bims-netuvo 2024-11-17 papers

bims-netuvo

Biomed News

on Nerves in tumours of visceral organs

Issue of 2024‒11‒17
thirteen papers selected by
Maksym V. Kopanitsa, Charles River Laboratories

Neurobiology of cancer: Adrenergic signaling and drug repurposing.
Sympathetic Neurons Promote Small Cell Lung Cancer Through the Beta-2 Adrenergic Receptor.
Spatial lipidomics reveals myelin defects and pro-tumor macrophage infiltration in MPNST adjacent nerves.
Preoperative Prediction of Perineural Invasion in Pancreatic Ductal Adenocarcinoma Using Machine Learning Radiomics Based on Contrast-Enhanced CT Imaging.
Genomic landscape of superficial malignant peripheral nerve sheath tumor.
Nerve Growth Factor from Pancreatic Cancer Cells Promotes the Cancer Progression by Inducing Nerve Cell-Secreted Interleukin-6.
Establishment and validation of a prediction model for gastric cancer with perineural invasion based on preoperative inflammatory markers.
Malignant Peripheral Nerve Sheath Tumour Presenting as Sciatica in a Patient with Neurofibromatosis Type 1: Is Magnetic Resonance Imaging an Effective Screening Tool?
The Association Between Lymphovascular or Perineural Invasion in Radical Prostatectomy Specimen and Biochemical Recurrence.
CXCL1-CXCR2 signaling mediates the activation of microglia in the nucleus tractus solitarii to promote pancreatic cancer-induced pain.
Non-small cell lung cancer with synchronous brain metastases: Identification of prognostic factors in a retrospective multicenter study (HOT 1701).
Cancer Therapy-Induced Encephalitis.
Targeted therapy: P2X3 receptor silencing in bone cancer pain relief.

Pharmacol Ther. 2024 Nov 09. pii: S0163-7258(24)00170-0. [Epub ahead of print] 108750

Neurobiology of cancer: Adrenergic signaling and drug repurposing.

Zi-Kai Dong, Yong-Fei Wang, Wei-Ping Li, Wei-Lin Jin.

  Cancer neuroscience, as an emerging converging discipline, provides us with new perspectives on the interactions between the nervous system and cancer progression. As the sympathetic nervous system, in particular adrenergic signaling, plays an important role in the regulation of tumor activity at every hierarchical level of life, from the tumor cell to the tumor microenvironment, and to the tumor macroenvironment, it is highly desirable to dissect its effects. Considering the far-reaching implications of drug repurposing for antitumor drug development, such a large number of adrenergic receptor antagonists on the market has great potential as one of the means of antitumor therapy, either as primary or adjuvant therapy. Therefore, this review aims to summarize the impact of adrenergic signaling on cancer development and to assess the status and prospects of intervening in adrenergic signaling as a therapeutic tool against tumors.

Keywords:  Adrenergic receptor; Beta-blocker; Cancer neuroscience; Chronic stress; Drug repurposing; Tumor macroenvironment; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.pharmthera.2024.108750
Cancer Discov. 2024 Nov 08.

Sympathetic Neurons Promote Small Cell Lung Cancer Through the Beta-2 Adrenergic Receptor.

Tala Fnu, Peiguo Shi, Wanwei Zhang, Sanny S W Chung, Christopher B Damoci, Yinshan Fang, Qi-Yue Chen, Anjali Saqi, Yuefeng Huang, Xuebing Wu, Chao Lu, Dian Yang, Timothy C Wang, Jianwen Que.

The vagal nerve is linked to tumorigenesis in multiple tissues including small cell lung cancer (SCLC). However, the role of sympathetic neuron in SCLC development remains unknown. Here, we observed a significant reduction in tumor growth following chemical denervation of local sympathetic nerves in a mouse model of SCLC. Further study identified that β2-adrenergic receptor (ADRB2) on cancer cells mediated the crosstalk with nerve fibers. Genetic deletion or pharmacological inhibition of ADRB2 led to reduced tumor growth and improved survival. Moreover, blocking ADRB2 also reduced the growth of human SCLC organoids and xenografts. Further studies revealed that ADRB2 promoted cancer cell expansion through activating Protein Kinase A (PKA) signaling. Consistently, inhibition of PKA also reduced the growth of SCLC cells. These findings offer the initial insight into the role played by sympathetic neurons in the development of SCLC and may open a new therapeutic avenue to treat this deadly malignancy.

DOI: https://doi.org/10.1158/2159-8290.CD-24-0718
Lab Invest. 2024 Nov 12. pii: S0023-6837(24)01864-6. [Epub ahead of print] 102186

Spatial lipidomics reveals myelin defects and pro-tumor macrophage infiltration in MPNST adjacent nerves.

Rick Ursem, Justus L Groen, Martijn J A Malessy, Inge Briaire-de Bruijn, Liam A McDonnell, Bram P A M Heijs, Judith V M G Bovee.

  Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas arising from peripheral nerves, accounting for 3-5% of soft tissue sarcomas. MPNSTs often recur locally, leading to poor survival. Achieving tumor-free surgical margins is essential to prevent recurrence, but current methods for determining tumor margins are limited, highlighting the need for improved biomarkers. In this study we investigated the degree to which MPNST extends into nerves adjacent to tumors. Alterations to the lipidome of MPNST and adjacent peripheral nerves were assessed using spatial lipidomics. Tissue samples from 5 MPNST patients were analyzed, revealing alterations of the lipid profile extending into the peripheral nerves beyond what was expected based on macroscopic and histological observations. Integration of spatial lipidomics and high-resolution accurate mass profiling identified distinct lipid profiles associated with healthy nerves, connective tissue, and tumors. Notably, histologically normal nerves exhibited myelin degradation and infiltration of pro-tumoral M2 macrophages, particularly near the tumor. Furthermore, aberrant osmium staining patterns and loss of H3K27me3 staining in absence of atypia were observed in a case with tumor recurrence. This exploratory study thereby highlights the changes occurring in the nerves affected by MPNST beyond what is visible on H&E, and provides leads for further biomarker studies, including aberrant osmium staining, to assess resection margins in MPNST.

Keywords:  Macrophages; Malignant peripheral nerve sheath tumor; Mass spectrometry imaging; Myelin; Recurrence; Spatial lipidomics

DOI:  https://doi.org/10.1016/j.labinv.2024.102186
J Imaging Inform Med. 2024 Nov 11.

Preoperative Prediction of Perineural Invasion in Pancreatic Ductal Adenocarcinoma Using Machine Learning Radiomics Based on Contrast-Enhanced CT Imaging.

Wenzheng Lu, Yanqi Zhong, Xifeng Yang, Yuxi Ge, Heng Zhang, Xingbiao Chen, Shudong Hu.

  The objective of the study is to assess the clinical value of machine learning radiomics based on contrast-enhanced computed tomography (CECT) images in preoperative prediction of perineural invasion (PNI) status in pancreatic ductal adenocarcinoma (PDAC). A total of 143 patients with PDAC were enrolled in this retrospective study (training group, n = 100; test group, n = 43). Radiomics features were extracted from CECT images and selected by the Mann-Whitney U-test, Pearson correlation coefficient, and least absolute shrinkage and selection operator (LASSO). The logistic regression (LR), support vector machine (SVM), random forest (RF), extreme gradient boosting (XGBoost), and decision tree (DT) algorithms were trained to build radiomics models by radiomic features. Multivariate logistic regression was employed to identify independent predictors and establish clinical models. A combined model was constructed by integrating clinical and radiomics features. Model performances were assessed by receiver operating characteristic curves (ROCs) and decision curve analyses (DCAs). A total of 788 radiomics features were extracted from CECT images, of which 14 were identified as significant through the three-step selection process. Among the machine learning models, the SVM radiomics model exhibited the highest predictive performance in the test group, achieving an area under the curve (AUC) of 0.831, accuracy of 0.698, sensitivity of 0.677, and specificity of 0.750. After logistic regression screening, the clinical model was established using carbohydrate antigen 19-9 (CA199) levels as one independent predictor. In the test group, the clinical model demonstrated an AUC of 0.644, accuracy of 0.744, sensitivity of 0.871, and specificity of 0.417. The combined model showed improved performance compared to both the clinical and radiomics models in the test group, with an AUC of 0.844, accuracy of 0.767, sensitivity of 0.806, and specificity of 0.667. Subsequently, DCA of the combined model indicated optimal clinical value for predicting PNI status. Machine learning radiomics models can accurately predict PNI status in patients with pancreatic ductal adenocarcinoma. The combined model, which incorporates clinical and radiomics features, enhances preoperative diagnostic performance and aids in the selection of treatment methods.

Keywords:  Contrast-enhanced computed tomography; Machine learning; Pancreatic ductal adenocarcinoma; Perineural invasion; Radiomics

DOI:  https://doi.org/10.1007/s10278-024-01325-1
Lab Invest. 2024 Nov 10. pii: S0023-6837(24)01861-0. [Epub ahead of print] 102183

Genomic landscape of superficial malignant peripheral nerve sheath tumor.

John L McAfee, Tyler J Alban, Vladimir Makarov, Amit Rupani, Prerana B Parthasarathy, Zheng Tu, Shira Ronen, Steven D Billings, C Marcela Diaz, Timothy A Chan, Jennifer S Ko.

  Superficial malignant peripheral nerve sheath tumors (SF-MPNSTs) are rare cancers and can be difficult to distinguish from spindle cell (SCM) or desmoplastic (DM) melanomas. Their biology is poorly understood. We performed whole-exome sequencing (WES) and RNA sequencing (RNA-seq) on SF-MPNST (n=8) and compared these to cases of SCM (n=7), DM (n=8), and deep MPNST (D-MPNST, n=8). Immunohistochemical staining for H3K27me3 and PRAME was also performed. SF-MPNST demonstrated intermediate features between D-MPNST and melanoma. Patients were younger than those with melanoma, and older than those with D-MPNST; outcome was worse and better respectively. SF-MPNST tumor mutational burden (TMB) was higher than D-MPNST and lower than melanoma; differences were significant only between SF-MPNST and SCM (p = 0.0454) and between D-MPNST and SCM (p = 0.001, Dunn's Kruskal-Wallis post-hoc test). Despite having an overlapping mutational profile in some common cancer-associated genes, the COSMIC mutational signatures clustered DM and SCM together with ultraviolet light exposure signatures (SBS7a, 7b), and SF- and D-MPNST together with defective DNA base excision repair (SBS30, 36). RNA-seq revealed differentially expressed genes between SF-MPNST and SCM (1670 genes), DM (831 genes), and D-MPNST (614 genes), some of which hold promise for development as immunohistochemical markers (SOX8, PLCH1) or aids (MLPH, CALB2, SOX11, TBX4). H3K27me3 immunoreactivity was diffusely lost in most D-MPNSTs (7/8, 88%), but showed variable and patchy loss in SF-MPNSTs (2/8, 25%). PRAME was entirely negative in the majority (0+ in 20/31, 65%), including 11/15 melanomas, and showed no significant difference between groups (p=0.105, Kruskal-Wallis test). Expression of immune cell transcripts was upregulated in melanomas relative to MPNSTs. Next-generation sequencing revealed multiple differential features between SF- MPNST, D-MPNST, SCM, and DM, including tumor mutation burden, mutational signatures, and differentially expressed genes. These findings help advance our understanding of disease pathogenesis and improve diagnostic modalities.

Keywords:  desmoplastic melanoma; molecular; sequencing; spindle cell melanoma; superficial malignant peripheral nerve sheath tumor

DOI:  https://doi.org/10.1016/j.labinv.2024.102183
J Interferon Cytokine Res. 2024 Nov 08.

Nerve Growth Factor from Pancreatic Cancer Cells Promotes the Cancer Progression by Inducing Nerve Cell-Secreted Interleukin-6.

Jianbiao Xu, Yun Shang, Tongmin Wang, Jianlin Song, Wenchuan Zhu, Yunjun Zeng, Jianxun Wang, Xiaochun Yang.

  Pancreatic cancer (PC) is a cancer with a poor prognosis, and nerve growth factor (NGF) is involved in the pathogenesis of PC within the unknown exact role. Herein, SW1990 cells and PC12 cells were co-cultured using transwell co-culture system and subsequently revealed that NGF was overexpressed in SW1990 cells and promoted PC12 cell proliferation. Knockdown of NGF expression in SW1990 cells using lentiviral shRNA effectively inhibited NGF expression in SW1990 cells and reduced its stimulatory effect on PC12 cell proliferation. Additionally, NGF in SW1990 cells increased the expression of IL-6, dopamine, and c-FOS, as well as decreased the level of lactate dehydrogenase, in PC12 cells, whereas the inhibition of NGF expression significantly reduced the levels of IL-6, dopamine and c-FOS, indicating the critical role of IL-6/STAT3 signaling in PC progression. Finally, cell proliferation, migration, and invasion were assessed using cell counting kit-8, scratch, and Transwell assays, which showed that activated neurons promoted the proliferation, migration, invasion, and NGF secretion of SW1990 cells through the IL-6/STAT3 pathway. The results revealed that NGF secreted by PC cells played a pivotal role in PC progression via regulating activated neural cells-secreted IL-6, providing new theoretical insights for the treatment of PC.

Keywords:  IL-6; IL-6/STAT3 signaling; nerve growth factor; neural cells; pancreatic cancer

DOI:  https://doi.org/10.1089/jir.2024.0154
Transl Cancer Res. 2024 Oct 31. 13(10): 5381-5394

Establishment and validation of a prediction model for gastric cancer with perineural invasion based on preoperative inflammatory markers.

Pan Jiang, Lijun Zheng, Yining Yang, Dongping Mo.

  Background: Gastric cancer (GC) is a prevalent malignant tumor of the digestive system, characterized by a poor prognosis and high recurrence rate. Perineural invasion (PNI), the neoplastic infiltration of nerves, is a significant predictor of survival outcome in GC. Accurate preoperative identification of PNI could facilitate patient stratification and optimal preoperative treatment. We therefore established and validated a preoperative risk assessment model for GC patients with PNI.Methods: We collected data from 1,195 patients who underwent surgical resection at our hospital between October 2020 and December 2023, with PNI confirmed by pathological examination. We gathered laboratory data, including blood cell count, blood type, coagulation index, biochemical indexes, and tumor markers. Eligible patients were randomly divided into a training set and a testing set at a ratio of 7:3. The important risk factors of PNI were evaluated by random forest package in RStudio. Receiver operating characteristic-area under the curve (ROC-AUC) analysis was used to evaluate the discriminatory ability of the factors for PNI. Univariate and multivariate logistic regression analyses were utilized to verity independent risk factors for patients with PNI, and the logistic regression model and nomogram were constructed based on the results. Calibration curve and decision curve analysis (DCA) were conducted to assess the predictive model. Finally, we verified the prediction equation model using the testing set.
Results: In the training set, 416 GC patients were pathologically diagnosed with PNI. The top 5 important risk factors for PNI were identified as carcinoembryonic antigen (CEA), fibrinogen-to-lymphocyte ratio (FLR), D-dimer, platelet-to-lymphocyte ratio (PLR), and carbohydrate antigen 19-9 (CA19-9), with optimal cut-off values of 3.89 ng/mL, 2.08, 0.24 mg/L, 122.37, and 14.85 U/mL, respectively. Multivariate logistic regression analysis confirmed that CEA, FLR, D-dimer, PLR, CA19-9, and CA72-4 as independent risk factors for PNI (P<0.05). We formulated the following predictive equation: Logit(P) = -1.211 + 0.695 × CEA + 0.546 × FLR + 0.686 × D-dimer + 0.653 × PLR + 0.515 × CA19-9 + 0.518 × CA72-4 (χ2=105.675, P<0.001). The model demonstrated an ROC-AUC value of 0.719 [95% confidence interval (CI): 0.681-0.757] in the training set, with a sensitivity of 68.51% and a specificity of 67.60%. The ROC-AUC value was 0.791 (95% CI: 0.750-0.831) in the testing set (sensitivity: 69.57%, specificity: 56.41%). Calibration curve and DCA confirmed that the model has good discrimination and accuracy.
Conclusions: We successfully established and validated a prediction model for GC patients with PNI based on hematological indicators, hoping that this model can provide an adjunctive tool for predicting PNI in clinical work.

Keywords:  Gastric cancer (GC); inflammatory markers; perineural invasion (PNI); prediction model; risk factors

DOI:  https://doi.org/10.21037/tcr-24-481
Eur J Case Rep Intern Med. 2024 ;11(11): 004818

Malignant Peripheral Nerve Sheath Tumour Presenting as Sciatica in a Patient with Neurofibromatosis Type 1: Is Magnetic Resonance Imaging an Effective Screening Tool?

Adisalem M Teferi, Sangam Sangam, Azana Newman, Osman Alvarado, Irvianny Madera, Julian Paniagua.

  Peripheral malignant nerve sheath tumours (MPNST) are rare and aggressive soft tissue sarcomas often associated with neurofibromatosis type I (NF-1). We describe a case of 26-year-old female with NF-1, initially misdiagnosed as sciatica, who was later found to have a malignant spindle cell peripheral nerve sheath tumour of the right sciatic nerve. Magnetic resonance imaging (MRI) proved to be a valuable tool for diagnosis. This case illustrates the importance of considering the transformation of neurofibromas into MPNST as a potential cause of worsening neuropathic pain in patients with NF-1. Given the overlap in clinical presentation with benign conditions, we analyse the utility of MRI for early screening for. Early detection is crucial to improve the chances of cure and prolonged disease-free survival.LEARNING POINTS: Malignant peripheral nerve sheath tumours can occur in patients with neurofibromatosis and present as sciatica.Magnetic resonance imaging screening should be considered early on in this patient population.

Keywords:  MPNST; Malignant peripheral nerve sheath tumor; NF-1; magnetic resonance imaging; neurofibromatosis type I; sciatica

DOI:  https://doi.org/10.12890/2024_004818
Cancers (Basel). 2024 Oct 29. pii: 3648. [Epub ahead of print]16(21):

The Association Between Lymphovascular or Perineural Invasion in Radical Prostatectomy Specimen and Biochemical Recurrence.

Carolin Siech, Mike Wenzel, Nico Grosshans, Cristina Cano Garcia, Clara Humke, Florestan Johannes Koll, Zhe Tian, Pierre I Karakiewicz, Luis A Kluth, Felix K H Chun, Benedikt Hoeh, Philipp Mandel.

  OBJECTIVE: The aim of this study was to test for the association between lymphovascular invasion or perineural invasion in radical prostatectomy (RP) specimens and biochemical recurrence (BCR).METHODS: Relying on a tertiary-care database, we identified prostate cancer patients treated with RP between January 2014 and June 2023. Of these, the majority underwent robotic-assisted RP (81%). Kaplan-Meier survival analyses and Cox regression models addressed BCR according to either lymphovascular invasion or perineural invasion in RP specimens. Additionally, the linear trend test assessed the association between the Gleason Grade Group or pathologic tumor stage and lymphovascular or perineural invasion.
RESULTS: Of 822 patients, 78 (9%) exhibited lymphovascular invasion and 633 (77%) exhibited perineural invasion in RP specimens. In survival analyses, the five-year BCR-free survival rates were 62% in patients with lymphovascular invasion vs. 70% in patients without lymphovascular invasion (p = 0.04) and 64% in patients with perineural invasion vs. 82% in patients without perineural invasion (p = 0.01). In univariable Cox regression models, lymphovascular invasion (hazard ratio 1.58, 95% confidence interval 1.01-2.47; p = 0.045) and perineural invasion (hazard ratio 1.77, 95% confidence interval 1.13-2.77; p = 0.013) were both associated with a higher BCR rate. After accounting for age at surgery, PSA value, pathologic tumor stage, Gleason Grade Group, lymph node invasion, positive surgical margin, surgical approach, and adjuvant radiation therapy, lymphovascular (p = 0.740) or perineural invasion (p = 0.341) were not significantly associated with a higher BCR since the Gleason Grade Group and pathologic tumor stage highly correlated with lymphovascular as well as perineural invasion.
CONCLUSIONS: In univariable models, lymphovascular or perineural invasion is associated with BCR. After adjustment for standard pathologic tumor characteristics, lymphovascular or perineural invasion is not an independent predictor for BCR.

Keywords:  BCR; lymphovascular invasion; perineural invasion; prostate cancer; radical prostatectomy

DOI:  https://doi.org/10.3390/cancers16213648
Brain Behav Immun. 2024 Nov 10. pii: S0889-1591(24)00698-6. [Epub ahead of print]123 1026-1041

CXCL1-CXCR2 signaling mediates the activation of microglia in the nucleus tractus solitarii to promote pancreatic cancer-induced pain.

Kang Chen, Qingqing Ye, Yanqun Zhang, Zhenhua Qi, Yue Huang, Weicheng Lu, Xintong Wang, Yuting Wang, Lan Cao, Shijuan Qiu, Yixin Xu, Junting Huang, Jingdun Xie.

  Pancreatic cancer can cause severe abdominal pain. Its peripheral mechanisms have been studied, but the role of central nervous system in pancreatic cancer-induced pain remains unclear. The current study focused on the nucleus tractus solitarii (NTS), a primary center of visceral sensation located in medulla oblongata. Neurons in the NTS were activated and exhibited increased excitability among mice with pancreatic cancer-induced pain. Transcriptome analysis revealed that pancreatic cancer-induced pain was associated with neuroinflammation in the NTS, involving changes in chemokines expression. In mice with pancreatic cancer-induced pain, the microglia activation in the NTS was observed, characterized by increased cell density and decreased process number and length, while injection of microglia inhibitor minocycline in the NTS alleviated pancreatic cancer-induced pain. The cytokine CXCL1 and its receptor CXCR2 were upregulated in the NTS of mice with pancreatic cancer-induced pain. Blocking CXCL1-CXCR2 signaling by injection of CXCL1 neutralizing antibody or CXCR2 antagonist SB225002 in the NTS of mice with pancreatic cancer-induced pain alleviated abdominal hypersensitivity and hunching behavior, and also reversed the activation of neurons and microglia. Additionally, injection of recombinant CXCL1 in the NTS of sham-operated mice induced abdominal pain, and activated the neurons and microglia. In summary, our study highlights the critical role of NTS microglia activation mediated by CXCL1-CXCR2 signaling in pancreatic cancer-induced pain.

Keywords:  CXCL1; CXCR2; Microglia; Nucleus tractus solitarii; Pancreatic cancer-induced pain

DOI:  https://doi.org/10.1016/j.bbi.2024.11.016
Neurooncol Adv. 2024 Jan-Dec;6(1):6(1): vdae168

Non-small cell lung cancer with synchronous brain metastases: Identification of prognostic factors in a retrospective multicenter study (HOT 1701).

Yoshihito Ohhara, Tetsuya Kojima, Osamu Honjo, Noriyuki Yamada, Toshitaka Sato, Hirofumi Takahashi, Kei Takamura, Taichi Takashina, Noriaki Sukoh, Hisashi Tanaka, Yasutaka Kawai, Yuka Fujita, Keiki Yokoo, Fumihiro Hommura, Toshiyuki Harada, Ryoichi Honda, Toraji Amano, Hirotoshi Dosaka-Akita, Satoshi Oizumi, Ichiro Kinoshita.

  Background: Non-small-cell lung cancer (NSCLC) is associated with a high incidence of brain metastasis (BM), and the prognosis of patients with NSCLC and BM is poor. This study aimed to identify the prognostic factors and elucidate the survival rates of Japanese patients with NSCLC and BM at initial diagnosis.Methods: HOT 1701 is a retrospective multicenter study of patients with NSCLC and BM at initial diagnosis. The medical records of all consecutive patients diagnosed with advanced or recurrent NSCLC and BM at 14 institutions of the Hokkaido Lung Cancer Clinical Study Group Trial (HOT) in Japan were reviewed. The participants were categorized based on the presence or absence of driver mutations. The Kaplan-Meier method was used to estimate median overall survival (OS). Univariate and multivariate analyses were performed to identify prognostic factors in these patients.
Results: Among 566 patients with NSCLC and BM, the median OS was 11.8 months. Patients with driver mutations survived longer than those without driver mutations. The univariate and multivariate analyses revealed 6 independent prognostic factors: age ≥65 years, poor performance status, T factor, absence of driver gene mutations, presence of extracranial metastases, and number of BM. According to the prognostic score based on these 6 factors, the patients were stratified into 3 risk groups: low-, intermediate-, and high-risk, with median OS of 27.8, 12.2, and 2.8 months, respectively.
Conclusions: We developed a new prognostic model for patients with NSCLC and BM, which may help determine prognosis at diagnosis.

Keywords:  brain metastasis; non-small cell lung cancer; prognostic factor

DOI:  https://doi.org/10.1093/noajnl/vdae168
Cancers (Basel). 2024 Oct 23. pii: 3571. [Epub ahead of print]16(21):

Cancer Therapy-Induced Encephalitis.

Nicolas P Desbaillets, Andreas F Hottinger.

  Encephalitis associated with cancer therapies is a rare but serious complication that can significantly impact patients' quality of life and it requires prompt identification and management. Over the past two decades, immunotherapy-particularly immune checkpoint inhibitors-has become a cornerstone of cancer treatment, with up to half of metastatic cancer patients in economically developed countries now receiving these therapies. The widespread adoption of immunotherapy has led to improved survival rates and long-term remissions, even in patients with advanced metastatic disease. However, as immune modulators, these therapies can trigger a range of immune-related adverse events, including a variety of novel neurological toxicities. Among these, encephalitis is of particular concern due to its potential severity, which can compromise treatment outcomes. This review aims to provide a comprehensive overview of the literature on this condition, highlighting optimal diagnostic strategies and management approaches to mitigate the risk of significant morbidity, while also comparing encephalitis induced by immunotherapy with that caused by traditional chemotherapies and targeted oncologic treatments.

Keywords:  BiTE; CAR-T; ICANS; adverse event; autoimmune; cancer; checkpoint inhibitor; encephalitis; immunotherapy; neurotoxicity

DOI:  https://doi.org/10.3390/cancers16213571
J Biochem Mol Toxicol. 2024 Nov;38(11): e70026

Targeted therapy: P2X3 receptor silencing in bone cancer pain relief.

Yuge Jiang, Xuan Liu, Hong Zhang, Longhe Xu.

  Bone cancer pain remains a significant clinical challenge, often refractory to conventional treatments. The upregulation of the P2X3 receptor in the dorsal root ganglia has been implicated in the pathogenesis of bone cancer pain. This study aimed to elucidate the role of the P2X3 receptor in this context and assess the therapeutic potential of receptor silencing. Utilizing a rat model with Walker 256 cells to simulate bone cancer pain, researchers conducted molecular analyses, including semi-quantitative RT-PCR and Western Blot, to investigate P2X3 receptor expression in the dorsal root ganglia. Results demonstrated a marked increase in P2X3 receptor levels in the dorsal root ganglia of the bone cancer pain model. Targeted silencing of the P2X3 receptor using specific shRNA delivered via lentiviral vectors significantly reduced pain sensitivity, underscoring the receptor's potential as a valuable therapeutic target. In addition, a comprehensive gene expression analysis leveraging the GEO data set GSE249443 was performed to explore the underlying biological pathways linked to bone cancer pain. This analysis provided insights into the intricate interplay between bone cancer pain and associated biological processes, offering a deeper understanding of the mechanisms involved in pain modulation and progression. In conclusion, this research identifies the P2X3 receptor as a critical molecular target for mitigating bone cancer pain. The selective silencing of the P2X3 receptor emerges as a promising and innovative therapeutic strategy, presenting novel avenues for managing bone cancer pain and potentially revolutionizing treatment approaches in this challenging domain.

Keywords:  P2X3 Receptor; bioinformatics analysis; bone cancer pain; dorsal root ganglia; lentiviral vectors; pain sensitivity

DOI:  https://doi.org/10.1002/jbt.70026