Clinically, the unique impact of perioperative distress on long-term cancer outcomes remains unclear and is thus overlooked medically. Operated cancer patients experience intertwined psychological and physiological stress, which are hard to disentangle. Therefore, herein we employed rodents to assess the specific impact of psycho-behavioral stress on cancer metastasis in the context of surgery and without it, and studied underlying neuroendocrine mechanisms and intratumoral transcriptional mediators. A tilt-light stress paradigm was employed along with surgery/tumor cell inoculation, using two mouse colorectal cancer models of liver metastases (MC38 C57BL/6, and CT26 BALB/c), and a rat mammary pulmonary metastases model (MADB106 F344). In the latter, we also assessed the efficacy of glucocorticoid, β-adrenergic, or COX-2 inhibitors/antagonists (mifepristone, propranolol, or etodolac) in preventing the effects of stress. A 48-h perioperative stress exposure, but not 24-h pre- or 24-h post-operative exposure, consistently increased the number of experimental metastases in all models, irrespective of the effects of surgery. Both mifepristone and propranolol, but not etodolac, prevented these effects. To better mimic the clinical setting, the 4T1 mammary cancer model of spontaneous metastases was used, along with six perioperative days of alternating stress. Perioperative stress increased metastasis, and a propranolol + etodolac regimen, as employed in recent clinical studies, abrogated pre-operative deleterious effects of stress on tumor epithelial-to-mesenchymal transition and other metastasis-related transcriptional activity. Overall, psycho-behavioral stress can uniquely contribute to metastatic progression through stress responses and malignant pro-metastatic transcriptional pathways. Thus, in cancer patients, managing perioperative distress may improve long-term cancer outcomes.

BackgroundThe perioperative use of the β-adrenergic blocker, propranolol, and/or the semi-selective COX-2 inhibitor, etodolac, has improved biomarkers of cancer metastasis in several small randomized controlled trials (RCTs). In colorectal cancer (CRC) patients, the combined regimen showed potential to improve disease-free survival (DFS).MethodsWe report data from our four RCTs including 148 patients with breast (n = 38), colorectal (n = 34 & n = 46), and pancreatic (n = 30) cancers. Treatment began 5 days pre-operatively, and continued for 5–30 postoperatively. Propranolol (slow-release) was initiated at 20 mg twice daily (b.i.d), increased to 80 mg b.i.d on surgery day, and gradually decreased thereafter to 20 mg b.i.d. Etodolac was provided at 400 mg b.i.d. The primary endpoints were perioperative safety outcomes, including adverse events (AEs) up to 30-day postoperatively, and 16 blood indices. Secondary outcomes were long-term oncological outcomes of 8-year DFS and overall survival (OS).ResultsBradycardia occurred in 12% of treated vs. 3% of placebo patients (p = 0.057), and was easily resolved by temporary withholding β-blockade. Weakness, nausea, pain, infection, bleeding, leakage, tissue-healing, or death were not significantly affected. Drug treatment promoted eosinophils in pancreatic cancer patients (p = 0.015), increased potassium (p = 0.013), and decreased albumin (p = 0.016) in CRC patients; however, these effects did not remain significant after false discovery rate (FDR) correction. In CRC, treatment improved 8-year DFS (2/15 vs. 9/18, p = 0.034), although this exploratory analysis was underpowered.ConclusionThese findings suggest the safety of this inexpensive and easy-to-implement perioperative propranolol and etodolac regimen in patients participating in these RCTs.Clinical Trial Registrationhttps://clinicaltrials.gov/study/NCT00502684, https://clinicaltrials.gov/study/NCT00888797, https://clinicaltrials.gov/study/NCT03919461, https://clinicaltrials.gov/study/NCT03838029, identifier NCT00502684, NCT00888797, NCT03919461, NCT03838029.

Cancer patients are often treated perioperatively with serotonin reuptake inhibitors (SSRIs) to counteract anxiety and depression. Recent studies suggest that long-term cancer outcomes may also be affected by SSRI use in an agent-dependent manner. Importantly, the perioperative use of SSRIs is prevalent clinically, but has rarely been studied empirically. Herein, we studied escitalopram, a commonly prescribed SSRI in cancer patients, in vitro, and in vivo in the context of surgery and/or cancer progression in immune-competent rodents, employing the Panc02 (pancreatic), MADB106, 4T1, EO771 (mammary), and CT26 (colon) syngeneic tumor models, assessing primary tumor growth and metastasis. Escitalopram (10-15mg/kg/day, 14-30 days) was administered along tumor and/or metastatic progression, via intraperitoneal injections, Alzet osmotic pumps, or drinking water. In vitro, escitalopram affected proliferation rates in a cell-line-, dose-, and exposure duration- dependent manner, mostly increasing or not affecting proliferation. In contrast, in vivo escitalopram consistently increased primary tumor growth, and experimental and spontaneous metastasis in all models tested. In pancreatic tumor-bearing mice, escitalopram increased tumor growth in two different studies by ∼1.5-fold, as indicated by bioluminescence imaging. In the mammary primary tumor models, escitalopram increased 4T1 and EO771 growth by 1.4 to 2.2-fold. Last, escitalopram increased experimental MADB106 lung metastasis and CT26 liver metastasis, as well as spontaneous post-excision 4T1 lung metastasis by 1.6 to 2.3-fold. Taken together, although additional research is needed to elucidate mediating in vivo mechanisms, and to assess clinical oncological risks of escitalopram, these findings raise concerns regarding the prevalent perioperative use of escitalopram in cancer patients.

BACKGROUND:The perioperative period often involves stress responses and surgery-induced hypothermia, which were suggested to hinder antimetastatic immunity and promote cancer metastasis. During this critical period, immunotherapies are rarely used, given contraindications to surgery. However, recent preclinical studies support the feasibility of perioperative TLR-9 activation using CpG-C. MATERIALS AND METHODS:Herein, we employed hypothermic-stress and normothermic-stress paradigms to assess their impact on perioperative CpG-C immune stimulation and resistance to experimental hepatic metastasis of CT26 colorectal cancer in BALB/c mice. RESULTS:Perioperative hypothermic wet-cage stress markedly abrogated CpG-C-induced increase in plasma IL-12 levels, a persistent deleterious effect across different CpG-C doses and administration routes. These effects were not attenuated by blocking glucocorticoids, adrenergic, or opioid signaling, nor by adrenalectomy, suggesting a direct immunosuppressive impact of hypothermia on immunocytes. Indeed, normothermic wet-cage stress, which induced a similar corticosterone response, caused significantly less deleterious effects on IL-12 levels, hepatic NK cell maturation and cytotoxicity, and CT26 metastasis. Additionally, in-vitro exposure of PBMCs to 33°C markedly decreased CpG-C-induced IL-12 production. Last, two normothermic stress paradigms, tilt&light and restraint, did not jeopardize CpG-C-induced IL-12 response nor resistance to CT26 metastases. Interestingly, attenuating glucocorticoid signaling under tilt&light conditions improved CpG-C efficacy. CONCLUSIONS:Overall, these findings suggest that perioperative hypothermic stress can jeopardize antimetastatic immunity and resistance to metastasis, and prevent perioperative response to immune stimulation and its beneficial antimetastatic impacts, effects that are not mediated through classical neuroendocrine stress responses, but potentially through direct hypothermic impact on leukocytes. These findings may have clinical implications in operated cancer patients, many of whom suffer hypothermic stress.

Tumor excision is a necessary life-saving procedure in most solid cancers. However, surgery and the days before and following it, known as the immediate perioperative period (IPP), entail numerous prometastatic processes, including the suppression of antimetastatic immunity and direct stimulation of minimal residual disease (MRD). Thus, the IPP is pivotal in determining long-term cancer outcomes, presenting a short window of opportunity to circumvent perioperative risk factors by employing several therapeutic approaches, including immunotherapy. Nevertheless, immunotherapy is rarely examined or implemented during this short timeframe, due to both established and hypothetical contraindications to surgery. Herein, we analyze how various aspects of the IPP promote immunosuppression and progression of MRD, and how potential IPP application of immunotherapy may interact with these deleterious processes. We discuss the feasibility and safety of different immunotherapies during the IPP with a focus on the latest approaches of immune checkpoint inhibition. Last, we address the few past and ongoing clinical trials that exploit the IPP timeframe for anticancer immunotherapy. Accordingly, we suggest that several specific immunotherapies can be safely and successfully applied during the IPP, alone or with supporting interventions, which may improve patients' resistance to MRD and overall survival.

Dataset summarizing for every State X Unit the auditory response features + the statistical models for all the different figures. Variables: corticosteroneRawData:the corticosterone measures in 12 animals across the five conditions described in the paper. statistics: statistical models for every figure isUnitValidForAnalysis: Logical vector with n units length describing which units were included in every analysis. resultsPerUnit: auditory response features per unit for all the different states/conditions described in the paper (Vigilant, Tired, NREM, REM, Q-Wakefulness during recovery sleep, movement-controlled Vigilant and Tired conditions). Each state is a struct with 496 entries (496 units). the different field in the struct are: - session: animal and session identifiers. - isContext: is Auditory Paradigm A (with 2,10,20,30,40 Hz Click Trains) or B (just 40 Hz click trains. - ch: recording channel/microwire # (1-16) - clus: cluster number in channel - clusType: is single-unit / multi-unit - spikeShape: the average spike waveform - baseFr: unit's baseline firing rate - baseFanoFactor: fano factor of each unit's baseline firing rate (not used in paper). - baseIsiCv: baseline ISI (inter-spike interval) CV (coefficient of variation), not used in paper - basePopCoupling: baseline population coupling values - clicks40Hz: 40Hz click responses - clicksAll: responses to all click trains (2,10,20,30,40 Hz) - offState: post-onset and off-state analysis. - clicksSim: simulated click response to different click rates based on the onset+post onset responses as in Supp. Fig. 6. - PostOnsetYoked: Surrogate post-onset response following spontaneous bursts as in Fig. 5A-C - drc: responses to Dynamic random chords used to get tuning.

We recently showed that a minimally-invasive removal of MDA-MB-231HM primary tumors (PTs) and elimination of their secreted factors (including IL-6, IL-8, VEGF, EGF, PDGF-aa, MIF, SerpinE1, and M-CSF), caused regression of spontaneous micro-metastases into a non-growing dormant state. To explore the underlying mechanisms and potential clinical ramifications of this phenomenon, we herein used the MDA-MB-231HM human breast cancer cell-line, in-vitro, and in vivo following orthotopic implantation in immune-deficient BALB/C nu/nu mice. Employing bioluminescence imaging, we found that adding laparotomy to minimally-invasive removal of the PT caused an outbreak of micro-metastases. However, perioperative beta-adrenergic and COX-2 inhibition, using propranolol + etodolac, maintained metastatic dormancy following laparotomy. In-vitro, beta-adrenergic agonists (epinephrine or metaproterenol) and prostaglandin-E2 markedly increased MDA-MB-231HM secretion of the pro -metastatic factors IL-6, IL-8, and VEGF, whereas cortisol reduced their secretion, effects that were maintained even 12 h after the washout of these agonists. In-vivo, laparotomy elevated IL-6 and IL-8 levels in both plasma and ex-vivo PT spontaneous secretion, whereas perioperative propranolol + etodolac administration blocked these effects. Similar trends were evident for EGF and MIF. Promoter-based bioinformatics analyses of excised PT transcriptomes implicated elevated NF-kB activity and reduced IRF1 activity in the gene regulatory effects of laparotomy, and these effects were inhibited by pre-surgical propranolol + etodolac. Taken together, our find-ings suggest a novel mechanism of post-operative metastatic outbreak, where surgery-induced adrenergic and prostanoid signaling increase the secretion of pro-metastatic factors, including IL-6, IL-8, and VEGF, from PT and possibly residual malignant tissue, and thereby prevent residual disease from entering dormancy.

A challenging part of foreign language acquisition is learning new vocabulary. Research has demonstrated the benefits of motor action to vocabulary learning, though these findings are rarely translated into teaching and learning practices. In this work we present a novel paradigm for vocabulary learning in a virtual reality environment, capitalizing on the prominent advantages of this technology as an ‘embodied’ learning tool. Hebrew-speaking adults explored a virtual room and learned the Finnish names of 40 daily objects. Every participant learned the new object names under 3 conditions: (1) Watch-only: watching the object without performing any movement (2) performing an irrelevant movement, or (3) performing a manipulation movement that implied its habitual use. Participants completed a word-picture matching test after each training block, as well as additional word-picture matching and recall tests a week after the initial training session. The overall results demonstrate improved comprehension rates for items that were learned in the manipulation movement condition compared to the irrelevant movement condition, both in the initial learning session and one week following it. These initial findings suggest that VR technology may indeed hold the potential to offer a more authentic, multisensory and motor context to efficient foreign language learning.

The notion that stress and cancer are interlinked has dominated lay discourse for decades. More recent animal studies indicate that stress can substantially facilitate cancer progression through modulating most hallmarks of cancer, and molecular and systemic mechanisms mediating these effects have been elucidated. However, available clinical evidence for such deleterious effects is inconsistent, as epidemiological and stress-reducing clinical interventions have yielded mixed effects on cancer mortality. In this Review, we describe and discuss specific mediating mechanisms identified by preclinical research, and parallel clinical findings. We explain the discrepancy between preclinical and clinical outcomes, through pointing to experimental strengths leveraged by animal studies and through discussing methodological and conceptual obstacles that prevent clinical studies from reflecting the impacts of stress. We suggest approaches to circumvent such obstacles, based on targeting critical phases of cancer progression that are more likely to be stress-sensitive; pharmacologically limiting adrenergic–inflammatory responses triggered by medical procedures; and focusing on more vulnerable populations, employing personalized pharmacological and psychosocial approaches. Recent clinical trials support our hypothesis that psychological and/or pharmacological inhibition of excess adrenergic and/or inflammatory stress signalling, especially alongside cancer treatments, could save lives.

An amendment to this paper has been published and can be accessed via the original article.

A challenging part of foreign language acquisition is learning new vocabulary. Research has demonstrated the benefits of motor action to vocabulary learning, though these findings are rarely translated into teaching and learning practices. In this work we present a novel paradigm for vocabulary learning in a virtual reality environment, capitalizing on the prominent advantages of this technology as an ‘embodied’ learning tool. Hebrew-speaking adults explored a virtual room and learned the Finnish names of 40 daily objects. Every participant learned the new object names under 3 conditions: (1) Watch-only: watching the object without performing any movement (2) performing an irrelevant movement, or (3) performing a manipulation movement that implied its habitual use. Participants completed a word-picture matching test after each training block, as well as additional word-picture matching and recall tests a week after the initial training session. The overall results demonstrate improved comprehension rates for items that were learned in the manipulation movement condition compared to the irrelevant movement condition, both in the initial learning session and one week following it. These initial findings suggest that VR technology may indeed hold the potential to offer a more authentic, multisensory and motor context to efficient foreign language learning.