Search

The role of immune checkpoint inhibitors (ICIs) for patients with gastroesophageal (GE) cancer with liver metastasis remains unclear. Our objective was to investigate if ICIs are beneficial in patients with GE cancer with liver metastasis. We searched PubMed, Embase, ESMO, and ASCO Meeting Abstracts for phase III randomized clinical trials (RCTs) testing ICIs in metastatic/advanced GE cancer from 2017 to 2023. Seven studies were included. OS was similar among all patients (HR 0.72 [0.67,0.77], p < .001), in patients without (HR 0.73 [0.67,0.81], p < .001, I2 = 0.0%), and with liver metastasis (HR 0.74 [0.67,0.81], p < .001, I2 = 0.0%). PFS was also similar among all patients (HR 0.63 [0.57,0.70], p < .001), without (HR 0.62 [0.51,0.76], p < .001), and with liver metastasis (HR 0.66 [0.57,0.76], p < .001). ICIs showed no difference in benefit in patients with GE cancer regardless of liver metastasis. Future studies could focus on deciphering the tumor microenvironment of liver metastasis as an area of translational research., (© The Author(s) 2024. Published by Oxford University Press.)

Background and Aims: The impact of inflammatory bowel disease [IBD] on work productivity remains unclear. In this systematic review and meta-analysis, we quantify work-related outcomes and employment data among persons with IBD., Methods: A systematic literature search was conducted in MEDLINE, EMBASE, the Cochrane library, Scopus, ProQuest, and clinicaltrials.gov from inception to February 2023, to identify studies on work productivity in persons with IBD aged > 18 years. Work productivity was defined primarily by the Work Productivity and Activity Impairment [WPAI] questionnaire which includes absenteeism, presenteeism, overall work impairment, and non-work activity impairment. In addition, we included data on employment, sick leaves, disability pensions, and indirect costs due to productivity loss. Pooled effect analysis was conducted using a random-effects model for pooled estimates of continuous and proportional data with 95% confidence intervals., Results: Among all patients with IBD, the pooled estimates were 16.4% for absenteeism, 35.9% for presenteeism, 39.4% for overall work impairment, and 46.0% for non-work activity impairment. Indirect costs from overall work impairment were 5131.09 euros/patient/year. Only two-thirds of IBD patients were employed, and one in three lost their jobs due to IBD. Among those employed, 39.5% report sick days, 21.3% report work disability, and 12.3% receive disability pensions. Most studies demonstrate clinically meaningful improvements in work productivity with medical and/or surgical therapies., Conclusion: Persons with IBD experience significant work impairment and associated indirect costs. This highlights the need for appropriate workplace accommodations and timely medical therapy to alleviate the burden of disease and improve work outcomes., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.)

Background: Many patients with inflammatory bowel disease (IBD) may use cannabis for relief of symptoms. During pregnancy, however, cannabis exposure may be associated with adverse pregnancy outcomes. We aimed to determine the prevalence and perceptions of cannabis use in women with IBD., Methods: Through recruitment at Mount Sinai Hospital and online platforms such as Twitter, women with IBD (age 18-45) were asked to complete anonymous surveys on demographics, cannabis use, perception of use during pregnancy, and discussing its use with healthcare providers (HCP). Categorical variables were reported as frequencies and compared across groups with the chi-square test., Results: One-hundred and two pregnant patients with IBD were included in this study, 19 (18.6%) reported using cannabis. Current users were more likely to report constant pain in the last 12 months and discuss its use with their HCP. Fifty-three (52.0%) women were unsure of the specific risks associated with cannabis use during pregnancy, and only 15 (14.7%) had ever discussed its use with their HCP. Those who had discussed cannabis use with their HCP were more likely to have prior IBD-related surgery, perceive its use unsafe during pregnancy, and be more likely to be using cannabis., Conclusion: Many women with IBD report uncertainty of the risks of cannabis use during pregnancy and the majority have never discussed cannabis use with their providers. With the increasing legalization of cannabis in many jurisdictions, it is imperative patients and healthcare providers discuss the risks and benefits of its use, particularly during vulnerable times such as pregnancy., Competing Interests: Dr. Steinhart has received education grants from Abbvie, Celgene (BMS), Janssen, Arena (Pfizer), Genentech/Roche, and Takeda; Has served as a consultant for Abbvie, BioJAMP, Fresenius Kabi, McKesson, Organon, Pfizer, Takeda, Lilly, Amgen, BMS, Janssen, Mylan Pharmaceuticals, Pendopharm, Sandoz, Viatris; Has attended educational events sponsored by Abvvie, BMS, Organon, Takeda, Amgen, Janssen, and Pfizer. Dr. Tandon has attended educational events supported by Takeda and Janssen. Other authors have no conflict of interest to report., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Canadian Association of Gastroenterology.)

Mammalian neurons undergo rapid excitotoxic cell death when deprived of oxygen; however, the common goldfish ( Carassius auratus ) has the unique ability of surviving in oxygen-free waters, under anoxia. This organism utilizes γ-amino butyric acid (GABA) signaling to suppress excitatory glutamatergic activity during anoxic periods. Although GABA A receptor antagonists are not deleterious to the cellular survival, coinhibition of GABA A and GABA B receptors is detrimental by abolishing anoxia-induced neuroprotective mechanisms. Here we show that blocking the anoxic GABAergic neurotransmission induces seizure-like activity (SLA) analogous to a paroxysmal depolarization shift (PDS), with hyperpolarization of action potential (AP) threshold and elevation of threshold currents. The observed PDS was attributed to an increase in excitatory postsynaptic currents (EPSCs) that are normally attenuated with decreasing oxygen levels. Furthermore, for the first time, we show that in addition to PDS, some neurons undergo depolarization block and do not generate AP despite a suprathreshold membrane potential. In conclusion, our results indicate that with severe hypoxia and absence of GABA receptor activity, telencephalic neurons of C. auratus manifest a paroxysmal depolarization shift, a key feature of epileptic discharge. NEW & NOTEWORTHY This work shows that the combination of anoxia and inhibition of GABA receptors induces seizure-like activities in goldfish telencephalic pyramidal and stellate neurons. Importantly, to prevent seizure-like activity, an intact GABA-mediated inhibitory pathway is required.

Unlike anoxia-intolerant mammals, painted turtles can survive extended periods without oxygen. This is partly accomplished by an anoxia-mediated increase in gamma-aminobutyric acid (GABA) release, which activates GABA receptors and mediates spike arrest in turtle neurons via shunting inhibition. Extracellular taurine levels also increase during anoxia; why this occurs is unknown but it is speculated that glycine and/or GABA A/B receptors are involved. Given the general importance of inhibitory neurotransmission in the anoxia-tolerant painted turtle brain, we investigated the function of taurine as an inhibitory neuromodulator in turtle pyramidal neurons. Using whole-cell patch-clamp electrophysiological methods to record from neurons within a cortical brain sheet, we found that taurine depolarized membrane potential by ∼8 mV, increased whole-cell conductance ∼2-fold, and induced an inward current that possessed characteristics similar to GABA- and glycine-evoked currents. These effects were mitigated following glycine receptor antagonism with strychnine and GABA A receptor antagonism with gabazine, bicuculine or picrotoxin, but were unchanged following GABA B or glutamatergic receptor inhibition. These data indicate that a high concentration of taurine in vitro mediates its effects through both glycine and GABA A receptors, and suggests that taurine, in addition to GABA, inhibits neuronal activity during anoxia in the turtle cortex., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2018. Published by The Company of Biologists Ltd.)

With oxygen deprivation, the mammalian brain undergoes hyper-activity and neuronal death while this does not occur in the anoxia-tolerant goldfish ( Carassius auratus ). Anoxic survival of the goldfish may rely on neuromodulatory mechanisms to suppress neuronal hyper-excitability. As γ-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain, we decided to investigate its potential role in suppressing the electrical activity of goldfish telencephalic neurons. Utilizing whole-cell patch-clamp recording, we recorded the electrical activities of both excitatory (pyramidal) and inhibitory (stellate) neurons. With anoxia, membrane potential ( V m ) depolarized in both cell types from -72.2 mV to -57.7 mV and from -64.5 mV to -46.8 mV in pyramidal and stellate neurons, respectively. While pyramidal cells remained mostly quiescent, action potential frequency (AP f ) of the stellate neurons increased 68-fold. Furthermore, the GABA A receptor reversal potential ( E - GABA ) was determined using the gramicidin perforated-patch-clamp method and found to be depolarizing in pyramidal (-53.8 mV) and stellate neurons (-42.1 mV). Although GABA was depolarizing, pyramidal neurons remained quiescent as E GABA was below the action potential threshold (-36 mV pyramidal and -38 mV stellate neurons). Inhibition of GABA A receptors with gabazine reversed the anoxia-mediated response. While GABA B receptor inhibition alone did not affect the anoxic response, co-antagonism of GABA A and GABA B receptors (gabazine and CGP-55848) led to the generation of seizure-like activities in both neuron types. We conclude that with anoxia, V m depolarizes towards E GABA which increases AP f in stellate neurons and decreases AP f in pyramidal neurons, and that GABA plays an important role in the anoxia tolerance of goldfish brain., (© 2017. Published by The Company of Biologists Ltd.)