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Biomedicine & Pharmacotherapy =... Nov 2022Perineural invasion (PNI) is the process of neoplastic invasion of peripheral nerves and is considered to be the fifth mode of cancer metastasis. PNI has been detected... (Review)
Review
Perineural invasion (PNI) is the process of neoplastic invasion of peripheral nerves and is considered to be the fifth mode of cancer metastasis. PNI has been detected in head and neck tumors and pancreatic, prostate, bile duct, gastric, and colorectal cancers. It leads to poor prognostic outcomes and high local recurrence rates. Despite the increasing number of studies on PNI, targeted therapeutic modalities have not been proposed. The identification of PNI-related biomarkers would facilitate the non-invasive and early diagnosis of cancers, the establishment of prognostic panels, and the development of targeted therapeutic approaches. In this review, we compile information on the molecular mediators involved in PNI-associated cancers. The expression and prognostic significance of molecular mediators and their receptors in PNI-associated cancers are analyzed, and the possible mechanisms of action of these mediators in PNI are explored, as well as the association of cells in the microenvironment where PNI occurs.
Topics: Male; Humans; Neoplasm Invasiveness; Peripheral Nerves; Head and Neck Neoplasms; Biomarkers; Retrospective Studies; Tumor Microenvironment
PubMed: 36095958
DOI: 10.1016/j.biopha.2022.113691 -
Cancer Communications (London, England) Aug 2021Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignant disease with a unique tumor microenvironment surrounded by an interlaced network of cancer and... (Review)
Review
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignant disease with a unique tumor microenvironment surrounded by an interlaced network of cancer and noncancerous cells. Recent works have revealed that the dynamic interaction between cancer cells and neuronal cells leads to perineural invasion (PNI), a clinical pathological feature of PDAC. The formation and function of PNI are dually regulated by molecular (e.g., involving neurotrophins, cytokines, chemokines, and neurotransmitters), metabolic (e.g., serine metabolism), and cellular mechanisms (e.g., involving Schwann cells, stromal cells, T cells, and macrophages). Such integrated mechanisms of PNI not only support tumor development, growth, invasion, and metastasis but also mediate the formation of pain, all of which are closely related to poor disease prognosis in PDAC. This review details the modulation, signaling pathways, detection, and clinical relevance of PNI and highlights the opportunities for further exploration that may benefit PDAC patients.
Topics: Carcinoma, Pancreatic Ductal; Humans; Neoplasm Invasiveness; Pancreatic Neoplasms; Signal Transduction; Tumor Microenvironment
PubMed: 34264020
DOI: 10.1002/cac2.12188 -
Anaesthesia Jan 2021Moderate-to-severe postoperative pain persists for longer than the duration of single-shot peripheral nerve blocks and hence continues to be a problem even with the... (Review)
Review
Moderate-to-severe postoperative pain persists for longer than the duration of single-shot peripheral nerve blocks and hence continues to be a problem even with the routine use of regional anaesthesia techniques. The administration of local anaesthetic adjuncts, defined as the concomitant intravenous or perineural injection of one or more pharmacological agents, is an attractive and technically simple strategy to potentially extend the benefits of peripheral nerve blockade beyond the conventional maximum of 8-14 hours. Historical local anaesthetic adjuncts include perineural adrenaline that has been demonstrated to increase the mean duration of analgesia by as little as just over 1 hour. Of the novel local anaesthetic adjuncts, dexmedetomidine and dexamethasone have best demonstrated the capacity to considerably improve the duration of blocks. Perineural dexmedetomidine and dexamethasone increase the mean duration of analgesia by up to 6 hour and 8 hour, respectively, when combined with long-acting local anaesthetics. The evidence for the safety of these local anaesthetic adjuncts continues to accumulate, although the findings of a neurotoxic effect with perineural dexmedetomidine during in-vitro studies are conflicting. Neither perineural dexmedetomidine nor dexamethasone fulfils all the criteria of the ideal local anaesthetic adjunct. Dexmedetomidine is limited by side-effects such as bradycardia, hypotension and sedation, and dexamethasone slightly increases glycaemia. In view of the concerns related to localised nerve and muscle injury and the lack of consistent evidence for the superiority of the perineural vs. systemic route of administration, we recommend the off-label use of systemic dexamethasone as a local anaesthetic adjunct in a dose of 0.1-0.2 mg.kg for all patients undergoing surgery associated with significant postoperative pain.
Topics: Anesthesia, Conduction; Anesthetics, Local; Conscious Sedation; Humans; Hypnotics and Sedatives; Nerve Block; Peripheral Nerves
PubMed: 33426668
DOI: 10.1111/anae.15245 -
Journal of Experimental & Clinical... Feb 2022Perineural invasion (PNI) and autophagy are two common features in the tumor microenvironment of pancreatic cancer (PanCa) and have a negative effect on prognosis....
BACKGROUND
Perineural invasion (PNI) and autophagy are two common features in the tumor microenvironment of pancreatic cancer (PanCa) and have a negative effect on prognosis. Potential mediator cells and the molecular mechanism underlying their relationships need to be fully elucidated.
METHODS
To investigate the autophagy of Schwann cells (SCs) in PNI, we reproduced the microenvironment of PNI by collecting clinical PNI tissue, performing sciatic nerve injection of nude mice with cancer cells and establishing a Dorsal root ganglion (DRG) coculture system with cancer cell lines. Autophagy was detected by IHC, IF, transmission electron microscopy (TEM) and western blotting assays. Apoptosis was detected by IF, TEM and western blotting. NGF targeting molecular RO 08-2750(RO) and the autophagy inhibitor Chloroquine (CQ) were utilized to evaluate the effect on autophagy and apoptosis in SCs and PanCa cells in PNI samples.
RESULTS
SC autophagy is activated in PNI by paracrine NGF from PanCa cells. Autophagy-activated Schwann cells promote PNI through a) enhanced migration and axon guidance toward PanCa cells and b) increased chemoattraction to PanCa cells. The NGF-targeting reagent RO and autophagy inhibitor CQ inhibited Schwann cell autophagic flux and induced Schwann cell apoptosis. Moreover, RO and CQ could induce PanCa cell apoptosis and showed good therapeutic effects in the PNI model.
CONCLUSIONS
PanCa cells can induce autophagy in SCs through paracrine pathways such as the NGF/ATG7 pathway. Autophagic SCs exert a "nerve-repair like effect", induce a high level of autophagy of cancer cells, provide a "beacon" for the invasion of cancer cells to nerve fibers, and induce directional growth of cancer cells. Targeting NGF and autophagy for PNI treatment can block nerve infiltration and is expected to provide new directions and an experimental basis for the research and treatment of nerve infiltration in pancreatic cancer.
Topics: Adenocarcinoma; Animals; Autophagy; Carcinoma, Pancreatic Ductal; Disease Models, Animal; Female; Humans; Mice; Neoplasm Invasiveness; Nerve Growth Factor; Paracrine Communication; Rats; Schwann Cells; Transfection; Tumor Microenvironment
PubMed: 35109895
DOI: 10.1186/s13046-021-02198-w -
Annual Review of Pathology Jan 2023Nerves not only regulate the homeostasis and energetic metabolism of normal epithelial cells but also are critical for cancer, as cancer recapitulates the biology of... (Review)
Review
Nerves not only regulate the homeostasis and energetic metabolism of normal epithelial cells but also are critical for cancer, as cancer recapitulates the biology of neural regulation of epithelial tissues. Cancer cells rarely develop in denervated organs, and denervation affects tumorigenesis, in vivo and in humans. Axonogenesis occurs to supply the new malignant epithelial growth with nerves. Neurogenesis happens later, first in ganglia around organs or the spinal column and subsequently through recruitment of neuroblasts from the central nervous system. The hallmark of this stage is regulation of homeostasis and energetic metabolism. Perineural invasion is the most efficient interaction between cancer cells and nerves. The hallmark of this stage is increased proliferation and decreased apoptosis. Finally, carcinoma cells transdifferentiate into a neuronal profile in search of neural independence. The latter is the last stage in neuroepithelial interactions. Treatments for cancer must address the biology of neural regulation of cancer.
Topics: Humans; Neoplasms; Neurons
PubMed: 36323005
DOI: 10.1146/annurev-pathmechdis-031521-023248 -
Frontiers in Pharmacology 2020Peripheral nerve entrapment syndromes commonly result in pain, discomfort, and ensuing sensory and motor impairment. Many conservative measures have been proposed as...
Peripheral nerve entrapment syndromes commonly result in pain, discomfort, and ensuing sensory and motor impairment. Many conservative measures have been proposed as treatment, local injection being one of those measures. Now with high-resolution ultrasound, anatomical details can be visualized allowing diagnosis and more accurate injection treatment. Ultrasound-guided injection technique using a range of injectates to mechanically release and decompress the entrapped nerves has therefore developed called hydrodissection or perineural injection therapy. Several different injectates from normal saline, local anesthetics, corticosteroids, 5% dextrose in water (D5W), and platelet-rich plasma (PRP) are available and present clinical challenges when selecting agents regarding effectiveness and safety. To systematically search and summarize the clinical evidence and mechanism of different commonly used injectates for ultrasound-guided hydrodissection entrapment neuropathy treatment. Four databases, including PubMed, EMBASE, Scopus, and Cochrane were systematically searched from the inception of the database up to August 22, 2020. Studies evaluating the effectiveness and safety of different commonly used injectates for ultrasound-guided hydrodissection entrapment neuropathy treatment were included. Injectate efficacy presents clinical effects on pain intensity, clinical symptoms/function, and physical performance, electrodiagnostic findings, and nerve cross-sectional areas. Safety outcomes and mechanism of action of each injectate were also described. From ten ultrasound-guided hydrodissection studies, nine studies were conducted in carpal tunnel syndrome and one study was performed in ulnar neuropathy at the elbow. All studies compared different interventions with different comparisons. Injectates included normal saline, D5W, corticosteroids, local anesthetics, hyaluronidase, and PRP. Five studies investigated PRP or PRP plus splinting comparisons. Both D5W and PRP showed a consistently favorable outcome than those in the control group or corticosteroids. The improved outcomes were also observed in comparison groups using injections with normal saline, local anesthetics, or corticosteroids, or splinting. No serious adverse events were reported. Local steroid injection side effects were reported in only one study. Ultrasound-guided hydrodissection is a safe and effective treatment for peripheral nerve entrapment. Injectate selection should be considered based on the injectate mechanism, effectiveness, and safety profile.
PubMed: 33746745
DOI: 10.3389/fphar.2020.621150 -
Anesthesiology Mar 2022The interscalene nerve block provides analgesia for shoulder surgery. To extend block duration, provide adequate analgesia, and minimize opioid consumption, the use of... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
The interscalene nerve block provides analgesia for shoulder surgery. To extend block duration, provide adequate analgesia, and minimize opioid consumption, the use of adjuvants such as dexamethasone as well as the application of perineural liposomal bupivacaine have been proposed. This randomized, double-blinded, noninferiority trial hypothesized that perineural liposomal bupivacaine is noninferior to standard bupivacaine with perineural dexamethasone in respect to average pain scores in the first 72 h after surgery.
METHODS
A total of 112 patients undergoing ambulatory shoulder surgery were randomized into two groups. The liposomal bupivacaine group received a 15-ml premixed admixture of 10 ml of 133 mg liposomal bupivacaine and 5 ml of 0.5% bupivacaine (n = 55), while the bupivacaine with dexamethasone group received an admixture of 15 ml of 0.5% standard bupivacaine with 4 mg dexamethasone (n = 56), respectively. The primary outcome was the average numerical rating scale pain scores at rest over 72 h. The mean difference between the two groups was compared against a noninferiority margin of 1.3. Secondary outcomes were analgesic block duration, motor and sensory resolution, opioid consumption, numerical rating scale pain scores at rest and movement on postoperative days 1 to 4 and again on postoperative day 7, patient satisfaction, readiness for postanesthesia care unit discharge, and adverse events.
RESULTS
A liposomal bupivacaine group average numerical rating scale pain score over 72 h was not inferior to the bupivacaine with dexamethasone group (mean [SD], 2.4 [1.9] vs. 3.4 [1.9]; mean difference [95% CI], -1.1 [-1.8, -0.4]; P < 0.001 for noninferiority). There was no significant difference in duration of analgesia between the groups (26 [20, 42] h vs. 27 [20, 39] h; P = 0.851). Motor and sensory resolutions were similar in both groups: 27 (21, 48) h versus 27 (19, 40) h (P = 0.436) and 27 [21, 44] h versus 31 (20, 42) h (P = 0.862), respectively. There was no difference in opioid consumption, readiness for postanesthesia care unit discharge, or adverse events.
CONCLUSIONS
Interscalene nerve blocks with perineural liposomal bupivacaine provided effective analgesia similar to the perineural standard bupivacaine with dexamethasone. The results show that bupivacaine with dexamethasone can be used interchangeably with liposomal bupivacaine for analgesia after shoulder surgery.
Topics: Adult; Ambulatory Surgical Procedures; Anesthetics, Local; Anti-Inflammatory Agents; Brachial Plexus Block; Bupivacaine; Dexamethasone; Double-Blind Method; Female; Humans; Male; Middle Aged; Pain, Postoperative; Shoulder
PubMed: 35041742
DOI: 10.1097/ALN.0000000000004111 -
Frontiers in Cell and Developmental... 2022Cancerous invasion of nerves has been reported in a list of malignant tumors as a high-risk pathological feature and marker of poor disease outcome especially in... (Review)
Review
Cancerous invasion of nerves has been reported in a list of malignant tumors as a high-risk pathological feature and marker of poor disease outcome especially in neurotrophic cancers (such as in pancreas and prostate), indicating that although once neglected, nerves could have played a pivotal role in tumorigenesis and cancer progression. In colorectal cancer, perineural invasion, a specific form of tumor-nerve interaction referring to the identification of tumor cells in proximity to the nerve, has been recognized as a strong and independent prognosis predictor; denervation of autonomic nerves and enteric nerves have shown that the existence of these nerves in the gut are accompanied by promoted cancer proliferation, further supporting that nerve is a potential accomplice to shield and nurture tumor cells. However, the precise role of nerve in CRC and the pattern of interaction between CRC cells and nerve has not been unveiled yet. Here we aim to review some basic knowledge of the importance of nerves in CRC and attempt to depict a mechanistic view of tumor-nerve interaction during CRC development.
PubMed: 35223829
DOI: 10.3389/fcell.2022.766653 -
Anesthesiology Jun 2023The authors hypothesized that both perineural and systemic dexamethasone as adjuncts to bupivacaine increase the duration of an ulnar nerve block compared with... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The authors hypothesized that both perineural and systemic dexamethasone as adjuncts to bupivacaine increase the duration of an ulnar nerve block compared with bupivacaine alone, and that systemic dexamethasone is noninferior to perineural dexamethasone.
METHODS
The authors performed bilateral ulnar nerve blocks with 3 ml bupivacaine 5 mg/ml in 16 healthy volunteers on two trial days. According to randomization, subjects received adjunct treatment with 1 ml dexamethasone 4 mg/ml + 1 ml of saline (perineural condition) in one arm and 2 ml saline in the other arm (systemic condition, through absorption and redistribution of the contralaterally administered perineural dexamethasone) on one trial day; and 2 ml saline in one arm (placebo condition) and 2 ml of lidocaine in the other arm (lidocaine condition) on the other trial day. The primary outcome was the duration of the sensory nerve block assessed by temperature discrimination.
RESULTS
Mean sensory block duration was 706 ± 94 min for the perineural condition, 677 ± 112 min for the systemic condition, and 640 ± 121 min for the placebo condition. The duration of the sensory nerve block was greater with perineural dexamethasone versus placebo (mean difference 66 min (95% CI, 23 to 108). Block duration was similar between systemic dexamethasone and placebo (mean difference 36 min; 95% CI, -30 to 103).
CONCLUSIONS
Perineural dexamethasone as an adjunct to bupivacaine in healthy volunteers resulted in a greater duration of an ulnar nerve block when compared with placebo. Systemic dexamethasone resulted in a similar duration as placebo.
Topics: Humans; Dexamethasone; Anesthetics, Local; Healthy Volunteers; Bupivacaine; Nerve Block; Lidocaine; Pain, Postoperative; Double-Blind Method
PubMed: 36912613
DOI: 10.1097/ALN.0000000000004557