bims-netuvo 2023-09-10 papers

bims-netuvo

Biomed News

on Nerves in tumours of visceral organs

Issue of 2023–09–10
thirteen papers selected by
Maksym V. Kopanitsa, The Francis Crick Institute

Genetic Profiling and Genome-Scale Dropout Screening to Identify Therapeutic Targets in Mouse Models of Malignant Peripheral Nerve Sheath Tumor.
Chemogenetic silencing of NaV1.8 positive sensory neurons reverses chronic neuropathic and bone cancer pain in FLEx PSAM4-GlyR mice.
Ion channels in cancer-induced bone pain: from molecular mechanisms to clinical applications.
The quest for effective immunotherapies against malignant peripheral nerve sheath tumors: Is there hope?
Mismatch Repair Deficient (dMMR) Colorectal Carcinoma in a Pakistani Cohort: Association With Clinical and Pathological Parameters.
Characteristic of penile cancer and prognostic factors of inguinal and pelvic lymph node involvement.
What is new in intraneural perineurioma?
Malignant peripheral nerve sheath tumor in the pelvis: a case report.
Surgery of Schwannoma in the upper limb - sensitivity and specificity of preoperative magnetic resonance imaging and relation between tumour size and symptoms.
Orbital Exenteration for Craniofacial Lesions: A Systematic Review and Meta-Analysis of Patient Characteristics and Survival Outcomes.
A synopsis of multitarget therapeutic effects of anesthetics on depression.
Ancient Schwannoma of the Radial Nerve: A Case Report.
FOXM1, MEK, and CDK4/6: New Targets for Malignant Peripheral Nerve Sheath Tumor Therapy.

J Vis Exp. 2023 Aug 25.

Genetic Profiling and Genome-Scale Dropout Screening to Identify Therapeutic Targets in Mouse Models of Malignant Peripheral Nerve Sheath Tumor.

Brittany Turner-Ivey, Jody Fromm Longo, Dorea P Jenkins, Stephen T Guest, Steven L Carroll.

Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are derived from Schwann cells or their precursors. In patients with the tumor susceptibility syndrome neurofibromatosis type 1 (NF1), MPNSTs are the most common malignancy and the leading cause of death. These rare and aggressive soft-tissue sarcomas offer a stark future, with 5-year disease-free survival rates of 34-60%. Treatment options for individuals with MPNSTs are disappointingly limited, with disfiguring surgery being the foremost treatment option. Many once-promising therapies such as tipifarnib, an inhibitor of Ras signaling, have failed clinically. Likewise, phase II clinical trials with erlotinib, which targets the epidermal growth factor (EFGR), and sorafenib, which targets the vascular endothelial growth factor receptor (VEGF), platelet-derived growth factor receptor (PDGF), and Raf, in combination with standard chemotherapy, have also failed to produce a response in patients. In recent years, functional genomic screening methods combined with genetic profiling of cancer cell lines have proven useful for identifying essential cytoplasmic signaling pathways and the development of target-specific therapies. In the case of rare tumor types, a variation of this approach known as cross-species comparative oncogenomics is increasingly being used to identify novel therapeutic targets. In cross-species comparative oncogenomics, genetic profiling and functional genomics are performed in genetically engineered mouse (GEM) models and the results are then validated in the rare human specimens and cell lines that are available. This paper describes how to identify candidate driver gene mutations in human and mouse MPNST cells using whole exome sequencing (WES). We then describe how to perform genome-scale shRNA screens to identify and compare critical signaling pathways in mouse and human MPNST cells and identify druggable targets in these pathways. These methodologies provide an effective approach to identifying new therapeutic targets in a variety of human cancer types.

DOI: https://doi.org/10.3791/65430
eNeuro. 2023 Sep 07. pii: ENEURO.0151-23.2023. [Epub ahead of print]

Chemogenetic silencing of NaV1.8 positive sensory neurons reverses chronic neuropathic and bone cancer pain in FLEx PSAM4-GlyR mice.

Rayan Haroun, Samuel J Gossage, Ana Paula Luiz, Manuel Arcangeletti, Shafaq Sikandar, Jing Zhao, James J Cox, John N Wood.

  Drive from peripheral neurons is essential in almost all pain states, but pharmacological silencing of these neurons to effect analgesia has proved problematic. Reversible gene therapy using long-lived chemogenetic approaches is an appealing option. We used the genetically-activated chloride channel PSAM4-GlyR to examine pain pathways in mice. Using recombinant AAV9-based delivery to sensory neurons, we found a reversal of acute pain behavior and diminished neuronal activity using in vitro and in vivo GCaMP imaging upon activation of PSAM4-GlyR with varenicline. A significant reduction in inflammatory heat hyperalgesia and oxaliplatin-induced cold allodynia was also observed. Importantly, there was no impairment of motor coordination, but innocuous von Frey sensation was inhibited. We generated a transgenic mouse that expresses a CAG-driven FLExed PSAM4-GlyR downstream of the Rosa26 locus that requires Cre recombinase to enable the expression of PSAM4-GlyR and tdTomato. We used NaV1.8 Cre to examine the role of predominantly nociceptive NaV1.8+ neurons in cancer-induced bone pain (CIBP) and neuropathic pain caused by chronic constriction injury (CCI). Varenicline activation of PSAM4-GlyR in NaV1.8-positive neurons reversed CCI-driven mechanical, thermal, and cold sensitivity. Additionally, varenicline treatment of mice with CIBP expressing PSAM4-GlyR in NaV1.8+ sensory neurons reversed cancer pain as assessed by weight-bearing. Moreover, when these mice were subjected to acute pain assays, an elevation in withdrawal thresholds to noxious mechanical and thermal stimuli was detected, but innocuous mechanical sensations remained unaffected. These studies confirm the utility of PSAM4-GlyR chemogenetic silencing in chronic pain states for mechanistic analysis and potential future therapeutic use.Significance StatementChronic pain is a massive problem. Peripheral nerve block is effective in many chronic pain conditions, demonstrating the importance of peripheral drive in chronic pain. We used chemogenetic tools based on the modified ligand-gated chloride channel PSAM4-GlyR to silence dorsal root ganglion neurons in vitro and in vivo This approach reduces pain-like behavior in acute and chronic pain models, including resistant pain conditions like neuropathic pain or cancer-induced bone pain. We generated a mouse line that expresses PSAM4-GlyR in a Cre-dependent manner, providing a useful research tool to address not only the role of nociceptive sensory neurons in pain states but also the function of genetically defined sets of neurons throughout the nervous system in normal and pathological conditions.

Keywords:  Cancer-induced bone pain; Nav1.8; Neuropathic pain; chemogenetics; pain; sensory neurons

DOI:  https://doi.org/10.1523/ENEURO.0151-23.2023
Front Mol Neurosci. 2023 ;16 1239599

Ion channels in cancer-induced bone pain: from molecular mechanisms to clinical applications.

Huan-Jun Lu, Xiao-Bo Wu, Qian-Qi Wei.

  Cancer-induced bone pain (CIBP) caused by bone metastasis is one of the most prevalent diseases, and current treatments rely primarily on opioids, which have significant side effects. However, recent developments in pharmaceutical science have identified several new mechanisms for CIBP, including the targeted modification of certain ion channels and receptors. Ion channels are transmembrane proteins, which are situated on biological cell membranes, which facilitate passive transport of inorganic ions across membranes. They are involved in various physiological processes, including transmission of pain signals in the nervous system. In recent years, there has been an increasing interest in the role of ion channels in chronic pain, including CIBP. Therefore, in this review, we summarize the current literature on ion channels, related receptors, and drugs and explore the mechanism of CIBP. Targeting ion channels and regulating their activity might be key to treating pain associated with bone cancer and offer new treatment avenues.

Keywords:  antinociception; cancer-induced bone pain; chronic pain; clinical application; ion channels

DOI:  https://doi.org/10.3389/fnmol.2023.1239599
Mol Ther Oncolytics. 2023 Sep 21. 30 227-237

The quest for effective immunotherapies against malignant peripheral nerve sheath tumors: Is there hope?

Siddhi N Paudel, Brian Hutzen, Timothy P Cripe.

  Immune-based therapies represent a new paradigm in the treatment of multiple cancers, where they have helped achieve durable and safe clinical responses in a growing subset of patients. While a wealth of information is available concerning the use of these agents in treating the more common malignancies, little has been reported about the use of immunotherapies against malignant peripheral nerve sheath tumors (MPNSTs), a rare form of soft tissue sarcoma that arises from the myelin sheaths that protect peripheral nerves. Surgical resection has been the mainstay of therapy in MPNSTs, but the recurrence rate is as high as 65%, and chemotherapy is generally ineffective. The immune contexture of MPNSTs, replete with macrophages and a varying degree of T cell infiltration, presents multiple opportunities to design meaningful therapeutic interventions. While preliminary results with macrophage-targeting strategies and oncolytic viruses are promising, identifying the subset of patients that respond to immune-based strategies will be a milestone. As part of our effort to help advance the use of immunotherapy for MPNSTs, here we describe recent insights regarding the immune contexture of MPNSTs, discuss emerging immune-based strategies, and provide a brief overview of potential biomarkers of response.

Keywords:  biomarkers; immune checkpoint inhibitors; immunosuppression; immunotherapy; macrophage targeting; malignant peripheral nerve sheath tumors; neurofibromatosis; oncolytic virotherapy; soft tissue sarcoma; tumor microenvironment

DOI:  https://doi.org/10.1016/j.omto.2023.07.008
Cureus. 2023 Aug;15(8): e42781

Mismatch Repair Deficient (dMMR) Colorectal Carcinoma in a Pakistani Cohort: Association With Clinical and Pathological Parameters.

Atif A Hashmi, Ummara Bukhari, Ramish Rizwan, Faiza Faisal, Ravi Kumar, Umair Arshad Malik, Shamail Zia, Abdur Rahim Khan, Sunder Sham, Muhammad Irfan.

  Introduction Microsatellite instability (MSI) is an important pathway in colorectal carcinoma (CRC) pathogenesis. MSI occurs due to mutations in mismatch repair (MMR) genes that include MutL protein homolog 1 (MLH1), postmeiotic segregation increased 2 (PMS2), MutS homolog 2 (MSH2), and MutS homolog 6 (MSH6). CRC with MSI is termed MMR deficient (dMMR) CRC. Conversely, CRC with intact MMR genes is called microsatellite stable (MSS) or MMR proficient (pMMR). In this study, we compared the clinicopathological features of dMMR CRC with pMMR CRC. Methods It was a retrospective study conducted in the Department of Histopathology, Liaquat National Hospital, Karachi, Pakistan, from March 2020 to February 2022, over a duration of two years. Biopsy-proven cases of CRC with upfront surgical resection were included in the study. Microscopic examination was performed to evaluate tumor type, grade, and extent of invasion, presence of necrosis, perineural invasion (PNI), lymphovascular invasion (LVI), peritumoral lymphocytes (PTL), intratumoral lymphocytes (ITL), and nodal metastasis. Immunohistochemical staining was performed using antibodies, namely, MLH1, PMS2, MSH2, and MSH6. Any loss of nuclear expression in tumor cells was termed dMMR or microsatellite instable, whereas the intact nuclear expression in tumor cells was labeled as MSS or pMMR. Results A total of 135 cases of CRC were included in the study. The mean age at diagnosis was 46.76 ± 17.74 years, with female predominance (60.7%). The loss of MLH1, PMS2, MSH2, and MSH6 expression was noted in 39.3%, 34.1%, 17.8%, and 16.3% cases, respectively. Overall, 59.3% of CRCs were pMMR, while 40.7% were dMMR. A significant association of MMR status was noted with respect to age, PNI, LVI, tumor grade, tumor (T) and nodal (N) stage, mucinous differentiation, and ITL. dMMR CRC was significantly above 50 years than pMMR CRC. The frequency of PNI and LVI was lower in dMMR CRC than in pMMR CRC. Conversely, the higher grade (grade 3) and higher T-stage (T4) were associated with dMMR CRC. Alternatively, the frequency of higher N stage (N2b) was more commonly seen in pMMR CRC. Moreover, mucinous differentiation and ITL were significantly associated with dMMR CRC. Conclusion A significant proportion of CRC patients in our population demonstrated dMMR status. dMMR CRC had a higher histological grade with a higher frequency of mucinous differentiation and higher T-stage. Conversely, the presence of LVI, PNI, and higher N stages were associated with pMMR CRC.

Keywords:  biomarkers; colorectal carcinoma; dmmr; microsatellite instability; mismatch repair; mlh1; msh2; msh6; pmmr; pms2

DOI:  https://doi.org/10.7759/cureus.42781
Urol Ann. 2023 Jul-Sep;15(3):15(3): 278-284

Characteristic of penile cancer and prognostic factors of inguinal and pelvic lymph node involvement.

Kritanu Kultravut, Satit Siriboonrid.

   Background: Penile cancer is a rare malignancy which inguinal and pelvic lymph node involvement plays a major role in patients' survival. The prognosis of patients with lymph node metastasis is poorer.
Objective: The objective of the study was to evaluate the prognostic factors for inguinal lymph node and pelvic lymph node involvement.
Materials and Methods: This was a retrospective analytic study of medical records between January 2010 and December 2020.
Results: Thirty-nine patients were diagnosed with penile cancer, median age of 59 ± 14.898 (range: 32-86 years) were included in the analysis. Twenty-eight patients underwent inguinal lymph node dissection, 13 patients had inguinal lymph node metastasis (46.4%), 8 patients underwent pelvic lymph node dissection, and 5 patients had pelvic lymph node metastasis (62.5%). Inguinal lymph node metastasis was associated with tumor grading (odds ratio [OR]: 2.92, confidence interval [CI]: 0.123-0.704), lymphovascular invasion (LVI) (OR: 5.182, CI: 0.430-0.996), perineural invasion (PNI) (OR: 3.687, CI: 0.277-0.975), and fixation of inguinal node (OR: 2.463, CI: 0.078-1.195). Pelvic lymph node metastasis was associated with tumor grading (OR: 2.619, CI: 0.033-0.967).
Conclusion: Grading, LVI and PNI of primary tumor, and fixation of inguinal node are significantly associated with inguinal lymph node metastasis. While primary tumor grading is significantly associated with pelvic lymph node metastasis. These factors are associated with poorer prognosis.

Keywords:  Inguinal lymph node; pelvic lymph node; penile cancer; squamous cell carcinoma

DOI:  https://doi.org/10.4103/ua.ua_6_22
Acta Neurochir (Wien). 2023 Sep 09.

What is new in intraneural perineurioma?

Karina A Lenartowicz, Brandon W Smith, Megan M Jack, Thomas J Wilson, Christopher J Klein, Kimberly K Amrami, Robert J Spinner.

  Since the initial description of intraneural (IN) perineurioma in 1964, advances in the understanding of the clinical presentation, diagnostic imaging, pathologic features, and genetic underpinnings have changed how this pathology is managed. IN perineuriomas are rare, benign peripheral nerve sheath tumors, most frequently coming to clinical attention when patients present with painless, progressive weakness or sensory loss in adolescence or young adulthood. The gold standard of diagnosis has traditionally been with targeted tissue biopsy demonstrating "pseudo-onion bulb" formation with positive epithelial membrane antigen (EMA) staining. However, modern magnetic resonance imaging is allowing some patients to forgo biopsy. Recent genetic studies of IN perineuriomas have demonstrated common TRAF7 point mutations and rare NF2 mutations, which may present targets for diagnosis or therapy in the future. Current advances have allowed for us to provide improved patient counseling with informed understanding for various clinical scenarios. With the workup and diagnosis now clearly defined, the next frontier is for improving the lives of patients with IN perineuriomas through the interaction between restoration of functional deficits and advances in our understanding of the genetics of this entity.

Keywords:  Intraneural perineurioma; Perineural cell tumor; Peripheral nerve sheath tumor; Pseudo-onion bulb

DOI:  https://doi.org/10.1007/s00701-023-05765-6
Surg Case Rep. 2023 Sep 06. 9(1): 157

Malignant peripheral nerve sheath tumor in the pelvis: a case report.

Rika Ono, Tetsuro Tominaga, Takashi Nonaka, Yuma Takamura, Kaido Oishi, Toshio Shiraishi, Shintaro Hashimoto, Keisuke Noda, Terumitsu Sawai, Takeshi Nagayasu.

   BACKGROUND: Malignant peripheral nerve sheath tumors (MPNSTs) are malignancies that arise or differentiate from or infiltrate peripheral nerves and account for approximately 5% of soft-tissue malignancies. Approximately half of MPNSTs develop in patients with neurofibromatosis type 1 (NF1), a hereditary disease. MPNSTs occur mainly in the trunk, proximal extremities, and neck, but can on rare occasion arise in or near the gastrointestinal tract, and intestinal complications have been reported. We describe herein a case with resection of an MPNST arising in the pelvic region.
CASE PRESENTATION: A 51-year-old woman had undergone repeated resections for systemic neurofibrosis associated with NF1. This time, a pelvic tumor was noted on follow-up positron emission tomography computed tomography (CT). She presented with slowly progressive radiating pain in the lower extremities and was referred to our hospital for tumor resection. Contrast-enhanced CT showed a 75 × 58-mm mass in the right greater sciatic foramen directly below a 24 × 28-mm mass. Open pelvic tumor resection was performed for pelvic neurofibroma. The obturator nerve was identified lateral to the main tumor and the sciatic nerve was identified dorsally, then dissection was performed. The closed nerve was spared, while the sciatic nerve was partially dissected and the two tumors were removed. Both tumors were elastic and hard. Pathologic findings were MPNST for the large specimen and neurofibroma with atypia for the small specimen. The patient developed temporary postoperative ileus, but is generally doing well and is currently free of recurrence or radiating pain. The patient is at high risk of recurrence and close monitoring should be continued.
CONCLUSIONS: We encountered a rare case of MPNST. Due to the high risk of recurrence, surgery with adequate margins was performed, with a requirement for appropriate follow-up.

Keywords:  Malignant peripheral nerve sheath tumors; Neurofibromatosis type 1; Surgery

DOI:  https://doi.org/10.1186/s40792-023-01733-5
BMC Musculoskelet Disord. 2023 Sep 07. 24(1): 713

Surgery of Schwannoma in the upper limb - sensitivity and specificity of preoperative magnetic resonance imaging and relation between tumour size and symptoms.

Emanuel Istefan, Johannes Belstock, Lars B Dahlin, Erika Nyman.

   BACKGROUND: Benign peripheral nerve tumours consist of different types, most commonly Schwannomas. Preoperative Magnetic Resonance Imaging (MRI) is commonly performed before surgery and Pathoanatomical Diagnosis (PAD) confirms the diagnosis. Our aims were to study the utility of MRI and the relation between tumour size and symptoms.
METHODS: Retrospectively, patients, surgically treated for benign nerve tumours between 2008 and 2019, were identified and preoperative MRI, with measurement of tumour size, PAD, symptoms, peroperative details, and symptomatic outcomes of surgery, were analysed.
RESULTS: The sensitivity and specificity to correctly identify Schwannomas with preoperative MRI were 85% and 50%, respectively, based on 30 Schwannomas and nine neurofibromas that were identified. Tumour size did not affect the presence of preoperative symptoms, but patients with sensory dysfunction at last follow-up had larger Schwannomas (p < 0.05). Symptoms as a palpable tumour, paraesthesia and pain improved by surgical excision (p < 0.001, p < 0.001 and p < 0.012, respectively), but sensory and motor dysfunction were common postoperatively. No malignant peripheral nerve sheath tumours (MPNST) were found. Using a surgical microscope, instead of only loop magnification, lowered the risk of perioperative nerve injuries (p < 0.05), but did not further diminish postoperative symptoms.
CONCLUSIONS: Early and accurate diagnosis of Schwannomas is valuable for adequate presurgical preparation and prompt surgical intervention. Preoperative examination with MRI has a high sensitivity, but low specificity; although recent advancement in MRI technology indicates improvement in diagnostic precision. Surgical excision is preferably performed early in conjunction with symptomatic debut to improve outcome.

Keywords:  Magnetic resonance imaging; Neoplasms; Peripheral nerve; Peripheral nervous system; Schwannoma; Surgery; Upper limb

DOI:  https://doi.org/10.1186/s12891-023-06838-4
Cancers (Basel). 2023 Aug 27. pii: 4285. [Epub ahead of print]15(17):

Orbital Exenteration for Craniofacial Lesions: A Systematic Review and Meta-Analysis of Patient Characteristics and Survival Outcomes.

Jumanah Qedair, Ali S Haider, Kishore Balasubramanian, Paolo Palmisciano, Taimur Hassan, Ataollah Shahbandi, Mohammadmahdi Sabahi, Abdurrahman F Kharbat, Hussam Abou-Al-Shaar, Kenny Yu, Aaron A Cohen-Gadol, Tarek Y El Ahmadieh, Othman Bin-Alamer.

   BACKGROUND: The outcomes of orbital exenteration (OE) in patients with craniofacial lesions (CFLs) remain unclear. The present review summarizes the available literature on the clinical outcomes of OE, including surgical outcomes and overall survival (OS).
METHODS: Relevant articles were retrieved from Medline, Scopus, and Cochrane according to PRISMA guidelines. A systematic review and meta-analysis were conducted on the clinical characteristics, management, and outcomes.
RESULTS: A total of 33 articles containing 957 patients who underwent OE for CFLs were included (weighted mean age: 64.3 years [95% CI: 59.9-68.7]; 58.3% were male). The most common lesion was squamous cell carcinoma (31.8%), and the most common symptom was disturbed vision/reduced visual acuity (22.5%). Of the patients, 302 (31.6%) had total OE, 248 (26.0%) had extended OE, and 87 (9.0%) had subtotal OE. Free flaps (33.3%), endosseous implants (22.8%), and split-thickness skin grafts (17.2%) were the most used reconstructive methods. Sino-orbital or sino-nasal fistula (22.6%), flap or graft failure (16.9%), and hyperostosis (13%) were the most reported complications. Regarding tumor recurrences, 38.6% were local, 32.3% were distant, and 6.7% were regional. The perineural invasion rate was 17.4%, while the lymphovascular invasion rate was 5.0%. Over a weighted mean follow-up period of 23.6 months (95% CI: 13.8-33.4), a weighted overall mortality rate of 39% (95% CI: 28-50%) was observed. The 5-year OS rate was 50% (median: 61 months [95% CI: 46-83]). The OS multivariable analysis did not show any significant findings.
CONCLUSIONS: Although OE is a disfiguring procedure with devastating outcomes, it is a viable option for carefully selected patients with advanced CFLs. A patient-tailored approach based on tumor pathology, extension, and overall patient condition is warranted.

Keywords:  carcinoma; craniofacial; meta-analysis; orbital exenteration; outcomes; survival; systematic review

DOI:  https://doi.org/10.3390/cancers15174285
Eur J Pharmacol. 2023 Sep 01. pii: S0014-2999(23)00544-7. [Epub ahead of print]957 176032

A synopsis of multitarget therapeutic effects of anesthetics on depression.

Guowei Wu, Hongwei Xu.

  Depression is a profound mental disorder that dampens the mood and undermines volition, which exhibited an increased incidence over the years. Although drug-based interventions remain the primary approach for depression treatment, the available medications still can't satisfy the patients. In recent years, the newly discovered therapeutic targets such as N-methyl-D-aspartate (NMDA) receptor, α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor, and tyrosine kinase B (TrkB) have brought new breakthroughs in the development of antidepressant drugs. Moreover, it has come to light that certain anesthetics possess pharmacological mechanisms intricately linked to the aforementioned therapeutic targets for depression. At present, numerous preclinical and clinical studies have explored the therapeutic effects of anesthetic drugs such as ketamine, isoflurane, N2O, and propofol, on depression. These investigations suggested that these drugs can swiftly ameliorate patients' depression symptoms and engender long-term effects. In this paper, we provide a comprehensive review of the research progress and potential molecular mechanisms of various anesthetic drugs for depression treatment. By shedding light on this subject, we aim to facilitate the development and clinical implementation of new antidepressant drugs based on anesthetic medications.

Keywords:  Anesthetics; Depression; Ketamine; Molecular mechanism

DOI:  https://doi.org/10.1016/j.ejphar.2023.176032
Cureus. 2023 Aug;15(8): e42920

Ancient Schwannoma of the Radial Nerve: A Case Report.

Duy Phan, Nu Tra My Ton, Thi Hong Khang Bui, Hoang Ngoc Anh Tran, Van Tri Truong.

  Ancient schwannoma is a very rare subtype of schwannoma. In this report, a case of ancient schwannoma in the upper extremity is reported. A 40-year-old man presented with a slowly growing tumor in the right forearm. He underwent surgery to remove the tumor. Investigation revealed an ancient schwannoma originated from the right radius. Careful preoperative imaging evaluation is important for correct preoperative diagnosis and surgical strategy.

Keywords:  ancient schwannoma; neural sheath tumor; radial nerve; radius; schwannoma

DOI:  https://doi.org/10.7759/cureus.42920
Int J Mol Sci. 2023 Sep 02. pii: 13596. [Epub ahead of print]24(17):

FOXM1, MEK, and CDK4/6: New Targets for Malignant Peripheral Nerve Sheath Tumor Therapy.

Ellen Voigt, Dawn E Quelle.

  Malignant peripheral nerve sheath tumors (MPNSTs) are deadly sarcomas, which desperately need effective therapies. Half of all MPNSTs arise in patients with neurofibromatosis type I (NF1), a common inherited disease. NF1 patients can develop benign lesions called plexiform neurofibromas (PNFs), often in adolescence, and over time, some PNFs, but not all, will transform into MPNSTs. A deeper understanding of the molecular and genetic alterations driving PNF-MPNST transformation will guide development of more targeted and effective treatments for these patients. This review focuses on an oncogenic transcription factor, FOXM1, which is a powerful oncogene in other cancers but little studied in MPNSTs. Elevated expression of FOXM1 was seen in patient MPNSTs and correlated with poor survival, but otherwise, its role in the disease is unknown. We discuss what is known about FOXM1 in MPNSTs relative to other cancers and how FOXM1 may be regulated by and/or regulate the most commonly altered players in MPNSTs, particularly in the MEK and CDK4/6 kinase pathways. We conclude by considering FOXM1, MEK, and CDK4/6 as new, clinically relevant targets for MPNST therapy.

Keywords:  CDK4/6; FOXM1; MEK; MPNST; sarcoma; targeted therapy

DOI:  https://doi.org/10.3390/ijms241713596