The immediate perioperative period (days before and after surgery) is hypothesized to be crucial in determining long-term cancer outcomes: during this short period, numerous factors, including excess ...stress and inflammatory responses, tumour-cell shedding and pro-angiogenic and/or growth factors, might facilitate the progression of pre-existing micrometastases and the initiation of new metastases, while simultaneously jeopardizing immune control over residual malignant cells. Thus, application of anticancer immunotherapy during this critical time frame could potentially improve patient outcomes. Nevertheless, this strategy has rarely been implemented to date. In this Perspective, we discuss apparent contraindications for the perioperative use of cancer immunotherapy, suggest safe immunotherapeutic and other anti-metastatic approaches during this important time frame and specify desired characteristics of such interventions. These characteristics include a rapid onset of immune activation, avoidance of tumour-promoting effects, no or minimal increase in surgical risk, resilience to stress-related factors and minimal induction of stress responses. Pharmacological control of excess perioperative stress-inflammatory responses has been shown to be clinically feasible and could potentially be combined with immune stimulation to overcome the direct pro-metastatic effects of surgery, prevent immune suppression and enhance immunostimulatory responses. Accordingly, we believe that certain types of immunotherapy, together with interventions to abrogate stress-inflammatory responses, should be evaluated in conjunction with surgery and, for maximal effectiveness, could be initiated before administration of adjuvant therapies. Such strategies might improve the overall success of cancer treatment.
Translational studies suggest that excess perioperative release of catecholamines and prostaglandins may facilitate metastasis and reduce disease-free survival. This trial tested the combined ...perioperative blockade of these pathways in breast cancer patients.
In a randomized placebo-controlled biomarker trial, 38 early-stage breast cancer patients received 11 days of perioperative treatment with a β-adrenergic antagonist (propranolol) and a COX-2 inhibitor (etodolac), beginning 5 days before surgery. Excised tumors and sequential blood samples were assessed for prometastatic biomarkers.
Drugs were well tolerated with adverse event rates comparable with placebo. Transcriptome profiling of the primary tumor tested
hypotheses and indicated that drug treatment significantly (i) decreased epithelial-to-mesenchymal transition, (ii) reduced activity of prometastatic/proinflammatory transcription factors (GATA-1, GATA-2, early-growth-response-3/EGR3, signal transducer and activator of transcription-3/STAT-3), and (iii) decreased tumor-infiltrating monocytes while increasing tumor-infiltrating B cells. Drug treatment also significantly abrogated presurgical increases in serum IL6 and C-reactive protein levels, abrogated perioperative declines in stimulated IL12 and IFNγ production, abrogated postoperative mobilization of CD16
"classical" monocytes, and enhanced expression of CD11a on circulating natural killer cells.
Perioperative inhibition of COX-2 and β-adrenergic signaling provides a safe and effective strategy for inhibiting multiple cellular and molecular pathways related to metastasis and disease recurrence in early-stage breast cancer.
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Highlights • Propranolol and etodolac (P + E) synergistically reduce CT26 hepatic metastasis. • P + E administration was effective in both sexes and irrespective of surgical extent. • NK cells are ...significant in controlling CT26 hepatic metastasis. • NK cells are involved in the beneficial effects of P + E. • P + E can be used preoperatively in cancers patients without contraindications.
Abstract Most in vitro and ex-vivo studies indicate a profound suppression of NK cell cytotoxicity (NKCC) by glucocorticoids; while catecholamines and prostaglandins were reported both to suppress ...and to enhance NKCC. However, methodological considerations hinder our ability to deduce from these findings to the impact of endogenous release of these factors on in vivo levels of NKCC and their implications to NK-dependent resistance to pathologies in living humans or animals. Here we used an in vivo approach that sensitively and specifically reflects NKCC in living F344 rats, based on lung clearance of NK-sensitive tumor cells (MADB106), and based on comparing effects between NK-intact and NK-depleted rats. To study the role of corticosterone, epinephrine, and prostaglandins, we administered these factors to rats, or antagonized their endogenous release following different stress paradigms or surgery. The results indicated that endogenous or exogenous elevated corticosterone levels can suppress in vivo NKCC levels, but only under some conditions, and mostly secondarily to the NK-suppressing impact of epinephrine. Specifically, corticosterone-induced NKCC suppression occurred (i) only under prolonged, but not short exposure to stress, and mainly in males; (ii) was smaller than the prominent impact of epinephrine; (iii) was mostly ascribed to corticosterone-induced potentiation of the effects of epinephrine or/and prostaglandins; and (iv) was completely abolished through antagonizing epinephrine or/and prostaglandins. Overall, these findings markedly limit the significance of stress/surgery-induced corticosterone release in the in vivo suppression of NKCC, and highlight the blockade of epinephrine or/and prostaglandins as effective and clinically feasible approaches to overcome such immuno-suppressive effects.
COVID-19 has continued to spread in the United States and globally. Closely monitoring public engagement and perceptions of COVID-19 and preventive measures using social media data could provide ...important information for understanding the progress of current interventions and planning future programs.
The aim of this study is to measure the public's behaviors and perceptions regarding COVID-19 and its effects on daily life during 5 months of the pandemic.
Natural language processing (NLP) algorithms were used to identify COVID-19-related and unrelated topics in over 300 million online data sources from June 15 to November 15, 2020. Posts in the sample were geotagged by NetBase, a third-party data provider, and sensitivity and positive predictive value were both calculated to validate the classification of posts. Each post may have included discussion of multiple topics. The prevalence of discussion regarding these topics was measured over this time period and compared to daily case rates in the United States.
The final sample size included 9,065,733 posts, 70% of which were sourced from the United States. In October and November, discussion including mentions of COVID-19 and related health behaviors did not increase as it had from June to September, despite an increase in COVID-19 daily cases in the United States beginning in October. Additionally, discussion was more focused on daily life topics (n=6,210,255, 69%), compared with COVID-19 in general (n=3,390,139, 37%) and COVID-19 public health measures (n=1,836,200, 20%).
There was a decline in COVID-19-related social media discussion sourced mainly from the United States, even as COVID-19 cases in the United States increased to the highest rate since the beginning of the pandemic. Targeted public health messaging may be needed to ensure engagement in public health prevention measures as global vaccination efforts continue.
Purpose
Extensive oncological surgeries were previously suggested to increase cancer recurrence rates. We herein studied the impact of different surgical procedures and sex on colorectal cancer liver ...metastasis, employing several tumor inoculation approaches in BALB/c mice.
Methods
Experimental hepatic metastases of the syngeneic CT26 colorectal cancer line were induced either by intra-portal inoculation or intra-splenic inoculation, employing different tumor loads. Following intra-splenic inoculation, the entire spleen or an injected hemi-spleen was removed. Additionally, the magnitude of the surgical trauma accompanying the injection procedure was manipulated.
Results
Increasing the surgical trauma by adding laparotomy or extending the length of the surgery and hypothermia did not significantly affect the number of liver metastases or liver weight for any of the injection methods and tumor loads. The development of metastasis was significantly greater in males than in females under all conditions studied—a difference not explained by the direct effects of sex hormones on in vitro CT26 proliferation or vitality.
Conclusion
Concurring with less controlled clinical observations, the surgical extensiveness did not significantly affect CT26 hepatic metastasis, potentially due to a ceiling effect of the surgical trauma on the metastatic process. The sexual dimorphism observed for the CT26 metastasis should be investigated in the context of surgical stress and considering anti-CT26 immunoreactivity.
Harnessing health-related data posted on social media in real time can offer insights into how the pandemic impacts the mental health and general well-being of individuals and populations over time.
...This study aimed to obtain information on symptoms and medical conditions self-reported by non-Twitter social media users during the COVID-19 pandemic, to determine how discussion of these symptoms and medical conditions changed over time, and to identify correlations between frequency of the top 5 commonly mentioned symptoms post and daily COVID-19 statistics (new cases, new deaths, new active cases, and new recovered cases) in the United States.
We used natural language processing (NLP) algorithms to identify symptom- and medical condition-related topics being discussed on social media between June 14 and December 13, 2020. The sample posts were geotagged by NetBase, a third-party data provider. We calculated the positive predictive value and sensitivity to validate the classification of posts. We also assessed the frequency of health-related discussions on social media over time during the study period, and used Pearson correlation coefficients to identify statistically significant correlations between the frequency of the 5 most commonly mentioned symptoms and fluctuation of daily US COVID-19 statistics.
Within a total of 9,807,813 posts (nearly 70% were sourced from the United States), we identified a discussion of 120 symptom-related topics and 1542 medical condition-related topics. Our classification of the health-related posts had a positive predictive value of over 80% and an average classification rate of 92% sensitivity. The 5 most commonly mentioned symptoms on social media during the study period were anxiety (in 201,303 posts or 12.2% of the total posts mentioning symptoms), generalized pain (189,673, 11.5%), weight loss (95,793, 5.8%), fatigue (91,252, 5.5%), and coughing (86,235, 5.2%). The 5 most discussed medical conditions were COVID-19 (in 5,420,276 posts or 66.4% of the total posts mentioning medical conditions), unspecified infectious disease (469,356, 5.8%), influenza (270,166, 3.3%), unspecified disorders of the central nervous system (253,407, 3.1%), and depression (151,752, 1.9%). Changes in posts in the frequency of anxiety, generalized pain, and weight loss were significant but negatively correlated with daily new COVID-19 cases in the United States (r=-0.49, r=-0.46, and r=-0.39, respectively; P<.05). Posts on the frequency of anxiety, generalized pain, weight loss, fatigue, and the changes in fatigue positively and significantly correlated with daily changes in both new deaths and new active cases in the United States (r ranged=0.39-0.48; P<.05).
COVID-19 and symptoms of anxiety were the 2 most commonly discussed health-related topics on social media from June 14 to December 13, 2020. Real-time monitoring of social media posts on symptoms and medical conditions may help assess the population's mental health status and enhance public health surveillance for infectious disease.
•Perioperative interventions to improve long-term cancer outcomes are rarely used.•Pre-operative psychological stress exacerbates the deleterious effects of surgery.•Pre-operative psychological ...stress jeopardizes the efficacy of immune stimulation.•Immune-stimulation combined with blockade of stress & surgery’s effects is optimal.
The perioperative period holds disproportionate impact on long-term cancer outcomes. Nevertheless, perioperative interventions to improve long-term cancer outcomes are not clinical routines, including perioperative stress-reducing or immune-stimulating approaches. Here, mimicking the clinical setting of pre-operative distress, followed by surgery, we examined the separate and combined effects of these events on the efficacy of pre-operative immune stimulation in rats and mice, and on post-operative resistance to tumor metastasis of the syngeneic mammary adenocarcinoma MADB106 in F344 rats and the CT26 colon carcinoma in Balb/C mice. The novel immune stimulating agents, GLA-SE or CpG-C (TLR-4 and TLR-9 agonists, respectively), were employed pre-operatively. Sixteen hours of pre-operative behavioral stressors (i) lowered CpG-C induced plasma IL-12 levels, and reduced resistance to MADB106 and CT-26 experimental metastases, and (ii) worsened the deleterious effects of laparotomy on metastasis in both tumor models. In rats, these effects of pre-operative stress were further studied and successfully abolished by the glucocorticoid receptor antagonist RU-486. Additionally, in vitro studies indicated the dampening effect of corticosterone on immune stimulation. Last, we tested a perioperative integrated intervention in the context of pre-operative stress and laparotomy, based on (i) antagonizing the impact of glucocorticoids before surgery, (ii) activating anti-metastatic immunity perioperatively, and (iii) blocking excessive operative and post-operative adrenergic and prostanoid responses. This integrated intervention successfully and completely abolished the deleterious effects of stress and of surgery on post-operative resistance to experimental metastasis. Such and similar integrated approaches can be studied clinically in cancer patients.
Following excision of colorectal tumors, metastatic disease is prevalent, primarily occurs in the liver, and is highly predictive of poor prognosis. The perioperative period is now recognized as ...critical in determining the incidence of postoperative metastases and long-term cancer outcomes. Thus, various perioperative prophylactic interventions are currently studied during this time frame. However, immune stimulation during the perioperative period has rarely been attempted due to specific contraindications to surgery and various adverse effects. Here, to prevent liver metastases, we perioperatively employed a TLR-9 agonist, CpG-C, which exhibits minimal pyrogenic and other adverse effects in patients. We found that marginating-hepatic (MH) cells in BALB/c mice contained high percentage of NK cells, but exhibited negligible NK cytotoxicity, as previously reported in humans. However, a single CpG-C administration (25-100 µg/mouse) doubled MH-NK cell numbers, increased NK cell activation and maturation markers (NKp46, CD11b), decreased the inhibitory NKG2A ligand, and dramatically increased MH-NK-cell cytotoxicity against the syngeneic CT26 colon cancer line. Moreover, in operated mice, this innocuous intervention also markedly improved resistance to CT26 and MC38 hepatic metastases in BALB/c and C57BL/6 mice, respectively. Beneficial effects of CpG-C were mediated through activation of MH-NK cells, as indicated by an in vivo NK depletion study. Last, CpG-C protected against surgery-induced suppression of MH-NK cytotoxicity and improved their activation indices. Thus, we suggest that systemic perioperative CpG-C treatment should be considered and studied as a novel therapeutic approach to improve long-term cancer outcomes in colorectal cancer patients.
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