bims-netuvo 2023-04-16 papers

bims-netuvo

Biomed News

on Nerves in tumours of visceral organs

Issue of 2023‒04‒16
nineteen papers selected by
Maksym V. Kopanitsa, The Francis Crick Institute

Cancer neuroscience: State of the field, emerging directions.
The neural addiction of cancer.
A CRISPR/Cas9-Based Assay for High-Throughput Studies of Cancer-Induced Innervation.
Pancreatic Ductal Adenocarcinoma Induces Neural Injury that Promotes a Transcriptomic and Functional Repair Signature by Peripheral Neuroglia.
Long noncoding RNA DIAPH2-AS1 promotes neural invasion of gastric cancer via stabilizing NSUN2 to enhance the m5C modification of NTN1.
GAP-43 targeted indocyanine green-loaded near-infrared fluorescent probe for real-time mapping of perineural invasion lesions in pancreatic cancer in vivo.
ASO Visual Abstract: Perineural Invasion in Papillary Thyroid Cancer-A Rare Indicator of Aggressive Disease.
Neurogenesis manifestations of solid tumor and tracer imaging studies: a narrative review.
Nervous regulation: beta-2-adrenergic signaling in immune homeostasis, cancer immunotherapy, and autoimmune diseases.
Perineurioma of the sciatic nerve with reticular, microcystic, and pseudolipoblastic features: illustrative case.
PATTERN OF A PRIMARY B-CELL LYMPHOMA IN ULNAR NERVE: INTRANEURAL OR EXTRANEURAL.
Imaging in gynecological disease: clinical and ultrasound characteristics of benign retroperitoneal pelvic nerve sheath tumors.
Risk Stratification of Low-Risk Prostate Cancer: Individualizing Care in the Era of Active Surveillance.
Beta-adrenergic receptor blocker propranolol triggers anti-tumor immunity and enhances irinotecan therapy in mice colorectal cancer.
Solving the Mystery of Giant Intrathoracic Mass.
A Rare Case of Hypoglossal Nerve Schwannoma Presenting as Hemiatrophy of the Tongue: A Case Report.
Epigenetic Rewiring of Metastatic Cancer to the Brain: Focus on Lung and Colon Cancers.
Diagnosis and Treatment of Peripheral and Cranial Nerve Tumors with Expert Recommendations: An EUropean Network for RAre CANcers (EURACAN) Initiative.
Lower extremity peripheral nerve pathology: Utility of preoperative ultrasound-guided needle localization before operative intervention.

Cell. 2023 Apr 13. pii: S0092-8674(23)00104-6. [Epub ahead of print]186(8): 1689-1707

Cancer neuroscience: State of the field, emerging directions.

Frank Winkler, Humsa S Venkatesh, Moran Amit, Tracy Batchelor, Ihsan Ekin Demir, Benjamin Deneen, David H Gutmann, Shawn Hervey-Jumper, Thomas Kuner, Donald Mabbott, Michael Platten, Asya Rolls, Erica K Sloan, Timothy C Wang, Wolfgang Wick, Varun Venkataramani, Michelle Monje.

The nervous system governs both ontogeny and oncology. Regulating organogenesis during development, maintaining homeostasis, and promoting plasticity throughout life, the nervous system plays parallel roles in the regulation of cancers. Foundational discoveries have elucidated direct paracrine and electrochemical communication between neurons and cancer cells, as well as indirect interactions through neural effects on the immune system and stromal cells in the tumor microenvironment in a wide range of malignancies. Nervous system-cancer interactions can regulate oncogenesis, growth, invasion and metastatic spread, treatment resistance, stimulation of tumor-promoting inflammation, and impairment of anti-cancer immunity. Progress in cancer neuroscience may create an important new pillar of cancer therapy.

DOI: https://doi.org/10.1016/j.cell.2023.02.002
Nat Rev Cancer. 2023 Apr 11.

The neural addiction of cancer.

Claire Magnon, Hubert Hondermarck.

The recently uncovered key role of the peripheral and central nervous systems in controlling tumorigenesis and metastasis has opened a new area of research to identify innovative approaches against cancer. Although the 'neural addiction' of cancer is only partially understood, in this Perspective we discuss the current knowledge and perspectives on peripheral and central nerve circuitries and brain areas that can support tumorigenesis and metastasis and the possible reciprocal influence that the brain and peripheral tumours exert on one another. Tumours can build up local autonomic and sensory nerve networks and are able to develop a long-distance relationship with the brain through circulating adipokines, inflammatory cytokines, neurotrophic factors or afferent nerve inputs, to promote cancer initiation, growth and dissemination. In turn, the central nervous system can affect tumour development and metastasis through the activation or dysregulation of specific central neural areas or circuits, as well as neuroendocrine, neuroimmune or neurovascular systems. Studying neural circuitries in the brain and tumours, as well as understanding how the brain communicates with the tumour or how intratumour nerves interplay with the tumour microenvironment, can reveal unrecognized mechanisms that promote cancer development and progression and open up opportunities for the development of novel therapeutic strategies. Targeting the dysregulated peripheral and central nervous systems might represent a novel strategy for next-generation cancer treatment that could, in part, be achieved through the repurposing of neuropsychiatric drugs in oncology.

DOI: https://doi.org/10.1038/s41568-023-00556-8
Cancers (Basel). 2023 Mar 29. pii: 2026. [Epub ahead of print]15(7):

A CRISPR/Cas9-Based Assay for High-Throughput Studies of Cancer-Induced Innervation.

Sapthala Loku Galappaththi, Brenna Katz, Patrick H Howze, Gregory Hoover, Simon Grelet.

  The aggressive nature of certain cancers and their adverse effects on patient outcomes have been linked to cancer innervation, where neurons infiltrate and differentiate within the cancer stroma. Recently we demonstrated how cancer plasticity and TGFβ signaling could promote breast cancer innervation that is associated with increased cancer aggressivity. Despite the promising potential of cancer innervation as a target for anti-cancer therapies, there is currently a significant lack of effective methods to study cancer-induced neuronal differentiation, hindering the development of high-throughput approaches for identifying new targets or pharmacological inhibitors against cancer innervation. To overcome this challenge, we used CRISPR-based endogenous labeling of the neuronal marker β3-tubulin in neuronal precursors to investigate cancer-induced neuronal differentiation in nerve-cancer cocultures and provide a tool that allows for better standardization and reproducibility of studies about cancer-induced innervation. Our approach demonstrated that β3-tubulin gene editing did not affect neuronal behavior and enabled accurate reporting of cancer-induced neuronal differentiation dynamics in high-throughput settings, which makes this approach suitable for screening large cohorts of cells or testing various biological contexts. In a more context-based approach, by combining this method with a cell model of breast cancer epithelial-mesenchymal transition, we revealed the role of cancer cell plasticity in promoting neuronal differentiation, suggesting that cancer innervation represents an underexplored path for epithelial-mesenchymal transition-mediated cancer aggressivity.

Keywords:  axonogenesis; cancer innervation; cancer plasticity; epithelial-mesenchymal transition; neurogenesis; neuronal differentiation; β3-tubulin

DOI:  https://doi.org/10.3390/cancers15072026
Res Sq. 2023 Mar 28. pii: rs.3.rs-2715023. [Epub ahead of print]

Pancreatic Ductal Adenocarcinoma Induces Neural Injury that Promotes a Transcriptomic and Functional Repair Signature by Peripheral Neuroglia.

Jonathan Weitz, Bharti Garg, Herve Tiriac, Alexei Martsinkovskiy, Sandip Patel, Andrew Lowy.

Perineural invasion (PNI) is the phenomenon whereby cancer cells invade the space surrounding nerves. PNI occurs frequently in epithelial malignancies, but is especially characteristic of pancreatic ductal adenocarcinoma (PDAC). The presence of PNI portends an increased incidence of local recurrence, metastasis and poorer overall survival. While interactions between tumor cells and nerves have been investigated, the etiology and initiating cues for PNI development is not well understood. Here, we used digital spatial profiling to reveal changes in the transcriptome and to allow for a functional analysis of neural-supportive cell types present within the tumor-nerve microenvironment of PDAC during PNI. We found that hypertrophic tumor-associated nerves within PDAC express transcriptomic signals of nerve damage including programmed cell death, Schwann cell proliferation signaling pathways, as well as macrophage clearance of apoptotic cell debris by phagocytosis. Moreover, we identified that neural hypertrophic regions have increased local neuroglial cell proliferation which was tracked using EdU tumor labeling in KPC mice. This study reveals a common gene expression pattern that characterizes solid tumor-induced damage to local nerves. These data provide new insights into the pathobiology of the tumor-nerve microenvironment during PDAC as well as other gastrointestinal cancers.

DOI: https://doi.org/10.21203/rs.3.rs-2715023/v1
Cell Death Dis. 2023 04 10. 14(4): 260

Long noncoding RNA DIAPH2-AS1 promotes neural invasion of gastric cancer via stabilizing NSUN2 to enhance the m5C modification of NTN1.

Ying Li, Yiwen Xia, Tianlu Jiang, Zetian Chen, Yikai Shen, Jie Lin, Li Xie, Chao Gu, Jialun Lv, Chen Lu, Diancai Zhang, Hao Xu, Li Yang, Zekuan Xu, Linjun Wang.

Neural invasion (NI) is a vital pathological characteristic of gastric cancer (GC), which correlates with tumor recurrence and a worse prognosis. Long noncoding RNAs (lncRNAs) play critical roles in various biological processes. However, the involvement of lncRNAs in NI of GC (GC-NI) remains unclear. DIAPH2-AS1 was upregulated in NI-positive GC tissues, which was confirmed by qRT-PCR. The higher expression of DIAPH2-AS1 predicted NI and worse survival for GC patients. Both in vitro and in vivo experiments, including wound-healing assay, Transwell assay, DRG-GC cells co-culture model, the mouse sciatic nerve model, and the lung metastasis model, indicated that DIAPH2-AS1 promoted the migration, invasion, and NI potential of GC cells. Mechanistically, pulldown assay and RNA immunoprecipitation assay revealed that DIAPH2-AS1 interacted with NSUN2. Subsequent experiments indicated that DIAPH2-AS1 stabilized NSUN2 from ubiquitin-proteasomal degradation via masking the K577 and K579 of NSUN2. The protection of DIAPH2-AS1 on NSUN2 improved the stability of NTN1 mRNA via m5C modification, which finally induced GC-NI. Our work uncovered DIAPH2-AS1 as a novel oncogenic lncRNA in GC-NI and validated the DIAPH2-AS1-NSUN2-NTN1 axis as a potential therapeutic target for NI-positive GC.

DOI: https://doi.org/10.1038/s41419-023-05781-5
Nanomedicine. 2023 Apr 11. pii: S1549-9634(23)00022-9. [Epub ahead of print] 102671

GAP-43 targeted indocyanine green-loaded near-infrared fluorescent probe for real-time mapping of perineural invasion lesions in pancreatic cancer in vivo.

Wen Liang Lu, Houfang Kuang, Jianyou Gu, Xiaojun Hu, Bo Chen, Yingfang Fan.

  OBJECTIVE: Perineural invasion (PNI) is associated with local recurrence, distant metastasis, and a poor prognosis in pancreatic cancer. However, rare attempt was made to identified the PNI intraoperative. To facilitate precise R0 excision of the tumor, we planned to develop a fluorescent probe for intraoperative imaging of the PNI using GAP-43 as the target and indocyanine green (ICG) as the carrier.METHODS: The probe was created by binding peptide antibody and ICG. Its targeting was tested in vitro and in vivo using a co-culture model of PC12 and tumor cells to create an in vitro neural invasion model and a mouse sciatic nerve invasion model. The small animal imaging system and surgical navigation system confirmed the probe's potential clinical applicability. The sciatic nerve damage model was created to confirm the probe's targeting.
RESULTS: We used the pancreatic cancer samples and the public database to confirm that GAP-43 was preferentially overexpressed in pancreatic cancer, particularly in PNI. PC12 cells showed high GAP-43RA-PEG-ICG probe-specific absorption after being co-cultured with tumor cells in vitro. In the sciatic nerve invasion experiment, animals in probe group displayed a significantly stronger fluorescence signal at the PNI compared to ICG-NP and the contralateral normal nerves groups. Although only 60 % of mice appeared to have R0 resections by the naked eye, small animal imaging systems and surgical fluorescence navigation systems could remove the tumor with R0 precision. The injury model used in the probe imaging experimental trials demonstrated that the probe was specifically targeted to the injured nerve, regardless of whether the injury was infiltrated by a tumor or physical.
CONCLUSION: We developed the GAP-43Ra-ICG-PEG, an active-targeting near-infrared fluorescent (NIF) probe, that specifically binds to GAP-43-positive neural cells in an in vitro model of PNI. The probe efficiently visualized PNI lesions in pancreatic cancer in preclinical models, opening up new possibilities for NIRF-guided pancreatic surgery, particularly for PNI patients.

Keywords:  GAP-43; NIF; PNI; Pancreatic cancer; Surgical navigation

DOI:  https://doi.org/10.1016/j.nano.2023.102671
Ann Surg Oncol. 2023 Apr 13.

ASO Visual Abstract: Perineural Invasion in Papillary Thyroid Cancer-A Rare Indicator of Aggressive Disease.

Jessica Limberg, Yeon J Lee-Saxton, Caitlin E Egan, AlAnoud AlAnazi, Imaani Easthausen, Dessislava Stefanova, Alexia Stamatiou, Toni Beninato, Rasa Zarnegar, Theresa Scognamiglio, Thomas J Fahey, Brendan M Finnerty.

DOI: https://doi.org/10.1245/s10434-023-13412-8
Am J Cancer Res. 2023 ;13(3): 713-726

Neurogenesis manifestations of solid tumor and tracer imaging studies: a narrative review.

Yan Huang, Boqi Xiang, Anne Manyande, Hongbing Xiang, Jun Xiong.

With the emergence of the scientific research field of tumor microenvironment, the idea that tumor growth and propagation cannot be separated from the tumor microenvironment has become common. The autonomic nervous system is involved in the whole process of growth and development of the organism, and it is undeniable that the tumor microenvironment is equally regulated by both the autonomic nervous system and the immune system. Our research focused on the cancer-nerve crosstalk process and revealed the regulatory mechanisms between the autonomic nervous system and prostate, gastric, pancreatic ductal and breast cancers, mainly elucidating that (1) the release of neurotransmitters and their receptors by autonomic nerves may be important for solid tumor progression, and (2) in combination with the latest targeted small molecule imaging technology, we summarized the biological pathways related to neurotransmitters as small molecule tracers to track solid tumor progression. This research focused on combining targeted small molecules and imaging techniques to observe sympathetic and parasympathetic processes that promote or inhibit cancer development, providing new potential therapeutic targets for prostate, gastric, pancreatic ductal and breast cancers. It also provided cutting-edge research evidence for the development of biological small molecule drugs and targeted tracers in cancer therapy.

Keywords: Cancer neuroscience; cancer-nerve crosstalk; tumor microenvironment
Cancer Immunol Immunother. 2023 Apr 15.

Nervous regulation: beta-2-adrenergic signaling in immune homeostasis, cancer immunotherapy, and autoimmune diseases.

Sagarina Thapa, Xuefang Cao.

  Beta-2-adrenergic receptor (β2-AR) mediates neural signaling from the sympathetic nervous system (SNS) to the immune system to modulate immunogenic and immunosuppressive responses for maintaining immune homeostasis. β2-AR regulates various cellular activities on the innate and adaptive immune cells through differential signaling to modulate activation, proliferation, differentiation, and cytokine production. This signaling pathway has been found to be critical for regulating anti-tumor immune responses and autoimmune responses. Recently, β2-AR has also been implicated in the mobilization of immune cells in peripheral blood and ex-vivo expansion of cytotoxic T cells from donor blood that has clinical implications for improving cancer immunotherapy. This review attempts to provide a comprehensive overview of the established and emerging roles of β2-AR signaling in immune homeostasis, cancer immunotherapy, and autoimmune diseases.

Keywords:  Autoimmune diseases; Beta-2-adrenergic receptor (β2-AR); Cancer immunotherapy; Immune homeostasis

DOI:  https://doi.org/10.1007/s00262-023-03445-z
J Neurosurg Case Lessons. 2023 Apr 10. pii: CASE23112. [Epub ahead of print]5(15):

Perineurioma of the sciatic nerve with reticular, microcystic, and pseudolipoblastic features: illustrative case.

Karina A Lenartowicz, Kimberly K Amrami, Jorge Torres-Mora, Robert J Spinner.

  BACKGROUND: Perineuriomas are peripheral nerve sheath tumors that are composed of benign, localized proliferations of perineural cells and further subclassified as intraneural or extraneural (soft tissue) based on their relationship to the histological boundaries of the nerve. Multiple histological variants have been described, and herein the authors present the first known case of a pseudolipoblastic perineurioma affecting the nerve.OBSERVATIONS: A 52-year-old woman presented with a 5-year history of progressive, severe left buttock pain radiating down to the top of her foot and ankle, without any associated weakness, with a large mass in her sciatic nerve noted on magnetic resonance imaging (MRI). She underwent resection, which demonstrated a pseudolipoblastic perineurioma of the sciatic nerve, an unusual histological subtype composed of perineurial cells with an abundant clear intracytoplasmic background. Postoperatively, her pain resolved, and follow-up MRI showed no tumor persistence or recurrence.
LESSONS: On imaging, this lesion had a benign appearance, with areas suggestive of subacute hemorrhage, and was associated with a nerve. Although the distinctive morphological features of this lesion may suggest liposarcoma, careful morphological evaluation and appropriate immunohistochemical studies allow its correct classification.

Keywords:  liposarcoma; perineurioma; sciatic nerve; soft tissue tumors

DOI:  https://doi.org/10.3171/CASE23112
Georgian Med News. 2023 Feb; 99-103

PATTERN OF A PRIMARY B-CELL LYMPHOMA IN ULNAR NERVE: INTRANEURAL OR EXTRANEURAL.

R De Vitis, M Passiatore, G Barchetti, I Ceravolo, L Larocca, M Starnoni, F Federico, F Castri, G Taccardo.

Primary lymphomas of peripheral nerves (PLPNs) are extremely rare and most commonly reported in lumbar nerves and have been found in only five cases in the upper extremities. We describe two patterns of presentation focusing on clinical, radiological, and pathological findings of two patients affected by primary multifocal lymphoma of the ulnar nerve without systemic involvement or other medical conditions. We report a case of extraneural lymphoma in a 72-years-old (patient #1) and a case of intraneural lymphoma in a 45-years old woman (Patient #2). Magnetic resonance imaging and ultrasound findings were similar to Peripheral Nerve Sheath Tumors (PNST). Surgical exploration and excision were performed. Morpho pathological results revealed in both cases a diffuse large B-cell non-Hodgkin lymphoma. In patient #1, the disease relapsed after only 4 months with brachial plexus involvement. The patient died about 10 months after the onset of symptoms. Patient #2 did not have post-surgical sensory or motor deficit and follow up at 6 years did not show recurrence or any other localizations. PLPN is a rare and challenging condition and is frequently misdiagnosed. PLPNs could have an intraneural or an extraneural pattern. As peripheral neuropathy may be caused by a nervous involvement by a lymphoma, in patients with atypical lesions, a complete preoperative imaging should be acquired.
Ultrasound Obstet Gynecol. 2023 Apr 14.

Imaging in gynecological disease: clinical and ultrasound characteristics of benign retroperitoneal pelvic nerve sheath tumors.

D Fischerova, G Santos, L Wong, V Yulzari, R J Bennett, P Dundr, A Burgetova, P Barsa, G Szabó, N Sousa, U Scovazzi, D Cibula.

  OBJECTIVE: To describe the clinical and sonographic characteristics of benign, retroperitoneal, pelvic peripheral nerve sheath tumors (PNST).METHODS: This was a retrospective, single, gynecologic oncology center study conducted between 1 January 2018 and 31 August 2022. All ultrasound images, clips, and final specimens of benign PNSTs were reviewed by the authors to describe (1) the ultrasound appearance of the tumors using the terminology of the International Ovarian Tumor Analysis (IOTA), Morphological Uterus Sonographic Assessment (MUSA) and Vulvar International Tumor Analysis (VITA) groups on a predefined ultrasound assessment form, (2) the origin of the tumors in relation to nerves and pelvic anatomy, and (3) the correlation between ultrasound features and histotopograms. A review of literature on benign, retroperitoneal, pelvic PNSTs with preoperative ultrasound examination was performed.
RESULTS: Five women (mean age 53 years) with benign, retroperitoneal, pelvic PNSTs were identified: four with schwannomas and one with a neurofibroma, all of which were sporadic and solitary. All patients had good quality ultrasound images and clips and final biopsies of surgically excised tumors, except for one patient managed conservatively with a tru-cut biopsy. In four of these cases, the findings were incidental. Size range for the five PNSTs was from 31-50 mm. All five PNSTs were solid, moderately vascular tumors, with non-uniform echogenicity, well-circumscribed by hyperechogenic epineurium, and had no acoustic shadowing. Most of the masses were round (n = 4 (80%)), and contained small, irregular, anechoic, cystic spaces (n = 3 (60%)), and hyperechoic areas (n = 4 (80%)). A literature search identified 47 cases of retroperitoneal schwannomas and neurofibromas, the characteristics of which were compared with the cases in our series.
CONCLUSIONS: On ultrasound, benign PNSTs were solid, non-uniform, moderately vascular tumors without acoustic shadowing. Most were round, containing small, irregular, anechoic, cystic spaces, and hyperechoic areas, consistent with degenerative changes on pathology. All tumors were well-circumscribed by a hyperechogenic rim composed of epineurium. No imaging characteristics reliably differentiated between schwannomas and neurofibromas. In fact, they overlap with the ultrasound appearance of malignant tumors. Hence, ultrasound-guided biopsy plays a pivotal role in diagnosis, and if confirmed as benign PNSTs, these tumors can undergo ultrasound surveillance. This article is protected by copyright. All rights reserved.

Keywords:  diagnostic imaging; female; nerve sheath neoplasms; neurilemmoma; neurofibroma; retroperitoneal neoplasms; schwannoma; ultrasonography

DOI:  https://doi.org/10.1002/uog.26223
J Urol. 2023 Apr 12. 101097JU0000000000003454

Risk Stratification of Low-Risk Prostate Cancer: Individualizing Care in the Era of Active Surveillance.

M D Ho, A E Ross, S E Eggener.

  PURPOSE: While active surveillance is the preferred management for most men with low-risk prostate cancer, a subset may harbor more aggressive disease. In this review we examine the evidence underlying an accurate and nuanced assessment of oncologic risk in these men.METHODS: We performed a non-systematic literature review current to January 2023 on PubMed for articles relating to clinical, pathologic, molecular and imaging-based modalities available for risk assessment in men with low-risk prostate cancer. Relevant articles were reviewed by the authors and evidence was summarized.
RESULTS: Many tools are available to personalize clinical decision making for men with low-risk prostate cancer. Total volume of cancer, PSA density, and presence of ductal components have been consistently and strongly associated with current or future evidence of higher-grade disease. PSA kinetics, PIRADS 4/5 lesions on MRI, perineural invasion, germline mutations and genomic classifiers all appear to be associated with an increased risk, although are not as extensively validated. Race, percent free PSA, and other serum biomarkers such as Prostate Health Index and 4Kscore do not appear to be associated with long-term elevated risk.
CONCLUSION: Long-term prognosis for men diagnosed with low-risk prostate cancer is excellent. There are many factors which should be routinely integrated into the initial management decision as well as determining intensity and frequency of active surveillance. Development of comprehensive multivariable instruments to guide clinical decisions is encouraged.

Keywords:  active surveillance; clinical decision-making; multiparametric MRI; prostate cancer; tumor biomarker

DOI:  https://doi.org/10.1097/JU.0000000000003454
Eur J Pharmacol. 2023 Apr 11. pii: S0014-2999(23)00229-7. [Epub ahead of print] 175718

Beta-adrenergic receptor blocker propranolol triggers anti-tumor immunity and enhances irinotecan therapy in mice colorectal cancer.

Yanting Lin, Yiming Liu, Zhenhua Gao, Dongquan Jing, Ran Bi, Xinmeng Cui, Qiuhua Cao, Qixiang Zhao, Rui Gao, Yali Su, Siliang Liu, Mingrui Zhao, Yong Yang, Anqi Chen, Beiying Dai, Xinghua Gao.

  Colorectal cancer (CRC) stands as the second leading cause of cancer-related deaths worldwide with limited available medicines. While drug repurposing comes as a promising strategy for cancer treatment, we discovered that propranolol (Prop), a non-selective β1 and β2 adrenergic receptor blocker, significantly inhibited the development of subcutaneous CT26 CRC and AOM/DSS-induced CRC models. The RNA-seq analysis highlighted the activated immune pathways after Prop treatment, with GO analysis enriched in T-cell differentiation, leukocyte-mediated immunity, regulation of leukocyte-mediated cytotoxicity, and interferon-gamma production. Routine analyses of blood revealed a decrease in neutrophil to lymphocyte ratio, a biomarker of systemic inflammation, and a prognostic indicator in the Prop-treated groups in both CRC models. Analysis of the tumor-infiltrating immune cells exhibited that Prop regressed the exhaustion of CD4+ and CD8+ T cells in the CT26-derived graft models, which was further corroborated in the AOM/DSS-induced models. Furthermore, bioinformatic analysis fitted well with the experimental data, showing that β2 adrenergic receptor (ADRB2) was positively correlated with T-cell exhaustion signature in various tumors. The in vitro experiment showed no direct effect of Prop on CT26 cell viability, while T cells were activated with significantly-upregulated production of IFN-γ and Granzyme B. Consistently, Prop was unable to restrain CT26 tumor growth in nude mice. At last, the combination of Prop and the chemotherapeutic drug Irinotecan acted out the strongest inhibition in CT26 tumor progress. Collectively, we repurpose Prop as a promising and economical therapeutic drug for CRC treatment and highlight T-cell as its target.

Keywords:  CRC; Drug repurposing; Propranolol; T-cell exhaustion

DOI:  https://doi.org/10.1016/j.ejphar.2023.175718
Kathmandu Univ Med J (KUMJ). 2022 Jul-Sep;20(79):20(79): 396-398

Solving the Mystery of Giant Intrathoracic Mass.

R M Karmacharya, A Singh, M Devbhandari, D Napit, K Ghimire, C Mahat, S Vaidya.

Intrathoracic schwannoma are highly vascular nerve sheath benign tumors arising from neural crest derived schwann cells of the intercostal nerves. Common clinical presentation is palpable mass but in our case patient presented with shortness of breath which is rare presentation in Schwannoma. Imaging studies of the patient showed the lesion in left lung, however surgical finding showed mass to arise from chest wall and it was confirmed to be schwannoma by histopathological examination.
Ann Indian Acad Neurol. 2023 Jan-Feb;26(1):26(1): 76-77

A Rare Case of Hypoglossal Nerve Schwannoma Presenting as Hemiatrophy of the Tongue: A Case Report.

Mrinmayi M Zurale, Ashish Patil.

DOI: https://doi.org/10.4103/aian.aian_876_22
Cancers (Basel). 2023 Apr 04. pii: 2145. [Epub ahead of print]15(7):

Epigenetic Rewiring of Metastatic Cancer to the Brain: Focus on Lung and Colon Cancers.

Annamaria Morotti, Francesco Gentile, Gianluca Lopez, Giulia Passignani, Luca Valenti, Marco Locatelli, Manuela Caroli, Claudia Fanizzi, Stefano Ferrero, Valentina Vaira.

  Distant metastasis occurs when cancer cells adapt to a tissue microenvironment that is different from the primary organ. This process requires genetic and epigenetic changes in cancer cells and the concomitant modification of the tumor stroma to facilitate invasion by metastatic cells. In this study, we analyzed differences in the epigenome of brain metastasis from the colon (n = 4) and lung (n = 14) cancer and we compared these signatures with those found in primary tumors. Results show that CRC tumors showed a high degree of genome-wide methylation compared to lung cancers. Further, brain metastasis from lung cancer deeply activates neural signatures able to modify the brain microenvironment favoring tumor cells adaptation. At the protein level, brain metastases from lung cancer show expression of the neural/glial marker Nestin. On the other hand, colon brain metastases show activation of metabolic signaling. These signatures are specific for metastatic tumors since primary cancers did not show such epigenetic derangements. In conclusion, our data shed light on the epi/molecular mechanisms that colon and lung cancers adopt to thrive in the brain environment.

Keywords:  brain metastases; colorectal cancer; epigenetics; lung cancer; methylation

DOI:  https://doi.org/10.3390/cancers15072145
Cancers (Basel). 2023 Mar 23. pii: 1930. [Epub ahead of print]15(7):

Diagnosis and Treatment of Peripheral and Cranial Nerve Tumors with Expert Recommendations: An EUropean Network for RAre CANcers (EURACAN) Initiative.

Alessia Pellerino, Robert M Verdijk, Lucia Nichelli, Nicolaus H Andratschke, Ahmed Idbaih, Roland Goldbrunner.

  The 2021 WHO classification of the CNS Tumors identifies as "Peripheral nerve sheath tumors" (PNST) some entities with specific clinical and anatomical characteristics, histological and molecular markers, imaging findings, and aggressiveness. The Task Force has reviewed the evidence of diagnostic and therapeutic interventions, which is particularly low due to the rarity, and drawn recommendations accordingly. Tumor diagnosis is primarily based on hematoxylin and eosin-stained sections and immunohistochemistry. Molecular analysis is not essential to establish the histological nature of these tumors, although genetic analyses on DNA extracted from PNST (neurofibromas/schwannomas) is required to diagnose mosaic forms of NF1 and SPS. MRI is the gold-standard to delineate the extension with respect to adjacent structures. Gross-total resection is the first choice, and can be curative in benign lesions; however, the extent of resection must be balanced with preservation of nerve functioning. Radiotherapy can be omitted in benign tumors after complete resection and in NF-related tumors, due to the theoretic risk of secondary malignancies in a tumor-suppressor syndrome. Systemic therapy should be considered in incomplete resected plexiform neurofibromas/MPNSTs. MEK inhibitor selumetinib can be used in NF1 children ≥2 years with inoperable/symptomatic plexiform neurofibromas, while anthracycline-based treatment is the first choice for unresectable/locally advanced/metastatic MPNST. Clinical trials on other MEK1-2 inhibitors alone or in combination with mTOR inhibitors are under investigation in plexiform neurofibromas and MPNST, respectively.

Keywords:  MEK inhibitors; cauda equine neuroendocrine tumor; hybrid nerve sheath tumor; mTOR inhibitors; malignant peripheral nerve sheath tumor; neurofibroma; perineurioma; plexiform neurofibroma; schwannoma

DOI:  https://doi.org/10.3390/cancers15071930
Skeletal Radiol. 2023 Apr 15.

Lower extremity peripheral nerve pathology: Utility of preoperative ultrasound-guided needle localization before operative intervention.

Emily R Finkelstein, Joanne Buitrago, Jean Jose, Allan D Levi, Kyle Y Xu, S Shelby Burks.

  Historically, the use of ultrasound (US) in the management of peripheral nervous system (PNS) pathology has been limited to diagnostic confirmation or guidance for interventional injections. This technical case series will demonstrate the utility and versatility of preoperative US-guided needle localization for the excision of lower extremity neuromas and other pathology of the PNS. Five patients with symptomatic lower extremity PNS tumors were retrospectively reviewed. This case series corroborates the technical nuances of localizing lower extremity neuromas by US-guided needle and wire placement prior to operative excision. This was achieved by a multidisciplinary team that included plastic surgery, neurosurgery, and radiology. Five patients had US-guided needle localization of a lower extremity PNS target prior to operative intervention. Three patients had lower extremity neuromas of varying origins, including the lateral femoral cutaneous nerve (LFCN), saphenous nerve, and sural nerve. The remaining two patients had a sciatic nerve sheath Schwannoma and a femoral nerve glomus tumor. Under sonographic visualization, a needle was advanced to the target perimeter and withdrawn, leaving behind a percutaneous guidewire. This technique simplified the marking of the nerve course prior to dissection and led to efficient intraoperative identification of all five PNS tumors without any complications. Preoperative US-guided needle localization led to safe, accurate, and efficient perioperative and intraoperative identification of neuromas and other PNS tumors of the lower extremity prior to excision. By reducing the challenges of nerve identification in a scarred tissue bed, this multidisciplinary approach may decrease postoperative patient morbidity.

Keywords:  Localization; Neuroma; Peripheral nerve; Schwannoma; Ultrasound-guided; Wire

DOI:  https://doi.org/10.1007/s00256-023-04347-y