bims-netuvo 2024-09-29 papers

bims-netuvo

Biomed News

on Nerves in tumours of visceral organs

Issue of 2024–09–29
thirteen papers selected by
Maksym V. Kopanitsa, Charles River Laboratories

Sensory nerves unlock the TOLL-7 gate for cancer spread.
Protocol for a non-surgical model of perineural invasion for assessing neural drivers of cancer aggressiveness in mice.
Neural control of tumor immunity.
Blood-brain barrier and blood-brain tumor barrier penetrating peptide-drug conjugate as targeted therapy for the treatment of lung cancer brain metastasis.
A brain-body feedback loop driving HPA-axis dysfunction in breast cancer.
A rare case of giant pelvic retroperitoneal schwannoma.
Schwannoma at an Unusual Site: Case Report and Surgical Technique Discussion for Nasal Dorsum.
Multi-dimensional immunotyping of human NF1-associated peripheral nerve sheath tumors uncovers tumor-associated macrophages as key drivers of immune evasion in the tumor microenvironment.
Radiomics to predict PNI in ESCC.
Comprehensive study of ancient schwannoma: Exploring histomorphological diversity and diagnostic challenges.
Role of Neurotropic Viruses in Brain Metastasis of Breast Cancer: Mechanisms and Therapeutic Implications.
Cancer characteristics in patients with schizophrenia: a 25-year retrospective analysis.
Neurological complications in oncology and their monitoring and management in clinical practice: a narrative review.

Trends Immunol. 2024 Sep 25. pii: S1471-4906(24)00213-8. [Epub ahead of print]

Sensory nerves unlock the TOLL-7 gate for cancer spread.

R K Subbarao Malireddi, Thirumala-Devi Kanneganti.

  Cancers hijack the nervous system for growth and spread. Thus, disrupting neuron-cancer crosstalk holds promise for blocking metastasis. Recently, Padmanaban et al. reported new therapeutic targets and showed that breast cancer cells activate sensory neurons to secrete the neuropeptide substance P (SP), leading to single-strand (ss)RNA release and noncanonical Toll-like receptor (TLR)7 signaling that drives metastasis.

Keywords:  TACR1; TLR7; apoptosis; aprepitant; breast cancer; ssRNA; substance P

DOI:  https://doi.org/10.1016/j.it.2024.09.005
STAR Protoc. 2024 Sep 26. pii: S2666-1667(24)00510-0. [Epub ahead of print]5(4): 103345

Protocol for a non-surgical model of perineural invasion for assessing neural drivers of cancer aggressiveness in mice.

Tiago H Zaninelli, Telma Saraiva-Santos, Brielle H Patlin, Michael Slade Stratton, David Y Chen, Felipe A Pinho-Ribeiro.

  Perineural invasion (PNI) is a significant risk factor for cancer recurrence and metastasis; however, its mechanisms relating to cancer aggressiveness remain poorly understood. Here, we present a protocol for a non-surgical model of PNI in mice using a neurotropic melanoma cell line that migrates from the skin to the sciatic nerve. We describe the steps for cell culture and injection, tumor burden measurements, mouse euthanasia, and tissue dissection. We then detail procedures for sample cross-section and confocal imaging.

Keywords:  Cancer; Model Organisms; Neuroscience

DOI:  https://doi.org/10.1016/j.xpro.2024.103345
FEBS J. 2024 Sep 20.

Neural control of tumor immunity.

Burak Kizil, Francesco De Virgiliis, Christoph Scheiermann.

  Communication between the nervous system and the immune system has evolved to optimally respond to potentially dangerous stimuli both from within and outside the body. Tumors pose a severe threat to an organism and current therapies are insufficient for tumor regression in the majority of cases. Studies show that tumors are innervated by peripheral nerves from the sensory, parasympathetic and sympathetic nervous systems. Interactions between cancer cells, nerves and immune cells regulate overall tumor progression. Clinical studies have indicated the potential of targeting the peripheral nervous system for promoting anti-tumor immune responses. This view point provides an opinion on the current evidence and therapeutic potential of manipulating neuro-immune communications in cancer.

Keywords:  cancer; cancer neuroimmunology; immune system; nervous system; neuroimmunology; tumor immunology

DOI:  https://doi.org/10.1111/febs.17280
Lung Cancer. 2024 Sep 18. pii: S0169-5002(24)00491-4. [Epub ahead of print]196 107957

Blood-brain barrier and blood-brain tumor barrier penetrating peptide-drug conjugate as targeted therapy for the treatment of lung cancer brain metastasis.

Meng-Zhu Zheng, Zhan-Qun Yang, Sun-Li Cai, Li-Ting Zheng, Yuan Xue, Long Chen, Jian Lin.

  Lung cancer is the leading cause of cancer deaths worldwide. Brain metastasis of lung cancer, which counts for nearly 50% of late-stage lung cancer patients, is a sign of a really poor prognosis. However, the presence of blood-brain barrier (BBB) and blood-brain tumor barrier (BBTB) limits the penetration of drugs from the blood into the brain and thus restricts their accumulation in brain tumors. Systematic delivery of drugs into brain and brain tumor lesion using BBB and BBTB penetrating vehicles represents a promising strategy to overcome the BBB and BBTB limitations. Hence, we validated one of our previously identified BBB/BBTB penetrating peptide and its drug conjugate form for the treatment of lung cancer brain metastasis. With in vitro experiment, we first validated that the receptor LRP1, which mediated the peptide penetration of the BBB, was expressed on lung cancer cells and thus can be targeted by the peptide to overcome BBTB. With this delivery peptide, we constructed peptide-paclitaxel conjugate (the PDC) and in vitro validation showed that the PDC can across the BBB and efficiently kill lung cancer cells. We therefore constructed mouse lung cancer brain metastasis xenograft. In vivo anti-tumor validations showed that the PDC efficiently inhibited the proliferation of the brain resident lung cancer cells and significantly expanded the survival of the mouse xenograft, with no visible damages to the organs. Overall, our study provided potential therapeutic drugs for the treatment of lung cancer brain metastasis that may be clinically effective in the near future.

Keywords:  Blood-Brain Barrier; Blood-Brain Tumor Barrier; LRP1; Lung cancer brain metastases; Peptide-drug conjugates

DOI:  https://doi.org/10.1016/j.lungcan.2024.107957
bioRxiv. 2024 Sep 14. pii: 2024.09.13.612923. [Epub ahead of print]

A brain-body feedback loop driving HPA-axis dysfunction in breast cancer.

Adrian Gomez, Yue Wu, Chao Zhang, Leah Boyd, Tse-Luen Wee, Joseph Gewolb, Corina Amor, Lucas Cheadle, Jeremy C Borniger.

Breast cancer patients often exhibit disrupted circadian rhythms in circulating glucocorticoids (GCs), such as cortisol. This disruption correlates with reduced quality of life and higher cancer mortality 1-3 . The exact cause of this phenomenon - whether due to treatments, stress, age, co-morbidities, lifestyle factors, or the cancer itself remains unclear. Here, we demonstrate that primary breast cancer alone blunts host GC rhythms by disinhibiting neurons in the hypothalamus, and that circadian phase-specific neuromodulation of these neurons can attenuate tumor growth by enhancing anti-tumor immunity. We find that mice with mammary tumors exhibit blunted GC rhythms before tumors are palpable, alongside increased activity in paraventricular hypothalamic neurons expressing corticotropin-releasing hormone (i.e., PVN CRH neurons). Tumor-bearing mice have fewer inhibitory synapses contacting PVN CRH neurons and reduced miniature inhibitory post-synaptic current (mIPSC) frequency, leading to net excitation. Tumor-bearing mice experience impaired negative feedback on GC production, but adrenal and pituitary gland functions are largely unaffected, indicating that alterations in PVN CRH neuronal activity are likely a primary cause of hypothalamic-pituitary-adrenal (HPA) axis dysfunction in breast cancer. Using chemogenetics (hM3Dq) to stimulate PVN CRH neurons at different circadian phases, we show that stimulation just before the light-to-dark transition restores normal GC rhythms and reduces tumor progression. These mice have significantly more effector T cells (CD8+) within the tumor than non-stimulated controls, and the anti-tumor effect of PVN CRH neuronal stimulation is absent in mice lacking CD8+ T cells. Our findings demonstrate that breast cancer distally regulates neurons in the hypothalamus that control output of the HPA axis and provide evidence that therapeutic targeting of these neurons could mitigate tumor progression.

DOI: https://doi.org/10.1101/2024.09.13.612923
Radiol Case Rep. 2024 Dec;19(12): 5738-5743

A rare case of giant pelvic retroperitoneal schwannoma.

Takashi Kawahori, Shoichiro Mukai, Yasufumi Saito, Toshihiro Nishida, Toshikatsu Fukuda, Hideki Ohdan.

  This report highlights the successful treatment of large pelvic schwannomas and underscores the importance of preoperative embolization. A 40-year-old male presented with a lower abdominal mass and reported pain and numbness in the left lower limb attributed to nerve compression. Preoperative embolization of the main feeding vessels was performed to mitigate intraoperative bleeding. The tumor was completely excised during surgery, with preservation of the hypogastric nerve. Histopathological examination confirmed the diagnosis of schwannoma. We underscore the significant role of preoperative embolization in effectively managing large pelvic tumors, such as schwannomas, by reducing the risk of excessive bleeding.

Keywords:  Embolization; Giant schwannoma; Retro-peritoneal tumor

DOI:  https://doi.org/10.1016/j.radcr.2024.08.109
Case Rep Otolaryngol. 2024 ;2024 9422104

Schwannoma at an Unusual Site: Case Report and Surgical Technique Discussion for Nasal Dorsum.

Sultan K Kadasah, Abdulrazaq M Alshammari, Nader S Alharbi, Ibtihal S Alshehri, Raghad Y Alasiri, Saud A Aldhabaan, Ghalib X Alsayed, Adnan Q Almalki.

Peripheral nerve sheath tumors (PNSTs), while uncommon, can have a significant impact on appearance and quality of life, especially when they form in prominent areas such as the nose dorsum. We discuss a case of a 29-year-old woman who developed a benign PNST on the right side of her nasal ala. This tumor gradually grew, impairing her face appearance. Diagnostic tests, such as computed tomography (CT) and magnetic resonance imaging (MRI), revealed the tumor as a slowly growing, well-defined mass. The tumor was removed via open rhinoplasty under general anesthesia, and pathological investigation verified its benign nature. After surgery, the patient's quality of life improved significantly, and there were no evidence of tumor recurrence after eight months. This case emphasizes the need of including PNST in the differential diagnosis of nasal tumors.

DOI: https://doi.org/10.1155/2024/9422104
Clin Cancer Res. 2024 Sep 25.

Multi-dimensional immunotyping of human NF1-associated peripheral nerve sheath tumors uncovers tumor-associated macrophages as key drivers of immune evasion in the tumor microenvironment.

Lindy Zhang, Alexandre Maalouf, Stavriani C Makri, Jineta Banerjee, Aditya Suru, Ada J Tam, Ana Calizo, Kai Pollard, Jiawan Wang, Ludmila Danilova, Maria Ioannou, Adam S Levin, Carol D Morris, Daniel S Rhee, Allan J Belzberg, Jaishri O Blakeley, Brian H Ladle, Drew M Pardoll, Calixto-Hope G Lucas, Fausto J Rodriguez, John M Gross, Robert A Anders, Christine A Pratilas, Nicolas J Llosa.

PURPOSE: Malignant peripheral nerve sheath tumors (MPNST) are aggressive soft tissue sarcomas and the leading cause of mortality in individuals with neurofibromatosis type 1 (NF1). Despite many clinical trials, outcomes for patients with MPNST have remained stagnant and most succumb to their disease; thus, novel therapeutic approaches are needed. A better understanding of the MPNST immune ecosystem will aid in the development of strategies to activate the immune system against the tumor. Herein, we profile the tumor immune microenvironment (TIME) in NF1-associated peripheral nerve sheath tumors (PNST) to discover insights on the role that tumor-infiltrating immune cells play in malignant transformation.
EXPERIMENTAL DESIGN: Utilizing fresh and formalin-fixed, paraffin-embedded tissue from patients diagnosed with NF1-PNST, we dissected the TIME by using immunohistochemistry, multiparameter flow cytometry, and comparative transcriptomic studies.
RESULTS: Immunophenotyping confirmed increased immune cells infiltration during malignant progression, with a predominance of infiltrating myeloid cells, particularly CD163+ tumor-associated macrophages (TAM). The T cells within MPNST exhibited signs of tumor activation, characterized by high PD-1 expression. Additionally, MPNST specimens demonstrated elevated levels of immunosuppressive TAM, with heightened PD-L1 expression. The proportion of CD163+ myeloid cells within the TIME correlated with poorer progression free survival. Notably, loss of H3K27 trimethylation correlated with low immune cell infiltration in MPNST.
CONCLUSIONS: Malignant transformation of NF1-PNST is characterized by an immunosuppressive microenvironment comprising of TAM with high expression of PD-L1, which are associated with inferior outcomes. These findings suggest a clinical potential of immune modulating therapeutics that can unleash an anti-tumor immune response.

DOI: https://doi.org/10.1158/1078-0432.CCR-24-1454
Abdom Radiol (NY). 2024 Sep 23.

Radiomics to predict PNI in ESCC.

Yang Li, Li Yang, Xiaolong Gu, Xiangming Wang, Qi Wang, Gaofeng Shi, Andu Zhang, Huiyan Deng, Xiaopeng Zhao, Jialiang Ren, Aijun Miao, Shaolian Li.

   OBJECTIVE: This study aimed to investigate whether contrast-enhanced computed tomography (CECT) based radiomics analysis could noninvasively predict the perineural invasion (PNI) in esophageal squamous cell carcinoma (ESCC).
METHODS: 398 patients with ESCC who underwent resection between February 2016 and March 2020 were retrospectively enrolled in this study. Patients were randomly divided into training and testing cohorts in a 7:3 ratio. Radiomics analysis was performed on the arterial phase images of CECT scans. From these images, 1595 radiomics features were initially extracted. The intraclass correlation coefficient (ICC), wilcoxon rank-sum test, spearman correlation analysis, and boruta algorithm were used for feature selection. Logistic regression (LR), random forest (RF), and support vector machine (SVM) models were established to preidict the PNI status. The performance of these radiomics models was assessed by the area under the receiver operating characteristic curve (AUC). Decision curve analysis (DCA) was conducted to evaluate their clinical utility.
RESULTS: Six radiomics features were retained to build the radiomics models. Among these models, the random forest (RF) model demonstrated superior performance. In the training cohort, the AUC value of the RF model was 0.773, compared to 0.627 for the logistic regression (LR) model and 0.712 for the support vector machine (SVM) model. Similarly, in the testing cohort, the RF model achieved an AUC value of 0.767, outperforming the LR model at 0.638 and the SVM model at 0.683. Decision curve analysis (DCA) suggested that the RF radiomics model exhibited the highest clinical utility.
CONCLUSIONS: CECT-based radiomics analysis, particularly utilizing the RF, can noninvasively predict the PNI in ESCC preoperatively. This novel approach could enhance patient management by providing personalized information, thereby facilitating the development of individualized treatment strategies for ESCC patients.

Keywords:  Computed tomography; Contrast-enhanced; Esophageal squamous cell carcinoma; Perineural invasion; Radiomics

DOI:  https://doi.org/10.1007/s00261-024-04562-8
Rare Tumors. 2024 ;16 20363613241274259

Comprehensive study of ancient schwannoma: Exploring histomorphological diversity and diagnostic challenges.

Chaithra Gowthuvalli Venkataramana, Soumya Gupta, Rakshatha Nayak, Sinchana Km, Sharada Rai, Ranjitha Rao.

  Background: Ancient schwannoma is a rare subtype of schwannoma characterized by an extended duration of development and distinctive degenerative changes. These changes encompass relative loss of Antoni type A areas, perivascular hyalinization, hemorrhage, cystic necrosis, calcification, and the presence of atypical nuclei that can mimic sarcomatous pleomorphism. These histologic features often lead to diagnostic challenges, with ancient schwannomas frequently being misdiagnosed as malignant tumors. Objectives: This study aims to provide a comprehensive evaluation of the histomorphological spectrum observed in ancient schwannoma. Methods: A retrospective analysis was conducted on 248 schwannoma cases received at our tertiary health centre, spanning the years 2017 to 2023. Among these cases, 25 were identified as ancient schwannoma. Extensive examination of degenerative changes was performed using hematoxylin and eosin-stained paraffin-embedded tissue sections under light microscopy. Results: Patient ages ranged from 22 to 82 years, with a nearly equal distribution between genders (12 females and 13 males). Tumors were located in various anatomical sites including the forearm, brain, abdomen, retroperitoneum, intradural space, lumbar region, and pelvis. Tumor dimensions varied from 1.5 to 11 cm. Histologically, most cases exhibited nuclear atypia, cystic changes, hemorrhage, and siderophages, along with perivascular hyalinization, myxoid change, calcification, and xanthomatous change. Immunohistochemistry confirmed the neural origin of these tumors. Conclusion: Recognition of the diverse spectrum of secondary changes, coupled with the presence of focal areas showing paucicellular and cellular spindle cell arrangements, is crucial for the accurate diagnosis of ancient schwannoma. This study underscores the importance of histomorphological evaluation in distinguishing these benign tumors from malignant counterparts, thereby guiding appropriate clinical management strategies.

Keywords:  Ancient schwannoma; degeneration; histomorphology; neurilemmoma; peripheral nerve

DOI:  https://doi.org/10.1177/20363613241274259
Rev Med Virol. 2024 Sep;34(5): e2584

Role of Neurotropic Viruses in Brain Metastasis of Breast Cancer: Mechanisms and Therapeutic Implications.

Ziran Qiu, Xinyu Liu, Wenqing Cao, Rui Li, Jun Yang, Chengyu Wang, Zhong Li, Xiaoqin Yao, Yuan Chen, Chunhua Ye, Shanzheng Chen, Na Jin.

  Neurotropic viruses have been implicated in altering the central nervous system microenvironment and promoting brain metastasis of breast cancer through complex interactions involving viral entry mechanisms, modulation of the blood-brain barrier, immune evasion, and alteration of the tumour microenvironment. This narrative review explores the molecular mechanisms by which neurotropic viruses such as Herpes Simplex Virus, Human Immunodeficiency Virus, Japanese Encephalitis Virus, and Rabies Virus facilitate brain metastasis, focusing on their ability to disrupt blood-brain barrier integrity, modulate immune responses, and create a permissive environment for metastatic cell survival and growth within the central nervous system. Current therapeutic implications and challenges in targeting neurotropic viruses to prevent or treat brain metastasis are discussed, highlighting the need for innovative strategies and multidisciplinary approaches in virology, oncology, and immunology.

Keywords:  blood–brain barrier; brain metastasis; immune modulation; neurotropic viruses; tumour microenvironment

DOI:  https://doi.org/10.1002/rmv.2584
Psychiatry Res. 2024 Sep 19. pii: S0165-1781(24)00491-8. [Epub ahead of print]342 116206

Cancer characteristics in patients with schizophrenia: a 25-year retrospective analysis.

Francesc Casanovas, Fernando Dinamarca, Margarita Posso, Anna Mané, Sílvia Oller, David Córcoles, Francesc Macià, Maria Sala, Víctor Pérez-Sola, Ada I Ruiz.

  Schizophrenia is associated with higher cancer-related mortality, perhaps due to delayed diagnosis and limited access to treatment. The study aimed to compare patients diagnosed with cancer with and without schizophrenia to determine whether these groups differ in terms of oncological variables and survival outcomes. This was a retrospective, observational cohort study that included 30.990 patients diagnosed with cancer between 1997 and 2021. We performed univariate and bivariate analyses for the sociodemographic and clinical variables, and constructed Kaplan-Meier survival curves and used the log-rank test to perform the comparisons. All variables were compared for each cancer type. One hundred and sixty-two (0.52 %) patients had a confirmed diagnosis of schizophrenia (ICD-9 criteria). The mean age at diagnosis was significantly lower in the schizophrenia group. A significantly higher proportion of the schizophrenia group was diagnosed with cancer through the emergency department and a lower percentage through scheduled appointments. A smaller percentage of patients in the schizophrenia group received radical treatment for cancer. The mortality rate was higher in the schizophrenia group and median survival was lower. These findings suggest that cancer patients with schizophrenia have worse outcomes than patients without schizophrenia in terms of oncological variables and survival.

Keywords:  Cancer survival; Oncological variables; Psychosis; Somatic comorbidity

DOI:  https://doi.org/10.1016/j.psychres.2024.116206
Support Care Cancer. 2024 Sep 25. 32(10): 685

Neurological complications in oncology and their monitoring and management in clinical practice: a narrative review.

Stefanie Fischer, Malte von Bonin, Martin Bornhäuser, Christian Beste, Tjalf Ziemssen.

   IMPORTANCE: New anti-tumor treatments, such as immune checkpoint inhibitors and CAR T-cell therapy, are associated with an increasing number of neurological issues linked to tumors not arising from nervous system such as neurological and neuropsychological side effects that can significantly impair quality of life in the short or long term. The science of pathomechanisms, therapeutic approaches, and preventive measures is still in its early stages, and the progress is hampered by the lack of studied connection between neurological and oncological disciplines.
OBJECTIVES: This work aimed to provide an overview of the questions raised in the field of clinical neuroscience that concern the outcomes of oncological diseases and their treatment. Furthermore, we give an outline of how a collaborative approach between neurology and oncology, with the implementation of neuroscience techniques including up-to-date diagnostics and therapy, can help to improve the quality of oncological patients' lives.
EVIDENCE REVIEW: The covered areas of investigation in the evaluated articles primarily encompassed the review of known neurological complications of oncological diseases caused by neurotoxic mechanisms of performed therapies or those linked to concurrent pathological conditions. Similarly, the methods of their diagnostics were assessed.
FINDINGS: Our literature review of 65 articles, including clinical trials, cohort studies, reviews, and theoretically based in vitro studies published between 1998 and 2023, outlines the broad spectrum of neurological complications primarily associated with malignant diseases and the anti-tumor therapies employed. Notably, immune-mediated complications, whose incidence is increasing due to the expanding use of new immunotherapies, require early detection and targeted treatment to prevent severe progression. In this context, neurological complications mediated by immune checkpoint inhibitors are often associated with significant impairments and high mortality, necessitating specialist consultation for early detection and differentiation from other phenotypically similar syndromes. Current data on the pathophysiology of these neurological complications are not reliable due to the limited number of studies. Moreover, there is a lack of evidence regarding the appropriate oncological approach in the event of therapy-related complications. Initial study results suggest that the establishment of interdisciplinary treatment interfaces for the management of oncology patients could improve the safety of these therapies and enhance the patients' quality of life.
CONCLUSIONS AND RELEVANCE: The accumulated knowledge on neurotoxicity caused by oncological diseases shows that the challenges in diagnosing and managing this condition are expanding in tandem with the growing array of therapies being employed. Therefore, it requires interdisciplinary approach with the introduction of new facilities enabling more personalized patient care.

Keywords:  Neurotoxicity; Oncology; Tumor

DOI:  https://doi.org/10.1007/s00520-024-08894-5