Odontogenic Carcinosarcoma: Clinicopathologic and Molecular Features of Three Cases, a Literature Review and Nomenclature Proposal.

BACKGROUND: Odontogenic carcinosarcoma (OCS) is a rare odontogenic malignancy with limited characterization and unexplored molecular features. We report clinicopathologic and molecular findings in 3 additional OCS and review the literature. METHODS: 3 OCS (5.1%) were identified among 59 malignant odontogenic tumors (in our archives from 1992 to 2022). Clinical, radiologic, histopathologic, immunophenotypic, and molecular findings were reviewed. Data from prior case reports and systematic or non-systematic reviews were extracted for analysis. RESULTS: Three mandibular OCS (age range: 66 to 72 years; 1 male, 2 females) were identified. Case 1 had novel clear-cell morphology, multiple recurrences, and a lethal outcome 28 months after resection. EWSR1 rearrangements were negative, but the tumor showed focal nuclear ß-catenin and strong LEF-1 immunoreactivity. Case 2 demonstrated ameloblastic and sclerosing features and encased the inferior alveolar nerve; the patient was disease-free 22 months after resection with adjuvant chemoradiation therapy. LEF-1 was again strongly positive, and next-generation sequencing demonstrated 9p region-(CDKN2A, CDKN2B) copy number loss, and 12q region-(MDM2, CDK4) copy number gain. Case 3 showed clear-cell and markedly sclerosing features; no follow-up information was available. Literature review along with the current cases yielded 20 cases. OCS showed a male predilection (1.5:1), mandibular predominance (80%, typically posterior), and a bimodal age distribution (modes: 27.7 years, 62.7 years). OCS presented as masses (100%), often with pain (55%), and paresthesia (45%). Tumors were typically radiolucent (88.9%), with bone destruction (61.1%), and/or tooth effacement (27.8%). Preoperative biopsy was sensitive for malignancy (85.7%). At least 45% show evidence for a precursor lesion. 3-year DSS and DFS were 58% and 35%, respectively. Regional and distant (usually lung) metastatic rates were 25% and 31.3%, respectively. Increased mitotic rates and presence of tumor necrosis trended toward worse DSS and DFS. CONCLUSION: OCS is a rare but aggressive malignancy, often arising from precursor tumors and may represent a terminal phenotype rather than a distinct entity. We describe novel clear-cell and sclerosing morphologies. Wnt pathway alterations appear important. Mitotic rates and necrosis may be adverse prognosticators. In keeping with nomenclature trends in other sites, OCS may be more appropriately designated as "biphasic sarcomatoid odontogenic carcinomas."

PPG neurons in the nucleus of the solitary tract modulate heart rate but do not mediate GLP-1 receptor agonist-induced tachycardia in mice.

OBJECTIVE: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are used as anti-diabetic drugs and are approved for obesity treatment. However, GLP-1RAs also affect heart rate (HR) and arterial blood pressure (ABP) in rodents and humans. Although the activation of GLP-1 receptors (GLP-1R) is known to increase HR, the circuits recruited are unclear, and in particular, it is unknown whether GLP-1RAs activate preproglucagon (PPG) neurons, the brain source of GLP-1, to elicit these effects. METHODS: We investigated the effect of GLP-1RAs on heart rate in anaesthetized adult mice. In a separate study, we manipulated the activity of nucleus tractus solitarius (NTS) PPG neurons (PPGNTS) in awake, freely behaving transgenic Glu-Cre mice implanted with biotelemetry probes and injected with AAV-DIO-hM3Dq:mCherry or AAV-mCherry-FLEX-DTA. RESULTS: Systemic administration of the GLP-1RA Ex-4 increased resting HR in anaesthetized or conscious mice, but had no effect on ABP in conscious mice. This effect was abolished by ß-adrenoceptor blockade with atenolol, but unaffected by the muscarinic antagonist atropine. Furthermore, Ex-4-induced tachycardia persisted when PPGNTS neurons were ablated, and Ex-4 did not induce expression of the neuronal activity marker cFos in PPGNTS neurons. PPGNTS ablation or acute chemogenetic inhibition of these neurons via hM4Di receptors had no effect on resting HR. In contrast, chemogenetic activation of PPGNTS neurons increased resting HR. Furthermore, the application of GLP-1 within the subarachnoid space of the middle thoracic spinal cord, a major projection target of PPG neurons, increased HR. CONCLUSIONS: These results demonstrate that both systemic application of Ex-4 or GLP-1 and chemogenetic activation of PPGNTS neurons increases HR. Ex-4 increases the activity of cardiac sympathetic preganglionic neurons of the spinal cord without recruitment of PPGNTS neurons, and thus likely recapitulates the physiological effects of PPG neuron activation. These neurons therefore do not play a significant role in controlling resting HR and ABP but are capable of inducing tachycardia and so are likely involved in cardiovascular responses to acute stress.

Preproglucagon Neurons in the Nucleus of the Solitary Tract Are the Main Source of Brain GLP-1, Mediate Stress-Induced Hypophagia, and Limit Unusually Large Intakes of Food.

Centrally administered glucagon-like peptide 1 (GLP-1) supresses food intake. Here we demonstrate that GLP-1-producing (PPG) neurons in the nucleus tractus solitarii (NTS) are the predominant source of endogenous GLP-1 within the brain. Selective ablation of NTS PPG neurons by viral expression of diphtheria toxin subunit A substantially reduced active GLP-1 concentrations in brain and spinal cord. Contrary to expectations, this loss of central GLP-1 had no significant effect on the ad libitum feeding of mice, affecting neither daily chow intake nor body weight or glucose tolerance. Only after bigger challenges to homeostasis were PPG neurons necessary for food intake control. PPG-ablated mice increased food intake after a prolonged fast and after a liquid diet preload. Consistent with our ablation data, acute inhibition of hM4Di-expressing PPG neurons did not affect ad libitum feeding; however, it increased refeeding intake after fast and blocked stress-induced hypophagia. Additionally, chemogenetic PPG neuron activation through hM3Dq caused a strong acute anorectic effect. We conclude that PPG neurons are not involved in primary intake regulation but form part of a secondary satiation/satiety circuit, which is activated by both psychogenic stress and large meals. Given their hypophagic capacity, PPG neurons might be an attractive drug target in obesity treatment.

AZD-3043: a novel, metabolically labile sedative-hypnotic agent with rapid and predictable emergence from hypnosis.

BACKGROUND: Propofol can be associated with delayed awakening after prolonged infusion. The aim of this study was to characterize the preclinical pharmacology of AZD-3043, a positive allosteric modulator of the γ-aminobutyric acid type A (GABA(A)) receptor containing a metabolically labile ester moiety. The authors postulated that its metabolic pathway would result in a short-acting clinical profile. METHODS: The effects of AZD-3043, propofol, and propanidid were studied on GABA(A) receptor-mediated chloride currents in embryonic rat cortical neurons. Radioligand binding studies were also performed. The in vitro stability of AZD-3043 in whole blood and liver microsomes was evaluated. The duration of the loss of righting reflex and effects on the electroencephalograph evoked by bolus or infusion intravenous administration were assessed in rats. A mixed-effects kinetic-dynamic model using minipigs permitted exploration of the clinical pharmacology of AZD-3043. RESULTS: AZD-3043 potentiated GABA(A) receptor-mediated chloride currents and inhibited [(35)S]tert-butylbicyclophosphorothionate binding to GABA(A) receptors. AZD-3043 was rapidly hydrolyzed in liver microsomes from humans and animals. AZD-3043 produced hypnosis and electroencephalograph depression in rats. Compared with propofol, AZD-3043 was shorter acting in rats and pigs. Computer simulation using the porcine kinetic-dynamic model demonstrated that AZD-3043 has very short 50 and 80% decrement times independent of infusion duration. CONCLUSIONS: AZD-3043 is a positive allosteric modulator of the GABA(A) receptor in vitro and a sedative-hypnotic agent in vivo. The esterase dependent metabolic pathway results in rapid clearance and short duration of action even for long infusions. AZD-3043 may have clinical potential as a sedative-hypnotic agent with rapid and predictable recovery.

A novel electroencephalographic analysis method discriminates alcohol effects from those of other sedative/hypnotics.

Here we describe a mathematical and statistical signal processing strategy termed event resolution imaging (ERI). Our principal objective was to determine if the acute intoxicating effects of ethanol on spontaneous EEG activity could be discriminated from those of other sedative/hypnotics. We employed ERI to combine and integrate standard analysis methods to learn multiple signal features of time-varying EEG signals. We recorded cortical EEG, electromyographic activity, and motor activity during intravenous administration of saline, ethanol (1.0 g/kg), chlordiazepoxide (10 mg/kg), pentobarbital (6 mg/kg), heroin (0.3 mg/kg), and methamphetamine (2 mg/kg) administered on separate days in six rats. A blind treatment of one of the drugs was readministered to validate the efficacy of ERI analysis. Significant changes in spontaneous EEG activity produced by all five drugs were detected by ERI analysis with a time resolution of 5-10 s. ERI analysis of spontaneous EEG activity also discriminated, with 90-95% accuracy, an ataxic dose of ethanol versus equivalent ataxic doses of chlordiazepoxide or pentobarbital, as well as the effects of saline, a reinforcing dose of heroin, or a locomotor activating dose of methamphetamine. ERI correctly matched the 'blind drug' as ethanol. These findings indicate that ERI analysis can detect the central nervous system effects of various psychoactive drugs and accurately discriminate the electrocortical effects of select sedative/hypnotics, with similar behavioral endpoints, but with dissimilar mechanisms of action.