AGBL4 promotes malignant progression of glioblastoma via modulation of MMP-1 and inflammatory pathways.

Introduction: Glioblastoma multiforme (GBM), the most common primary malignant brain tumor, is notorious for its aggressive growth and dismal prognosis. This study aimed to elucidate the molecular underpinnings of GBM, particularly focusing on the role of AGBL4 and its connection to inflammatory pathways, to discover viable therapeutic targets. Methods: Single-cell sequencing was utilized to examine the expression levels of AGBL4 and functional assays were performed to assess the effects of AGBL4 modulation. Results: Our findings identified the significant upregulation of AGBL4 in GBM, which correlated with adverse clinical outcomes. Functional assays demonstrated that AGBL4 knockdown inhibited GBM cell proliferation, migration, and invasion and influenced inflammatory response pathways, while AGBL4 overexpression promoted these activities. Further investigation revealed that AGBL4 exerted its oncogenic effects through modulation of MMP-1, establishing a novel regulatory axis critical for GBM progression and inflammation. Discussion: Both AGBL4 and MMP-1 may be pivotal molecular targets, offering new avenues for targeted therapy in GBM management.

Progress on immuno-microenvironment and immune-related therapies in patients with pseudomyxoma peritonei.

Pseudomyxoma peritonei (PMP) is an indolent malignant syndrome. The standard treatment for PMP is cytoreductive surgery plus intraperitoneal hyperthermic chemotherapy (CRS + HIPEC). However, the high recurrence rate and latent clinical symptoms and signs are major obstacles to further improving clinical outcomes. Moreover, patients in advanced stages receive little benefit from CRS + HIPEC due to widespread intraperitoneal metastases. Another challenge in PMP treatment involves the progressive sclerosis of PMP cell-secreted mucus, which is often increased due to activating mutations in the gene coding for guanine nucleotide-binding protein alpha subunit (GNAS). Consequently, the development of other PMP therapies is urgently needed. Several immune-related therapies have shown promise, including the use of bacterium-derived non-specific immunogenic agents, radio-immunotherapeutic agents, and tumor cell-derived neoantigens, but a well-recognized immunotherapy has not been established. In this review the roles of GNAS mutations in the promotion of mucin secretion and disease development are discussed. In addition, the immunologic features of the PMP microenvironment and immune-associated treatments are discussed to summarize the current understanding of key features of the disease and to facilitate the development of immunotherapies.

Intraoperative urinary tract resection and construction in CRS + HIPEC procedures: a single center retrospective analysis.

INTRODUCTION: The safety and efficacy of CRS + HIPEC combined with urinary tract resection and reconstruction are controversial. This study aims to summarize the clinicopathological features and to evaluate the safety and survival prognosis of CRS + HIPEC combined with urinary tract resection and reconstruction. METHODS: The patients who underwent urinary tract resection and reconstruction as part of CRS surgery were retrospectively selected from our disease-specific database for analysis. The clinicopathological characteristics, treatment-related variables, perioperative adverse events (AEs), and survival outcomes were studied using a descriptive approach and the K-M analysis with log-rank comparison. RESULTS: Forty-nine patients were enrolled. Perioperative serious AEs (SAEs) were observed in 11 patients (22.4%), with urinary SAEs occurring in 3 patients (6.1%). Additionally, there were 23 cases (46.8%) involving urinary adverse events (UAEs). The median overall survival (OS) in the entire cohort was 59.2 (95%CI: 42.1-76.4) months. The median OS of the UAE group and No-UAE group were 59.2 months (95%CI not reached), and 50.5 (95%CI: 11.5 to 89.6) months, respectively, with no significant difference (P = 0.475). Furthermore, there were no significant differences in OS based on the grade of UAEs or the number of UAEs (P = 0.562 and P = 0.622, respectively). CONCLUSION: The combination of CRS + HIPEC with urinary tract resection and reconstruction is associated with a high incidence of Grade I-II UAEs, which do not have an impact on OS. The safety profile of this combined technique is acceptable. However, this is a retrospective single-center single-arm analysis, with limitations of generalizability and potential selection bias. The findings need high-level validation.

A nomogram prediction model of pseudomyxoma peritonei established based on new prognostic factors of HE stained pathological images analysis.

BACKGROUND: Pseudomyxoma peritonei (PMP) is a rare clinical malignant syndrome, and its rarity causes a lack of pathology research. This study aims to quantitatively analyze HE-stained pathological images (PIs), and develop a new predictive model integrating digital pathological parameters with clinical information. METHODS: Ninety-two PMP patients with complete clinic-pathological information, were included. QuPath was used for PIs quantitative feature analysis at tissue-, cell-, and nucleus-level. The correlations between overall survival (OS) and general clinicopathological characteristics, and PIs features were analyzed. A nomogram was established based on independent prognostic factors and evaluated. RESULTS: Among the 92 PMP patients, there were 34 (37.0%) females and 58 (63.0%) males, with a median age of 57 (range: 31-76). A total of 449 HE stained images were obtained for QuPath analysis, which extracted 40 pathological parameters at three levels. Kaplan-Meier survival analysis revealed eight clinicopathological characteristics and 20 PIs features significantly associated with OS (p < 0.05). Partial least squares regression was used to screen the multicollinearity features and synthesize four new features. Multivariate survival analysis identified the following five independent prognostic factors: preoperative CA199, completeness of cytoreduction, histopathological type, component one at tissue-level, and tumor nuclei circularity variance. A nomogram was established with internal validation C-index 0.795 and calibration plots indicating improved prediction performance. CONCLUSIONS: The quantitative analysis of HE-stained PIs could extract the new prognostic information on PMP. A nomogram established by five independent prognosticators is the first model integrating digital pathological information with clinical data for improved clinical outcome prediction.

Risk factors and prognosis of malignant peritoneal mesothelioma with paraneoplastic syndrome.

BACKGROUND: Malignant peritoneal mesothelioma (MPM) is a rare and highly aggressive tumor. Its clinical manifestations are diverse, and the symptoms are not specific. Some patients will develop paraneoplastic syndrome (PS) during the disease course. This study aims to analyze the risk factors of PS in patients with MPM and their impacts on prognosis. METHODS: The clinical data of MPM patients who underwent cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy (CRS + HIPEC) at our center from June 2015 to May 2023 were retrospectively analyzed. MPM patients were divided into PS group and non-PS group according to the diagnostic criteria. Univariate and multivariate analyses were performed to explore the risk factors of PS in MPM patients, and to analyze the impact of PS on prognosis. RESULTS: There were 146 MPM patients in this study, including 60 patients (41.1%) with PS and 86 patients (58.9%) without PS. The highest incidence of PS was thrombocytosis (33.6%), followed by neoplastic fever (9.6%). Univariate analysis revealed 8 factors (P < 0.05) with statistically significant differences between the two groups: prior surgical scores, targeted therapy history, Karnofsky performance status score, preoperative carbohydrate antigen (CA) 125 level, vascular tumor embolus, peritoneal cancer index, completeness of cytoreduction (CC) score and intraoperative ascites. Multivariate analysis identified 3 independent factors associated with PS: preoperative CA 125 level, vascular tumor embolus, and CC score. Survival analysis demonstrated that MPM patients with PS had worse prognosis, although PS was not an independent prognostic factor. CONCLUSIONS: PS is not rare in patients with MPM, and is independently associated with preoperative CA 125 level, vascular tumor embolus and CC score. PS often indicates advanced disease and poor prognosis.

Methylthioadenosine Phosphorylase and Breast Cancer 1 Protein-Associated Protein 1 as Biomarkers for the Peritoneal Mesothelioma.

OBJECTIVES: Combination of Breast Cancer 1 protein-associated protein 1 (BAP1) and methylthioadenosine phosphorylase (MTAP) in the peritoneal mesothelioma (PeM) has yet to be explored. We aim to assess the diagnostic value of combined BAP1 and MTAP to distinguish biphasic mesothelioma (BM) from epithelioid mesothelioma (EM) with reactive stroma in peritoneum, as well as its prognostic value in PeM. METHODS: This is a retrospective study from June 2014 to December 2021. This study included 18 cases of BM and 27 cases of EM with reactive stroma, excluded sarcomatoid, and EM without reactive stroma cases, and clinicopathological information was collected. The associations between MTAP and BAP1 levels and clinicopathological features or prognosis were analyzed. Clinical follow-up data were reviewed to correlate with pathological prognostic factors using Kaplan-Meier estimator and univariate/multivariate Cox proportional hazards regression models. RESULTS: Loss/decrease of BAP1/MTAP was observed in 6 (33.3%) BM cases and 12 (44.4%) EM cases. In 5 (27.8%) cases, loss of or decreased BAP1/MTAP expression was observed in both EC and SC of BM. BAP1/MTAP loss/decrease was observed in 12 (44.4%) cases of only EC of EM but not in reactive stroma. Compared with histology alone, a combination of BAP1 and MTAP immunohistochemistry (IHC) in spindled PeM provides a more objective mean to distinguish BM from EM with reactive stroma. Loss/decrease of BAP1/MTAP was associated with peritoneal cancer index (PCI) score (P = 0.047) and completeness of cytoreduction (CC) score (P = 0.038). BM patients have worse overall survival (OS) than EM with reactive stroma (P = 0 .007). CONCLUSIONS: Combination of BAP1/MTAP by IHC is helpful for differential diagnosis of peritoneal BM from EM with reactive stroma. Nevertheless, BAP1/MTAP may help to evaluate the biological behavior of PeM.

Long-term survival in patients with PMP: a single-institutional retrospective study from China.

BACKGROUND: As the standard treatment for pseudomyxoma peritonei (PMP), cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) can significantly prolong the survival of PMP patients, and some patients can even achieve long-term survival (LTS) or clinical cure. The purpose of this study was to analyze the clinicopathological and treatment features of PMP patients with LTS and to explore the survival benefit factors of PMP patients. METHODS: The clinicopathological and prognostic data of PMP patients who received CRS + HIPEC at our center from December 2004 to May 2023 were retrospectively analyzed. PMP patients were divided into LTS group (≥ 10 years) and short-term survival (STS) group (< 5 years) according to the length of natural history. Univariate and multivariate analyses were performed to explore the beneficial factors of PMP patients with LTS. RESULTS: A total of 609 patients with PMP received CRS + HIPEC treatment at our center. Two-hundred one patients with PMP were included in the study after screening, including 39 patients (19.4%) in the LTS group and 162 patients (80.6%) in the STS group. In STS group and LTS group, median overall survival based on natural history was 29.2 (2.4-59.9) vs. 138.9 (120.3-416.7) months. Univariate analysis revealed 8 factors (P < 0.05) with statistically significant differences between the two groups: gender, chemotherapy history, previous surgical score, Karnofsky Performance Status score, pathological diagnosis, lymphatic metastasis, peritoneal cancer index, and completeness of cytoreduction (CC). Multivariate analysis identified only two factors independently associated with LTS of PMP patients: CC and pathological diagnosis. CONCLUSION: Complete CRS and pathological features are two key factors affecting LTS in PMP patients.

Etiological analysis of infection after CRS + HIPEC in patients with PMP.

BACKGROUND: Cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) is the standard treatment for pseudomyxoma peritonei (PMP). It can significantly prolong the survival of patients, but at the same time may increase the risk of postoperative infection. METHOD: Patients with PMP who underwent CRS + HIPEC at our center were retrospectively analyzed. According to PMP patients, basic clinical data and relevant information of postoperative infection, we analyzed the common sites of postoperative infection, results of microbial culture and the antibiotics sensitivity. Univariate and multivariate analysis were performed to explore infection-related risk factors. RESULT: Among the 482 patients with PMP, 82 (17.0%) patients were infected after CRS + HIPEC. The most common postoperative infection was central venous catheter (CVC) infection (8.1%), followed by abdominal-pelvic infection (5.2%). There were 29 kinds of microbes isolated from the culture (the most common was Staphylococcus epidermidis), including 13 kinds of Gram-positive bacteria, 12 kinds of Gram-negative bacteria, and 4 kinds of funguses. All the antibiotics sensitivity results showed that the most sensitive antibiotics were vancomycin to Gram-positive bacteria (98.4%), levofloxacin to Gram-negative bacteria (68.5%), and fluconazole to fungus (83.3%). Univariate and multivariate analysis revealed the infection independent risk factors as follow: intraoperative blood loss ≥ 350 mL (P = 0.019), ascites volume ≥ 300 mL (P = 0.008). CONCLUSION: PMP patients may have increased infection risk after CRS + HIPEC, especially CVC, abdominal-pelvic and pulmonary infections. The microbial spectrum and antibiotics sensitivity results could help clinicians to take prompt prophylactic and therapeutic approaches against postoperative infection for PMP patients.

Analysis of risk factors and short-term prognostic factors of arrhythmia in patients infected with mild/moderate SARS-CoV-2 Omicron variant.

Background: Complications, including arrhythmia, following severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection continue to be of concern. Omicron is the mainstream SARS-CoV-2 mutant circulating in mainland China. At present, there are few epidemiological studies concerning the relationship between arrhythmia and Omicron variant infection in mainland China. Objectives: To investigate the risk factors of arrhythmia in patients infected with the SARS-CoV-2 Omicron variant and the factors influencing prognosis. Methods: Data from 192 Omicron infected patients with symptoms of arrhythmia (AH group) and 100 Omicron infected patients without arrhythmia (Control group) were collected. Patients in the AH group were divided into the good and poor prognosis groups, according to the follow-up results 4-6 weeks after infection. The general and clinical data between the AH and Control groups, and between the good and poor prognosis groups were compared. The variables with differences between the groups were included in the multivariate logistic regression analysis, and the quantitative variables were analyzed by receiver operating characteristic curve to obtain their cut-off values. Results: Compared with the control group, the body mass index (BMI), proportion of patients with a history of arrhythmia, proportion of antibiotics taken, heart rate, moderate disease severity, white blood cell (WBC) count, and the aspartate aminotransferase, creatine kinase (CK), CK isoenzyme (CK-MB), myoglobin (Mb), high-sensitive troponin I (hs-cTnI), lymphocyte ratio and high sensitivity C-reactive protein (hs-CRP) levels in the AH group were significantly higher (p < 0.05). In addition, obesity (BMI ≥24 kg/m2), fast heart rate (≥100 times/min), moderate disease severity, and WBC, CK-MB and hs-cTnI levels were independent risk factors of arrhythmia for patients with Omicron infection (p < 0.05), and hs-CRP was a protective factor (p < 0.05). Compared with the good prognosis group, the age, proportion of patients with a history of arrhythmia, heart rate, proportion of moderate disease severity, and hs-CRP, CK, Mb and hs-cTnI levels were significantly higher in the poor prognosis group, while the proportion of vaccination was lower in the poor prognosis group (p < 0.05). Advanced age (≥65 years old), proportion of history of arrhythmia, moderate disease severity, vaccination, and hs-CRP, Mb and cTnI levels were independent factors for poor prognosis of patients with arrhythmia (p < 0.05). Conclusion: The factors that affect arrhythmia and the prognosis of patients infected with Omicron include obesity, high heart rate, severity of the disease, age. history of arrhythmia, WBC, hs-CRP, and myocardial injury indexes, which could be used to evaluate and prevent arrhythmia complications in patients in the future.

Establishment of a Bayesian network model to predict the survival of malignant peritoneal mesothelioma patients after cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy.

OBJECTIVES: To establish a Bayesian network (BN) model to predict the survival of patients with malignant peritoneal mesothelioma (MPM) treated with cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC). METHODS: The clinicopathological data of 154 MPM patients treated with CRS + HIPEC at our hospital from April 2015 to November 2022 were retrospectively analyzed. They were randomly divided into two groups in a 7:3 ratio. Survival analysis was conducted on the training set and a BN model was established. The accuracy of the model was validated using a confusion matrix of the testing set. The receiver operating characteristic (ROC) curve and area under the curve were used to evaluate the overall performance of the BN model. RESULTS: Survival analysis of 107 patients (69.5%) in the training set found ten factors affecting patient prognosis: age, Karnofsky performance score, surgical history, ascites volume, peritoneal cancer index, organ resections, red blood cell transfusion, pathological types, lymphatic metastasis, and Ki-67 index (all p < 0.05). The BN model was successfully established after the above factors were included, and the BN model structure was adjusted according to previous research and clinical experience. The results of confusion matrix obtained by internal validation of 47 cases in the testing set showed that the accuracy of BN model was 72.7%, and the area under ROC was 0.74. CONCLUSIONS: The BN model was established successfully with good overall performance and can be used as a clinical decision reference.

Effect of standardized fluid management on cardiac function after CRS + HIPEC in patients with PMP: a single-center case-control study.

OBJECTIVE: To investigate the effects of standardized fluid management (SFM) on cardiac function in patients with pseudomyxoma peritonei (PMP) after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). METHOD: Patients with PMP who underwent CRS + HIPEC at our center were retrospectively analyzed. The patients were divided into control and study groups according to whether SFM was applied after CRS + HIPEC. We compared the preoperative and postoperative cardiac and renal function parameters, daily fluid volume three days after CRS, and cardiovascular-related adverse events. Univariate and multivariate analyses were performed to identify the indicators affecting clinical prognosis. RESULT: Among the 104 patients, 42 (40.4%) were in the control group and 62 (59.6%) in the study group. There were no statistically significant differences between the two groups in the main clinicopathological characteristics, preoperative cardiac and renal function parameters, and CRS + HIPEC-related indicators. The incidences of cardiac troponin I (CTNI) > upper limit of normal (ULN), >2 × ULN, >3 × ULN, serum creatinine > ULN, and blood urea nitrogen > ULN were higher in the control group than in the study group (p < 0.05). The median daily fluid volume of the control group was higher than that of the study group 3 days after CRS (p < 0.05). Postoperative CTNI > 2 × ULN was an independent risk factor for serious circulatory adverse events. Survival analysis revealed pathological grading, completeness of cytoreduction score, and postoperative CTNI > ULN as independent prognostic factors. CONCLUSIONS: SFM after CRS + HIPEC in patients with PMP may reduce cardiovascular adverse events risk and improve clinical outcomes.

Clinical epidemiology of peritoneal metastases in China: The construction of professional peritoneal metastases treatment centers based on the prevalence rate.

OBJECTIVE: To understand the tumor burden of peritoneal metastases (PM) in China, and to guide the construction of professional PM treatment centers in China. METHODS: Based on the cancer statistics by the National Cancer Center of China published in 2016, the prevalence of PM in 2020 was calculated according to the population statistics in China and the survival and mortality rates of various PM. RESULTS: The prevalence rates of PM in China were as follows: gastric cancer PM 371.0/million, absolute number 523,937; colorectal cancer PM 47.1/million, absolute number 66,482; ovarian cancer PM 97.1/million, absolute number 137,083; pseudomyxoma peritonei 25.1/million, absolute number 35,425; malignant peritoneal mesothelioma 2.6/million, absolute number 3737; the above total was 766,664. According to the annual high-quality treatment volume of 365 cases in each professional PM treatment center, China needs to establish 1194 specialized PM treatment centers. At present, there are 1580 tertiary first-class hospitals in China. Therefore, for every 3 first-class tertiary hospitals in China there should be at least 2 PM treatment centers in full operation. CONCLUSIONS: Considering the large number of PM patients in China and the relatively small number of professional PM treatment centers, more resources should be devoted to the promotion and construction of PM treatment centers.

Loss of NPM2 expression is a potential immunohistochemical marker for malignant peritoneal mesothelioma: a single-center study of 92 cases.

BACKGROUND: Malignant peritoneal mesothelioma (MPM) is a rare malignant tumor with a high mortality rate and extremely poor prognosis. In-depth pathological analysis is essential to assess tumor biological behaviors and explore potential therapeutic targets of MPM. Nucleoplasmin 2 (NPM2) is a molecular chaperone that binds histones and may play a key role in the development and progression of tumors. This study aimed to analyze the correlation between the expression level of NPM2 and the main clinicopathological characteristics and prognosis of MPM. METHODS: Ninety-two postoperative specimens from MPM patients following cytoreductive surgery were collected. Postoperative specimens were stained with immunohistochemistry. The expression level of NPM2 was quantitatively analyzed by QuPath-0.3.2 software. Univariate and multivariate analyses were conducted to investigate the correlation between NPM2 expression and other conventional clinicopathological characteristics. RESULTS: Among the 92 MPM patients, there were 47 males (48.9%) and 45 females (51.1%), with a median age of 56 (range: 24-73). There were 70 (76.0%) cases with loss of NPM2 protein expression, 11 (12.0%) cases with low expression, and 11 (12.0%) cases with high expression. Univariate analysis showed that NPM2 protein expression level (negative vs. low expression vs. high expression) was negatively correlated with the following three clinicopathological factors: completeness of cytoreduction (CC) score, vascular tumor emboli, and serious adverse events (SAEs) (all P < 0.05). Multivariate analysis showed that NPM2 protein expression level (negative vs. low expression vs. high expression) was independently negatively correlated with the following two clinicopathological factors: CC score [odds ratio (OR) = 0.317, 95% CI: 0.317-0.959, P = 0.042] and vascular tumor emboli (OR = 0.092, 95% CI = 0.011-0.770, P = 0.028). Survival analysis showed that loss of NPM2 protein expression (negative vs. positive) was associated with poor prognosis of MPM. CONCLUSIONS: Loss of NPM2 expression is a potential immunohistochemical marker for MPM.

Efficacy and Adverse Events of Apatinib Salvage Treatment for Refractory Diffuse Malignant Peritoneal Mesothelioma: A Pilot Study.

Objective: To investigate the clinical efficacy and adverse events (AEs) of apatinib salvage treatment for diffuse malignant peritoneal mesothelioma (DMPM) that has failed to respond to the recommended treatments. Methods: 27 patients with refractory DMPM were treated with apatinib at our center from April 2014 to October 2020, at the initial dose of 250 mg/d. The dose was reduced to 125 mg/d when serious adverse events (SAEs) occurred. 28-day was set as a treatment cycle. The frequency of follow up was once every 28 days. The efficacy evaluation was conducted according to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria and the serum tumor markers before and after apatinib treatment. The safety assessment was performed with the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The primary endpoints were objective response rate (ORR) and disease control rate (DCR), and the secondary endpoints were AEs. Results: The 27 patients completed a median treatment-cycle of 15.0, ranging from 5.1 to 39.4 cycles. At the median follow-up of 14.3 (4.8-51.8) months, median overall survival (OS) was 59.4 months, median apatinib-treatment-related survival (ATRS) was 14.0 (4.8-36.8) months. Complete response (CR) was observed in 0 case (0.0%), partial response (PR) in 4 cases (14.8%), stable disease (SD) in 12 cases (44.4%), and progression disease (PD) in 11 cases (40.7%). The ORR was 14.8%, and DCR was 59.3%. The median serum CA125 values before and after apatinib treatment were 32.9 (7.0-4592.4) U/mL and 29.7 (6.1-4327.4) U/mL, respectively (P=0.009). The common AEs were hypertension (6/27; 22.2%), hand-foot syndrome (5/27; 18.5%), albuminuria (4/27; 14.8%), anemia (4/27; 14.8%), leukopenia (4/27; 14.8%), rash (2/27; 7.4%), fatigue (2/27; 7.4%), oral ulcers (2/27; 7.4%), hoarseness (2/27; 7.4%), nausea/vomiting (2/27; 7.4%), diarrhea (2/27; 7.4%), headache (1/27; 3.7%), and fever (1/27; 3.7%). The incidence rate of grade III/IV AEs was 16.2%. Conclusions: Apatinib is effective in treating refractory DMPM, with promising efficacy and acceptable safety.

Glioma­neuronal interactions in tumor progression: Mechanism, therapeutic strategies and perspectives (Review).

An increasing body of evidence has become available to reveal the synaptic and functional integration of glioma into the brain network, facilitating tumor progression. The novel discovery of glioma­neuronal interactions has fundamentally challenged our understanding of this refractory disease. The present review aimed to provide an overview of how the neuronal activities function through synapses, neurotransmitters, ion channels, gap junctions, tumor microtubes and neuronal molecules to establish communications with glioma, as well as a simplified explanation of the reciprocal effects of crosstalk on neuronal pathophysiology. In addition, the current state of therapeutic avenues targeting critical factors involved in glioma­euronal interactions is discussed and an overview of clinical trial data for further investigation is provided. Finally, newly emerging technologies, including immunomodulation, a neural stem cell­based delivery system, optogenetics techniques and co­culture of neuron organoids and glioma, are proposed, which may pave a way towards gaining deeper insight into both the mechanisms associated with neuron­ and glioma­communicating networks and the development of therapeutic strategies to target this currently lethal brain tumor.

NPM2 in malignant peritoneal mesothelioma: from basic tumor biology to clinical medicine.

BACKGROUND: This review systematically summarizes gene biology features and protein structure of nucleoplasmin2 (NPM2) and the relationship between NPM2 and malignant peritoneal mesothelioma (MPM), in order to explore the molecular pathological mechanism of MPM and explore new therapeutic targets. METHODS: NCBI PubMed database was used for the literature search. NCBI Gene and Protein databases, Ensembl Genome Browser, UniProt, and RCSB PDB database were used for gene and protein review. Three online tools (Consurf, DoGSiteScorer, and ZdockServer), the GEPIA database, and the Cancer Genome Atlas were used to analyze bioinformatics characteristics for NPM2 protein. RESULTS: The main structural domains of NPM2 protein include the N-terminal core region, acidic region, and motif and disordered region. The N-terminal core region, involved in histone binding, is the most conserved domain in the nucleoplasmin (NPM) family. NPM2 with a large acidic tract in its C-terminal tail (NPM2-A2) is able to bind histones and form large complexes. Bioinformatics results indicated that NPM2 expression was correlated with the pathology of multiple tumors. Among mesothelioma patients, 5-year survival of patients with low-NPM2-expression was significantly higher than that of the high-NPM2-expression patients. NPM2 can facilitate the formation of histone deacetylation. NPM2 may promote histone deacetylation and inhibit the related-gene transcription, thus leading to abnormal proliferation, invasion, and metastasis of MPM. CONCLUSION: NPM2 may play a key role in the development and progression of MPM.

Key factors for successful cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy to treat diffuse malignant peritoneal mesothelioma: results from specialized peritoneal cancer center in China.

OBJECTIVES: To investigate independent factors for the efficacy and safety of cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) for the treatment of diffuse malignant peritoneal mesothelioma (DMPM). METHODS: The clinical database of 110 DMPM patients treated with CRS + HIPEC at our hospital was retrospectively analyzed. Independent prognostic factors were screened using univariate and multivariate analyses and the safety of the perioperative period was evaluated based on adverse events. RESULTS: Among the 110 patients with DMPM, 34 (30.9%) had a peritoneal cancer index (PCI) < 20 and 76 (69.1%) had PCI ≥20; 59 (53.6%) patients achieved completeness of cytoreduction (CC) 0/1 and 51 (46.4%) cases achieved CC 2/3. At the median follow-up of 43.3 (95%CI: 37.3-49.4) months, 48 (43.6%) patients were still alive and 62 (56.4%) patients died. The median overall survival was 32.6 months. Serious adverse events (SAEs) occurred in 41 patients (37.3%) and the perioperative mortality rate was 2.7%. Univariate analysis identified nine prognostic factors: Karnofsky performance status score, perioperative tumor markers, PCI, red blood cell infusion, pathological type, vascular tumor emboli, lymphatic metastasis, Ki-67 index, and perioperative SAEs (all p < 0.05). Multivariate analysis identified four independent prognostic factors: pathological type (p = 0.007), vascular tumor emboli (p = 0.044), Ki-67 index (p = 0.044), and SAEs (p = 0.004). CONCLUSIONS: CRS + HIPEC for DMPM treatment resulted in prolonged survival with acceptable safety. Tumor pathology and SAEs are key factors for successful CRS + HIPEC.

Combined Therapy Sensitivity Index Based on a 13-Gene Signature Predicts Prognosis for IDH Wild-type and MGMT Promoter Unmethylated Glioblastoma Patients.

Glioblastoma (GBM) is one of the lethal tumors with poor prognosis. However, prognostic prediction approaches need to be further explored. Therefore, we developed an evaluation system that could be used for prognostic prediction of GBM patients. Published mRNA expression datasets from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO) and Chinese Glioma Genome Atlas (CGGA) were analyzed. Quantitative Realtime-PCR of signature genes and molecular aberrations of 178 Xiangya GBM patients were used for confirmation. Gene set enrichment analysis (GSEA) was performed for functional annotation. As a result, we established a 13-gene signature which named Combined Therapy Sensitivity Index (CTSI). Based on a cutoff point, we divided patients into high-risk group and low-risk group. Based on Kaplan-Meier analysis and multivariate Cox regression analysis, we found that patients in the high-risk group had a shorter overall survival time than patients in the low-risk group (p<0.001 in TCGA and CGGA datasets, p=0.047 in GSE4271 dataset, p=0.008 in Xiangya GBM cohort, HR: 1.65-3.42). By comparing the status of IDH mutation, TERT promoter mutation (TERTp-mut) and MGMT promoter methylation, CTSI was predictable in IDH wild-type (IDH-wt)/MGMT promoter unmethylated (MGMTp-unmeth) patients (p=0.037 in IDH-wt/TERTp-mut/MGMTp-unmeth subgroup, HR: 1.98; p=0.032 in IDH-wt/TERTp-wt/MGMTp-unmeth subgroup, HR: 2.09). Based on GESA, the Gene Ontology (GO) gene sets were enriched differently between CTSI high-risk and low-risk groups. Our results showed CTSI risk score can predict the prognosis of IDH-wt/MGMTp-unmeth GBM patients. Based on CTSI, combined with the status of IDH mutation, TERT promoter mutation and MGMT promoter methylation, a stepwise prognosis evaluation system which can provide precise prognosis prediction for GBM patients was established.

Microsurgical Outcomes After Gross Total Resection on Vestibular Schwannoma in Elderly Patients: A Matched Cohort Study.

OBJECTIVES: To compare and analyze the differences in clinical manifestations and surgical outcomes after gross total resection (GTR) for vestibular schwannoma between elderly and younger patients. METHODS: We conducted a retrospective study of 40 elderly (≥65 years) and 40 younger (<65 years) patients, and matched operation dates and tumor size in the 2 groups were matched. All 80 patients underwent microsurgical resection though the sigmoid approach, by the same surgeon (X.Y.). We then summarized clinical manifestations, image data, perioperative complications, tumor recurrence, and functional outcomes and assessed the differences between the 2 groups. RESULTS: The mean follow-up time was 52.64 months. Elderly patients had a poorer preoperative American Society of Anesthesiology physical status scores than younger patients (62.5% vs. 30%, P = 0.004) and were more likely to have balance disorders (72.5% vs. 25%, P < 0.01), without other preoperative differences. Both groups of patients achieved GTR. The incidence of infection was slightly but not significantly greater in elderly patients (P > 0.05). There were also no significant differences in perioperative complications, recurrence rate, facial nerve function, hearing level, or Karnofsky Performance Status Scale scores between younger and older patients. CONCLUSIONS: Elderly patients tended to suffer from poorer health (American Society of Anesthesiology score) and poor balance before the operation; however, they did not experience more complications, worse nerve function, or worse quality of life in the perioperative or follow-up times. We conclude that GTR of vestibular schwannomas, even large or giant ones, is a safe and effective option for elderly patients.