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Cancer Cell Apr 2024Intratumor morphological heterogeneity of pancreatic ductal adenocarcinoma (PDAC) predicts clinical outcomes but is only partially understood at the molecular level. To...
Intratumor morphological heterogeneity of pancreatic ductal adenocarcinoma (PDAC) predicts clinical outcomes but is only partially understood at the molecular level. To elucidate the gene expression programs underpinning intratumor morphological variation in PDAC, we investigated and deconvoluted at single cell level the molecular profiles of histologically distinct clusters of PDAC cells. We identified three major morphological and functional variants that co-exist in varying proportions in all PDACs, display limited genetic diversity, and are associated with a distinct organization of the extracellular matrix: a glandular variant with classical ductal features; a transitional variant displaying abortive ductal structures and mixed endodermal and myofibroblast-like gene expression; and a poorly differentiated variant lacking ductal features and basement membrane, and showing neuronal lineage priming. Ex vivo and in vitro evidence supports the occurrence of dynamic transitions among these variants in part influenced by extracellular matrix composition and stiffness and associated with local, specifically neural, invasion.
Topics: Humans; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Extracellular Matrix; Basement Membrane; Nervous System
PubMed: 38518775
DOI: 10.1016/j.ccell.2024.02.017 -
Current Opinion in Anaesthesiology Oct 2023Moderate-to-severe pain is common and remains a significant problem. Compared with opioid analgesia alone, single-shot peripheral nerve blockade has been associated with... (Review)
Review
PURPOSE OF REVIEW
Moderate-to-severe pain is common and remains a significant problem. Compared with opioid analgesia alone, single-shot peripheral nerve blockade has been associated with improved pain relief and the potential of decreased side effects. Single-shot nerve blockade, however, is limited by its relatively short duration of action. In this review, we aim to summarize the evidence related to local anaesthetic adjuncts for peripheral nerve blockade.
RECENT FINDINGS
Dexamethasone and dexmedetomidine exhibit characteristics that most closely resemble the ideal local anaesthetic adjunct. In upper limb block, dexamethasone has been demonstrated to be superior to dexmedetomidine regardless of administration route for the duration of sensory and motor blockade as well as the duration of analgesia. No clinically significant differences between intravenous and perineural dexamethasone were found. Perineural and intravenous dexamethasone have the potential to prolong sensory blockade to a greater extent than motor blockade. The evidence indicates that the mechanism of action of perineural dexamethasone in upper limb block is systemic in nature. Unlike perineural dexmedetomidine, intravenous dexmedetomidine has not been shown to result in differences in the characteristics of regional blockade compared with local anaesthetic alone.
SUMMARY
Intravenous dexamethasone is the local anaesthetic adjunct of choice, increasing the duration of sensory and motor blockade as well as the duration of analgesia by 477, 289 and 478 min, respectively. In view of this, we recommend consideration of the intravenous administration of dexamethasone at a dose of 0.1-0.2 mg/kg for all patients undergoing surgery whatever the level of postoperative pain, mild, moderate or severe. Further research should focus on the potential synergism of action between intravenous dexamethasone and perineural dexmedetomidine.
Topics: Humans; Anesthetics, Local; Dexamethasone; Dexmedetomidine; Pain, Postoperative; Peripheral Nerves
PubMed: 37314172
DOI: 10.1097/ACO.0000000000001272 -
International Journal of Molecular... Sep 2023Adenoid cystic carcinoma (ACC) has a worldwide incidence of three to four cases per million population. Although more cases occur in the minor and major salivary glands,... (Review)
Review
Adenoid cystic carcinoma (ACC) has a worldwide incidence of three to four cases per million population. Although more cases occur in the minor and major salivary glands, it is the most common lacrimal gland malignancy. ACC has a low-grade, indolent histological appearance, but is relentlessly progressive over time and has a strong proclivity to recur and/or metastasise. Current treatment options are limited to complete surgical excision and adjuvant radiotherapy. Intra-arterial systemic therapy is a recent innovation. Recurrent/metastatic disease is common due to perineural invasion, and it is largely untreatable as it is refractory to conventional chemotherapeutic agents. Given the rarity of this tumour, the molecular mechanisms that govern disease pathogenesis are poorly understood. There is an unmet, critical need to develop effective, personalised targeted therapies for the treatment of ACC in order to reduce morbidity and mortality associated with the disease. This review details the evidence relating to the molecular underpinnings of ACC of the lacrimal gland, including the chromosomal translocations, -signalling pathway aberrations, DNA damage repair gene mutations and epigenetic modifications.
Topics: Humans; Carcinoma, Adenoid Cystic; Lacrimal Apparatus; Salivary Gland Neoplasms; Neoplasm Recurrence, Local; Salivary Glands
PubMed: 37762061
DOI: 10.3390/ijms241813755 -
Frontiers in Oncology 2023Adenoid cystic carcinoma (ACC) is an aggressive tumor with a high propensity for distant metastasis and perineural invasion. This tumor is more commonly found in regions... (Review)
Review
Adenoid cystic carcinoma (ACC) is an aggressive tumor with a high propensity for distant metastasis and perineural invasion. This tumor is more commonly found in regions of the head and neck, mainly the salivary glands. In general, the primary treatment modality for ACC is surgical resection and, in some cases, postoperative radiotherapy. However, no effective systemic treatment is available for patients with advanced disease. Furthermore, this tumor type is characterized by recurrent molecular alterations, especially rearrangements involving the , and genes. In addition, they also reported copy number alterations (CNAs) that impact genes. One of them is , mutations that affect signaling pathways such as NOTCH, PI3KCA, and PTEN, as well as alterations in chromatin remodeling genes. The identification of new molecular targets enables the development of specific therapies. Despite ongoing investigations into immunotherapy, tyrosine kinase inhibitors, and anti-angiogenics, no systemic therapy is approved by the FDA for ACC. In this review, we report the genetic and cytogenetic findings on head and neck ACC, highlighting possible targets for therapeutic interventions.
PubMed: 37476370
DOI: 10.3389/fonc.2023.1191218 -
Pathology, Research and Practice Mar 2024Perineuriomatous melanocytic nevi are rare and this may indicate the similar embryological source of melanocytes and peripheral nerves in the neural crest. Neurotized...
BACKGROUND
Perineuriomatous melanocytic nevi are rare and this may indicate the similar embryological source of melanocytes and peripheral nerves in the neural crest. Neurotized melanocytic nevi may resemble nerve sheath tumors histologically, and show schwannian differentiation. However, literature on whether neurotized nevi differentiate into perineural cells is controversial. We examined our cases of neurotized nevi for evidence of perineural differentiation.
MATERIALS AND METHODS
A total of 100 benign nevi with large neurotized component (microscopically involved a low power field 4.2 mm in diameter) were prospectively evaluated in excisional biopsy samples. Immunohistochemical stainings for EMA, Claudin1, Glut1 and neurofilament were performed.
RESULTS
Perineural differentiation was immunohistochemically detected in the neurotized component of the nevi in 61% of the cases with EMA and in all the cases with Glut1 and Claudin1. Axonal differentiation was not detected with neurofilament. The expression pattern, especially with Glut1, was usually in form of partial or complete staining surrounding the Meissner's corpuscle-like structure (MCLS). Also, a linear/curvilinear staining pattern was observed particularly with Claudin1. A diffuse staining pattern with EMA, Glut1 and Claudin1 was detected in a case with a microscopically distinct whorl structure, and in which spindle cells are separated from the superficial epithelioid melanocytes with an abrupt transition histologically. These findings of the case are compatible with previous reports of perineuromatous nevus.
CONCLUSION
Perineural differentiation is not uncommon and immunohistochemically observed in all nevi with a relatively large component of neurotization. To prevent misdiagnosing desmoplastic melanoma and overtreating patients, it is crucial to be aware of perineuromatous nevi.
Topics: Humans; Skin Neoplasms; Glucose Transporter Type 1; Immunohistochemistry; Nevus; Nevus, Pigmented; Melanocytes
PubMed: 38324967
DOI: 10.1016/j.prp.2024.155184 -
Oral and Maxillofacial Surgery Clinics... Aug 2023Perineural tumor spread (PNS) is a well-recognized entity in head and neck cancers and represents a mode of metastasis along nerves. The trigeminal and facial nerves are... (Review)
Review
Perineural tumor spread (PNS) is a well-recognized entity in head and neck cancers and represents a mode of metastasis along nerves. The trigeminal and facial nerves are most affected by PNS, and their connections are reviewed. MRI is the most sensitive modality for detecting PNS, and their anatomy and interconnections are reviewed. MRI is the most sensitive modality for detecting PNS, and imaging features of PNS and important imaging checkpoints are reviewed. Optimal imaging protocol and techniques are summarized as well as other entities that can mimic PNS.
Topics: Humans; Cranial Nerve Neoplasms; Neoplasm Invasiveness; Head and Neck Neoplasms; Skull Base; Magnetic Resonance Imaging
PubMed: 37005170
DOI: 10.1016/j.coms.2023.02.004 -
Cellular Oncology (Dordrecht) Feb 2024In recent years, the significance of the nervous system in the tumor microenvironment has gained increasing attention. The bidirectional communication between nerves and... (Review)
Review
BACKGROUND
In recent years, the significance of the nervous system in the tumor microenvironment has gained increasing attention. The bidirectional communication between nerves and cancer cells plays a critical role in tumor initiation and progression. Perineural invasion (PNI) occurs when tumor cells invade the nerve sheath and/or encircle more than 33% of the nerve circumference. PNI is a common feature in various malignancies and is associated with tumor invasion, metastasis, cancer-related pain, and unfavorable clinical outcomes. The colon and rectum are highly innervated organs, and accumulating studies support PNI as a histopathologic feature of colorectal cancer (CRC). Therefore, it is essential to investigate the role of nerves in CRC and comprehend the mechanisms of PNI to impede tumor progression and improve patient survival.
CONCLUSION
This review elucidates the clinical significance of PNI, summarizes the underlying cellular and molecular mechanisms, introduces various experimental models suitable for studying PNI, and discusses the therapeutic potential of targeting this phenomenon. By delving into the intricate interactions between nerves and tumor cells, we hope this review can provide valuable insights for the future development of CRC treatments.
Topics: Humans; Clinical Relevance; Colorectal Neoplasms; Neoplasm Invasiveness; Tumor Microenvironment
PubMed: 37610689
DOI: 10.1007/s13402-023-00857-y -
Radiographics : a Review Publication of... Jul 2023Malignancies and other diseases may spread by multiple pathways, including direct extension, hematogenous spread, or via lymphatic vessels. A less-well-understood route...
Malignancies and other diseases may spread by multiple pathways, including direct extension, hematogenous spread, or via lymphatic vessels. A less-well-understood route is the peripheral nervous system, which is known as perineural spread (PNS). In addition to accounting for pain and other neurologic symptoms, PNS affects both disease prognosis and management. Although PNS is commonly discussed in relation to head and neck tumors, there is emerging data regarding PNS in abdominopelvic malignancies and other conditions such as endometriosis. Due to improved contrast and spatial resolution, perineural invasion, a finding heretofore diagnosed only at pathologic examination, can be detected at CT, MRI, and PET/CT. PNS most commonly manifests as abnormal soft-tissue attenuation extending along neural structures, and diagnosis of it is aided by optimizing imaging parameters, understanding pertinent anatomy, and becoming familiar with the typical neural pathways of spread that largely depend on the disease type and location. In the abdomen, the celiac plexus is a central structure that innervates the major abdominal organs and is the principal route of PNS in patients with pancreatic and biliary carcinomas. In the pelvis, the lumbosacral plexus and inferior hypogastric plexus are the central structures and principal routes of PNS in patients with pelvic malignancies. Although the imaging findings of PNS may be subtle, a radiologic diagnosis can have a substantial effect on patient care. Knowledge of anatomy and known routes of PNS and optimizing imaging parameters is of utmost importance in providing key information for prognosis and treatment planning. RSNA, 2023 and Quiz questions for this article are available through the Online Learning Center.
Topics: Female; Humans; Tomography, X-Ray Computed; Positron Emission Tomography Computed Tomography; Clinical Relevance; Head and Neck Neoplasms; Radiography; Magnetic Resonance Imaging
PubMed: 37319024
DOI: 10.1148/rg.220148 -
Oncogene May 2024Perineural invasion (PNI) is an essential form of tumor metastasis in multiple malignant cancers, such as pancreatic cancer, prostate cancer, and head and neck cancer....
Perineural invasion (PNI) is an essential form of tumor metastasis in multiple malignant cancers, such as pancreatic cancer, prostate cancer, and head and neck cancer. Growing evidence has revealed that pancreatic cancer recurrence and neuropathic pain positively correlate with PNI. Therefore, targeting PNI is a proper strategy for pancreatic cancer treatment. Exosomal lncRNA derived from pancreatic cancer cells is an essential component of the tumor microenvironment. However, whether exosomal lncXIST derived from pancreatic cancer cells can promote PNI and its exact mechanism remains to be elucidated. We show that lncXIST mediates nerve-tumor crosstalk via exosomal delivery. Our data reveal that exosomal lncXIST derived from pancreatic cancer cells is delivered to neural cells and promotes their release of glial-cell-line-derived neurotrophic factor (GDNF), essential in facilitating the PNI of pancreatic cancer. Mechanistically, microRNA-211-5p negatively regulates GDNF, and lncXIST serves as a miR-211-5p sponge. The function of exosomes in the dynamic interplay between nerves and cancer is confirmed in both in vivo and in vitro PNI models. Therefore, targeting pancreatic cancer cell-derived exosomal lncXIST may provide clues for a promising approach for developing a new strategy to combat PNI of pancreatic cancer.
Topics: Humans; MicroRNAs; Pancreatic Neoplasms; Exosomes; RNA, Long Noncoding; Neoplasm Invasiveness; Glial Cell Line-Derived Neurotrophic Factor; Animals; Cell Line, Tumor; Mice; Gene Expression Regulation, Neoplastic; Tumor Microenvironment
PubMed: 38454138
DOI: 10.1038/s41388-024-02994-6