preoperative treatment duration. We found that a combination of immunotherapy and chemotherapy administered preoperatively was an independent protective factor for reducing residual lymph node metastases in study patients whose primary tumor regression was TRG1 (OR=0.147, 95%CI: 0.026-0.828, P=0.030). Conclusion: Compared with preoperative chemotherapy alone, a combination of preoperative immunotherapy and chemotherapy achieved greater reduction of residual lymph node metastases in the study patients who achieved TRG1 tumor regression in their primary lesions.

[The relationship between clinical characteristics and pathological features in patients with pheochromocytomas/paragangliomas].

Objective: To explore the correlation between clinical characteristics and pathological features in patients with pheochromocytoma/paraganglioma (PPGLs). Methods: A case series study. A retrospective analysis was conducted on patients with single and primary PPGLs after postoperative pathological diagnosis who were admitted to Peking Union Medical College Hospital between January 2019 and December 2022. The patients were divided into the Ki-67<3% group and the Ki-67≥3% group with Ki-67 proliferation index of 3% as the threshold. The relationship between clinical and pathological characteristics of PPGLs was analyzed. Results: A total of 399 PPGLs patients were included, with 177 males and 222 females, aged [M(Q1, Q3)] 45.0(35.5, 53.0) years. Among them, 226 (56.6%) cases originated from the adrenal gland, while 104 cases (26.1%) from the retroperitoneum. 20.9% (27/129) of the patients were found to harbor germline mutations of susceptibility genes, with SDHB mutations being the most common (10.1%, 13/129). The Ki-67 staining was performed on 302 cases, with a Ki-67 proliferation index [M(Q1, Q3)] of 2.0% (1.0%, 3.0%). There were 194 cases in Ki-67<3% group and 108 cases in Ki-67≥3% group. Compared with the patients in Ki-67<3% group, the age of onset in Ki-67≥3% group was younger (P=0.029). Compared with the patients with paragangliomas without SDHB or Cluster 1A-related gene mutations, positive 131I-meta-iodobenzylguanidine (131I-MIBG) imaging or negative O-6-methylguanine-DNA methyltransferase (MGMT) immunohistochemistry staining, those with SDHB or Cluster 1A-related gene mutations, negative 131I-MIBG imaging or positive MGMT immunohistochemistry staining had a higher Ki-67 index (all P<0.05). Compared with adrenal pheochromocytoma, retroperitoneal paragangliomas had a higher proportion of SDHB mutations and a higher proportion of normetanephrine (NMN) secretory types (all P<0.05). Compared with adrenal pheochromocytoma, the maximum diameter of head and neck paraganglioma tumors was smaller [3.0 (1.9, 3.8) cm vs 4.7 (3.4, 6.4) cm, P<0.001] and the proportion of Ki-67≥3% was higher (61.3% vs 33.8%, P=0.007). Conclusions: PPGLs patients with earlier onset age, SDHB or Cluster 1A-related gene mutations, negative 131I-MIBG imaging, or positive MGMT immunohistochemistry staining tend to have a higher Ki-67 index. Head and neck tumors, though smaller, exhibit a higher proliferation potential.

Experimental Limits on Solar Reflected Dark Matter with a New Approach on Accelerated-Dark-Matter-Electron Analysis in Semiconductors.

Recently a dark matter-electron (DM-electron) paradigm has drawn much attention. Models beyond the standard halo model describing DM accelerated by high energy celestial bodies are under intense examination as well. In this Letter, a velocity components analysis (VCA) method dedicated to swift analysis of accelerated DM-electron interactions via semiconductor detectors is proposed and the first HPGe detector-based accelerated DM-electron analysis is realized. Utilizing the method, the first germanium based constraint on sub-GeV solar reflected DM-electron interaction is presented with the 205.4 kg·day dataset from the CDEX-10 experiment. In the heavy mediator scenario, our result excels in the mass range of 5-15 keV/c^{2}, achieving a 3 orders of magnitude improvement comparing with previous semiconductor experiments. In the light mediator scenario, the strongest laboratory constraint for DM lighter than 0.1 MeV/c^{2} is presented. The result proves the feasibility and demonstrates the vast potential of the VCA technique in future accelerated DM-electron analyses with semiconductor detectors.

Regulation of epidermal growth factor receptor tyrosine kinase inhibitor resistance via Ambra1-mediated autophagy in non-small cell lung cancer.

To explore the molecular mechanisms related to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) resistance, along with potential therapeutic targets and strategies. The autophagy and Beclin 1 regulator 1 (Ambra1) short hairpin ribonucleic acid (shRNA) lentivirus vector and Ambra1 overexpression plasmid, constructed with a plasmid cloning deoxyribonucleic acid (pcDNA) 3.1 vector, were used to down-regulate and up-regulate Ambra1 expression in the human lung adenocarcinoma erlotinib-resistant cell line (PC9/ER), respectively, as well as to screen stable transgenic cell lines. The IC50 of Erlotinib in these cell lines were measured to determine their resistance status. The real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to measure messenger ribonucleic acid (mRNA) expression of resistance-related genes like multidrug resistance protein 1 (MDR1), multidrug resistance-associated protein 1 (MRP1), and lung drug-resistant-related protein (LRP). Western blot was performed to analyze the protein expressions of the autophagy-related genes Beclin 1, LC3II/I, and p62. Each stable transgenic line formed a tumor under the skin in nude mice; the mice with subcutaneous tumorigenesis of PC9/ER cells and shAmbra1-PC9/ER cells were subsequently treated with rapamycin (RAPA) and chloroquine (CQ), respectively. The mRNA expressions of MDR1, MRP1, and LRP in each tumor tissue sample were detected by qRT-PCR. The protein expressions of adenosine monophosphate-activated protein kinase (AMPK), phosphorylated-AMPK (p-AMPK), forkhead box O3 (FoxO3a), and phosphorylated forkhead box O3 (p-FoxO3a) in the AMPK/FoxO3a signaling pathway were analyzed via Western blot. The qRT-PCR result revealed that the level of Ambra1 in EGFR-TKI-resistant cells had increased. This was further exacerbated by the overexpression of Ambra1 and was reduced after its inhibition. Additionally, Ambra1 upregulated the mRNA expression of drug-resistant genes and the expression of autophagy-related proteins. Subcutaneous tumorigenesis of RAPA-treated shAmbra1-PC9/ER cells resulted in increased expression of drug resistance-related genes and a concomitant decrease in p-AMPK and increase in p-FoxO3a. The results revealed that Beclin-1/ß-actin, p62/ß-actin, and LC3II/I in the model group were all significantly increased compared to the control group, with P<0.05. Compared to the model group, Beclin-1/ß-actin, p62/ß-actin, and LC3II/I were all significantly higher in the pcDNA-Ambra1 group, with P<0.05. Compared to the model group, Beclin-1/ß-actin, p62/ß-actin, and LC3II/I were all significantly decreased in the shAmbra1 group, with P<0.05. Thus, these data suggest that Ambra1 promotes cellular autophagy. In addition, subcutaneous tumorigenesis of CQ-treated shAmbra1-PC9/ER cells resulted in reduced expression of drug resistance-related genes, and a concomitant increase in p-AMPK and decrease in p-FoxO3a. The results of this study revealed that Ambra1-mediated autophagy regulated EGFR-TKI resistance in NSCLC, most probably through the AMPK/FoxO3a signaling pathway.

[Advances in clinical studies of chronic cough].

Chronic cough is a common complaint in respiratory specialist clinics, with a significant impact on cough-specific quality of life and psychophysiological health. The diagnosis, treatment and management of chronic cough remains a major challenge. We summarized a series of recent advances from clinical studies in the epidemiology, diagnosis and management of chronic cough over the past year.

[Recognition of the membrane anatomy-based laparoscopic assisted right hemicolectomy].

Although it has become a consensus in the field of colorectal surgery to perform radical tumor treatment and functional protection under the minimally invasive concept, there exist many controversies during clinical practice, including the concept of embryonic development of abdominal organs and membrane anatomy, the principle of membrane anatomy related to right hemicolectomy, D3 resection, and identification of the inner boundary. In this paper, we analyzed recently reported literature with high-level evidence and clinical data from the author's hospital to recognize and review the membrane anatomy-based laparoscopic assisted right hemicolectomy for right colon cancer, emphasizing the importance of priority of surgical dissection planes, vascular orientation, and full understanding of the fascial space, and proposing that the surgical planes should be dissected in the parietal-prerenal fascial space, and the incision should be 1 cm from the descending and horizontal part of the duodenum. The surgery should be performed according to a standard procedure with strict quality control. To identify the resection range of D3 dissection, it is necessary to establish a clinical, imaging, and pathological evaluation model for multiple factors or to apply indocyanine green and nano-carbon lymphatic tracer intraoperatively to guide precise lymph node dissection. We expect more high-level evidence of evidence-based medicine to prove the inner boundary of laparoscopic assisted radical right colectomy and a more rigorous consensus to be established.

[Value of contrast-enhanced ultrasonography in detection of endoleak after endovascular repair of infrarenal abdominal aortic aneurysm].

Objective: To investigate the value of contrast-enhanced ultrasound in detecting endoleak after endovascular repair of infrarenal abdominal aortic aneurysm (EVAR). Methods: The postoperative follow-up data of 102 patients with infrarenal abdominal aortic aneurysm treated with EVAR in Tianjin Medical University General Hospital from August 2015 to December 2021 were retrospectively analyzed. There were 79 males and 23 females, aged 50-91 (69.6±7.6) years old. Using CT angiography (CTA) as the gold standard for diagnosing endoleaks, the effectiveness of contrast-enhanced ultrasound and CDUS in detecting endoleaks was evaluated by paired design chi-square test, and the Kappa value was calculated for consistency test. Patients were divided into groups according to body mass index (BMI), and the number of false-negative endoleaks detected by contrast-enhanced ultrasound in each group was calculated, and its ratio to the actual number of endoleaks was calculated to evaluate whether BMI was related to false-negative ultrasound-enhanced ultrasound. Results: A total of 203 follow-up visits met the inclusion criteria. Endoleaks were detected 36 times (17.7%) by CTA, 31 times (15.3%) by contrast-enhanced ultrasound, 16 times (7.9%) by CDUS, and they all detected type Ⅰ, type Ⅱ and type Ⅲ endoleaks. There was no significant difference between contrast-enhanced ultrasound and CTA in endoleak detection rate and determination of endoleak types (endoleak detection rate: 15.3% vs 17.7%; determination of endoleak types: type Ⅰ 4 vs 4, type Ⅱ 26 vs 31, type Ⅲ 1 vs 1; all P>0.05). CDUS and CTA had statistically significant differences in the detection rate of endoleaks and determination of endoleak types (endoleak detection rate: 7.9% vs 17.7%; determination of endoleak types: type Ⅰ 4 vs 4, type Ⅱ 11 vs 31, type Ⅲ 1 vs 1; all P<0.001). Compared with CTA, contrast-enhanced ultrasound has a sensitivity of 83.3%, a specificity of 99.4%, a Youden index of 0.827, a coincidence rate of 96.6%, a positive predictive value of 96.8%, a negative predictive value of 96.5%, and a Kappa value of 0.875(P<0.001). The two showed excellent diagnostic consistency. All 6 endoleaks not detected by contrast-enhanced ultrasound were type Ⅱ endoleak that did not require treatment, and 3(15.8%) occurred in obese patients with a BMI≥32 kg/m2. Compared with CTA, CDUS had a sensitivity of 38.9%, a specificity of 98.8%, a Youden index of 0.377, a coincidence rate of 88.2%, a positive predictive value of 87.5%, a negative predictive value of 88.2%, and a Kappa value of 0.482 (P<0.001). The two showed moderate diagnostic agreement. The correlation coefficient of the maximum diameter of aneurysms measured by ultrasound and CT was r=0.873(P<0.001). Conclusions: Contrast-enhanced ultrasound is accurate in detecting endoleak after infrarenal EVAR, and its sensitivity to endoleak detection in obese patients with BMI≥32 kg/m2 will be reduced. CDUS is not suitable for detection of endoleak after infrarenal EVAR, but it can be used to monitor the change of the largest diameter of aneurysm after EVAR.

[Efficacy and outcomes of shunt surgery for secondary hydrocephalus].

Records of secondary hydrocephalus patients undergoing shunt surgery in the Department of Neurosurgery of Peking Union Medical College Hospital from September 2012 to April 2022 and their clinical characteristics and outcomes were retrospectively reviewed and analyzed. Among 121 patients who received first time shunt placement, the most common causes of secondary hydrocephalus were brain hemorrhage (55, 45.5%) and trauma (35, 28.9%). Cognition decline (106, 87.6%), abnormal gait (50, 41.3%) and incontinence (40, 33.1%) were the most prevalent manifestations. Postoperative central nervous system infection (4, 3.3%), shunt obstruction (3, 2.5%) and subdural hematoma/effusion (4, 3.3%) were the most frequent neurological complications. Overall incidence of postoperative complications was 9% (11 cases) in the current cohort. And 50.5% (54/107) of the patients receiving shunting achieved a Glasgow outcome scale (GOS) score of at least 4. Shunt surgery is preferred for secondary hydrocephalus, especially for secondary normal pressure hydrocephalus. Moreover, it is recommended to complete cranioplasty in staged operation or one-stage operation for the patients with decompressive craniectomy.

A deep-learning model using enhanced chest CT images to predict PD-L1 expression in non-small-cell lung cancer patients.

AIM: To develop a deep-learning model using contrast-enhanced chest computed tomography (CT) images to predict programmed death-ligand 1 (PD-L1) expression in patients with non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS: Preoperative enhanced chest CT images and immunohistochemistry results for PD-L1 expression (<1% and ≥1% were defined as negative and positive, respectively) were collected retrospectively from 125 NSCLC patients to train and validate a deep-learning radiomics model (DLRM) for the prediction of PD-L1 expression in tumours. The DLRM was developed by combining the deep-learning signature (DLS) obtained from a convolutional neural network and clinicopathological factors. The indexes of the area under the curve (AUC), integrated discrimination improvement (IDI), and decision curve analysis (DCA) were used to evaluate the efficiency of the DLRM. RESULTS: DLS and tumour stage were identified as independent predictors of PD-L1 expression by the DLRM. The AUCs of the DLRM were 0.804 (95% confidence interval: 0.697-0.911) and 0.804 (95% confidence interval: 0.679-0.929) in the training and validation cohorts, respectively. IDI analysis showed the DLRM had better diagnostic accuracy than DLS (0.0028 [p<0.05]) in the validation cohort. Additionally, DCA revealed that the DLRM had more net benefit than the DLS for clinical utility. CONCLUSION: The proposed DLRM using enhanced chest CT images could function as a non-invasive diagnostic tool to differentiate PD-L1 expression in NSCLC patients.

[Progress in research of long-term protective efficacy of human papillomavirus vaccine].

The efficacy of HPV vaccine in preventing cervical cancer has been demonstrated in numerous clinical trials and clinical uses. The follow-up after clinical trials usually last for 5-6 years to evaluate the long-term efficacy, and a series of long-term follow-up studies have been conducted in some regions. The literature retrieval of HPV vaccine long term efficiency research both at home and abroad indicated that the protective efficacy of the vaccine against vaccine-type-related cervical intraepithelial neoplasia grade 2 and above is higher than 90%.

Social association predicts immunological similarity in rewilded mice.

Environmental influences on immune phenotypes are well-documented, but our understanding of which elements of the environment affect immune systems, and how, remains vague. Behaviors, including socializing with others, are central to an individual's interaction with its environment. We tracked behavior of rewilded laboratory mice of three inbred strains in outdoor enclosures and examined contributions of behavior, including social associations, to immune phenotypes. We found that the more associated two individuals were, the more similar their immune phenotypes were. Social association was particularly predictive of similar memory T and B cell profiles and was more influential than sibling relationships or worm infection status. These results highlight the importance of social networks for immune phenotype and reveal important immunological correlates of social life.

[Endovascular abdominal aortic aneurysm repair with a new stent graft:early results from a multicenter study].

Objective: To examine the safety and effectiveness of a new stent graft system for endovascular repair of abdominal aortic aneurysm(AAA). Methods: This is a prospective,multi-center,single-arm clinical trial. The patients with AAA treated with a new stent graft system were enrolled at 21 centers from September 2018 to September 2019 in China. Follow-up was performed before discharge, and at 30, 180, 360 days after operation, respectively. The primary safety endpoint was the incidence of major adverse events(MAE) within 30 days. The primary efficacy endpoint was the success rate of AAA treatment at 360 days. Secondary safety endpoints were the incidence of perioperative access complications and acute lower limb ischemia,all-cause mortality, AAA related mortality and incidence of serious adverse events (SAE) at 180 and 360 days. Secondary efficacy endpoints were the incidence of type Ⅰ or Ⅲ endoleak,stent displacement,and conversion to open surgery or re-intervention at 180 and 360 days. Results: One hundred and fifty-six patients were enrolled,including 137 males and 19 females. The age was (68.9±6.9) years (range:48.2 to 84.6 years).Maximum aneurysm diameter was (50.8±11.2) mm (range:25.0 to 85.0 mm),diameter of proximal landing zone was (21.2±2.5) mm (range:17.0 to 29.5 mm),and length of proximal landing zone was (31.4±13.0) mm (range:11.0 to 75.0 mm).The incidence of MAE was 1.3% (2/156) at 30 days,both were all-cause death cases. The success rate of AAA treatment was 88.5% (138/156) at 360 days. No perioperative access complication and acute lower limb ischemia occurred. All-cause mortality was 2.0% (3/154) at 180 days and 2.6% (4/153) at 360 days,and there was no AAA related death. The incidence of SAE was 23.0%(35/152) at 180 days and 30.5%(46/151) at 360 days, and no device-related SAE occurred. The incidence of type Ⅰor Ⅲ endoleak was 3.4% (5/147) at 180 days and 3.5% (5/144) at 360 days. Conclusion: The new stent graft system is easy to operate,and early-term safety and effectiveness results are expected.

74 Ge( n , γ ) cross section below 70 keV measured at n_TOF CERN.

Neutron capture reaction cross sections on 74 Ge are of importance to determine 74 Ge production during the astrophysical slow neutron capture process. We present new resonance data on 74 Ge( n , γ ) reactions below 70 keV neutron energy. We calculate Maxwellian averaged cross sections, combining our data below 70 keV with evaluated cross sections at higher neutron energies. Our stellar cross sections are in agreement with a previous activation measurement performed at Forschungszentrum Karlsruhe by Marganiec et al., once their data has been re-normalised to account for an update in the reference cross section used in that experiment.

Predicting adverse drug effects: A heterogeneous graph convolution network with a multi-layer perceptron approach.

We apply a heterogeneous graph convolution network (GCN) combined with a multi-layer perceptron (MLP) denoted by GCNMLP to explore the potential side effects of drugs. Here the SIDER, OFFSIDERS, and FAERS are used as the datasets. We integrate the drug information with similar characteristics from the datasets of known drugs and side effect networks. The heterogeneous graph networks explore the potential side effects of drugs by inferring the relationship between similar drugs and related side effects. This novel in silico method will shorten the time spent in uncovering the unseen side effects within routine drug prescriptions while highlighting the relevance of exploring drug mechanisms from well-documented drugs. In our experiments, we inquire about the drugs Vancomycin, Amlodipine, Cisplatin, and Glimepiride from a trained model, where the parameters are acquired from the dataset SIDER after training. Our results show that the performance of the GCNMLP on these three datasets is superior to the non-negative matrix factorization method (NMF) and some well-known machine learning methods with respect to various evaluation scales. Moreover, new side effects of drugs can be obtained using the GCNMLP.

Constraints on Sub-GeV Dark Matter-Electron Scattering from the CDEX-10 Experiment.

We present improved germanium-based constraints on sub-GeV dark matter via dark matter-electron (χ-e) scattering using the 205.4 kg·day dataset from the CDEX-10 experiment. Using a novel calculation technique, we attain predicted χ-e scattering spectra observable in high-purity germanium detectors. In the heavy mediator scenario, our results achieve 3 orders of magnitude of improvement for m_{χ} larger than 80 MeV/c^{2} compared to previous germanium-based χ-e results. We also present the most stringent χ-e cross-section limit to date among experiments using solid-state detectors for m_{χ} larger than 90 MeV/c^{2} with heavy mediators and m_{χ} larger than 100 MeV/c^{2} with electric dipole coupling. The result proves the feasibility and demonstrates the vast potential of a new χ-e detection method with high-purity germanium detectors in ultralow radioactive background.