Is pre-operative heart rate variability a prognostic indicator for overall survival and cancer recurrence in patients with primary colorectal cancer?

BACKGROUND: Heart Rate Variability (HRV) represents efferent vagus nerve activity which is suggested to be inversely related to fundamental mechanisms of tumorigenesis and to be a predictor of prognosis in various types of cancer. HRV is also believed to predict the occurrence and severity of post-operative complications. We aimed to determine the role of pre-operative HRV as a prognostic factor in overall and cancer free survival in patients with colorectal cancer. METHODS: Retrospective analysis was performed in a detailed dataset of patients diagnosed with primary colorectal cancer between January 2010 and December 2016, who underwent curative surgical treatment. HRV was measured as time-domain parameters (SDNN (Standard Deviation of NN-intervals) and RMSSD (Root Mean Square of Successive Differences)) based on pre-operative 10 second ECGs. Groups were created by baseline HRV: Low HRV (SDNN <20ms or RMSSD <19ms) and normal HRV (SDNN ≥20ms or RMSSD ≥19ms). Primary endpoints were overall and cancer free survival. RESULTS: A total of 428 patients were included in this study. HRV was not significantly associated with overall survival (SDNN <20ms vs SDNN ≥20ms:24.4% vs 22.8%, adjusted HR = 0.952 (0.607-1.493), p = 0.829; RMSSD <19ms vs RMSSD ≥19ms:27.0% vs 19.5%, adjusted HR = 1.321 (0.802-2.178), p = 0.274) or cancer recurrence (SDNN <20ms vs ≥20ms:20.1% vs 18.7%, adjusted HR = 0.976 (0.599-1.592), p = 0.924; RMSSD <19ms vs ≥19ms, 21.5% vs 16.9%, adjusted HR = 1.192 (0.706-2.011), p = 0.511). There was no significant association between HRV and CEA-level at one year follow-up, or between HRV and occurrence of a post-operative complication or the severity of post-operative complications. CONCLUSIONS: Heart rate variability was not associated with overall or cancer free survival in patients with primary colorectal cancer who underwent curative surgical treatment. These results do not align with results found in studies including only patients with advanced cancer, which suggests that there is only an association in the other direction, cancer causing low HRV.

The Relationship between a New Biomarker of Vagal Neuroimmunomodulation and Survival in Two Fatal Cancers.

BACKGROUND: The vagus nerve may slow tumor progression because it inhibits inflammation. This study examined the relationship between a new vagal neuroimmunomodulation (NIM) index and survival in fatal cancers. METHOD: We retroactively derived markers of vagal nerve activity indexed by heart rate variability (HRV), specifically the root mean square of successive differences (RMSSD), from patients' electrocardiograms near diagnosis. The NIM index was the ratio of RMSSD to C-reactive protein levels (RMSSD/CRP). Sample 1 included 202 Belgian patients with advanced pancreatic cancer (PC), while sample 2 included 71 Belgian patients with non-small cell lung cancer (NSCLC). In both samples, we examined the overall survival, while in sample 2, we additionally examined the survival time in deceased patients. RESULTS: In PC patients, in a multivariate Cox regression controlling for confounders, the NIM index had a protective relative risk (RR) of 0.68 and 95% confidence interval (95% CI) of 0.51-0.92. In NSCLC patients, the NIM index also had a protective RR of 0.53 and 95% CI of 0.32-0.88. Finally, in NSCLC, patients with a higher NIM index survived more days (475.2) than those with lower NIM (285.1) (p < 0.05). CONCLUSIONS: The NIM index, reflecting vagal modulation of inflammation, may be a new independent prognostic biomarker in fatal cancers.

Effects of short and prolonged transcutaneous vagus nerve stimulation on heart rate variability in healthy subjects.

The vagus nerve is strategically located in the body, and has multiple homeostatic and health-promoting effects. Low vagal activity predicts onset and progression of diseases. These are the reasons to activate this nerve. This study examined the effects of transcutaneous vagus nerve stimulation (t-VNS) on a main index of vagal activity, namely heart rate variability (HRV). In Study 1, we compared short (10min) left versus right ear t-VNS versus sham (no stimulation) in a within-subjects experimental design. Results revealed significant increases in only one HRV parameter (standard deviation of the RR intervals (SDNN)) following right-ear t-VNS. Study 2 examined the prolonged effects of t-VNS (1h) in the right ear. Compared to baseline, right-t-VNS significantly increased the LF and LF/HF components of HRV, and SDNN in women, but not in men. These results show limited effects of t-VNS on HRV, and are discussed in light of neuroanatomical and statistical considerations and future directions are proposed.

If you have an active vagus nerve, cancer stage may no longer be important.

The parasympathetic system, and primarily the vagus nerve, informs the brain about multiple signals and returns the body to homeostasis. Recent studies have shown that vagal nerve activity independently predicts prognosis in cancer. Here, we take this one step further and show that when vagal nerve activity is high, cancer stage no longer predicts tumor burden. We examined whether vagal nerve activity, indexed by Heart Rate Variability (HRV), moderated the effects of initial tumor stage on tumor burden at followup. Patients' HRVs were derived from ECGs near diagnosis in colorectal cancer (CRC) and in prostate cancer (PC) patients. Outcomes included the tumor markers carcinoembryonic antigen (CEA) at 12 months for CRC and prostate-specific antigen (PSA) at 6 months for PC. As would be expected, initially advanced tumor stages of CRC or PC predicted higher tumor marker levels at follow-up than did early stages. However, this occurred only in patients with low, not high, vagal activity (HRV). Furthermore, in patients with advanced tumor stage at diagnosis, high HRV predicted lower tumor marker levels than did low HRV, in both cancers. Estimating a cancer patient's prognosis by determining his tumor stage needs to also consider the vagal nerve activity. This activity is easily measurable, and it determines in which subjects the tumor stage is prognostic. Importantly, higher vagal activity may even protect against the adverse effects of advanced cancer stage. These findings, observed in two distinct cancers, support the hypothesized neuroimmunomodulatory effects of vagal nerve activity on tumors.

Differential expression of placental glucocorticoid receptors and growth arrest-specific transcript 5 in term and preterm pregnancies: evidence for involvement of maternal stress.

Pregnancy-specific stress predicts birth outcomes. We hypothesized that there is a maternal stress-GR interaction that can influence fetal birth weight. This study examined the relationship between mothers' stress and attitude towards their pregnancies, placental glucocorticoid receptors (GRs) and growth arrest-specific transcript 5 (GAS5) expression, and the status of GR polymorphism, with their infants' birth weights. GAS5 and GR α were the predominant transcripts in both term and preterm placentas, with GAS5 being primarily localized in the syncytiotrophoblasts. In an attempt to mimic moderate and high stress environment in vitro, BeWo and JEG-3 cytotrophoblast cell lines were treated with 10 nM-1000 nM cortisol. Only expression of GAS5 was significantly upregulated by cortisol in all treatments compared with basal levels, but none of the GRs changed expression significantly. In an attempt to assess a stress versus gene interaction, we studied four GR polymorphisms. In the homozygous group for Tth111I polymorphism, mothers with negative attitudes towards the pregnancy gave birth to infants with significantly lower birth weights compared to women with positive/neutral attitudes. None of the GR splice variants were associated with maternal stress. However, placental GAS5 levels were inversely correlated with maternal stress. This study points towards a potential gene-environment interaction that could be of predictive value for fetal weight.

Norms of vagal nerve activity, indexed by Heart Rate Variability, in cancer patients.

Recent research has begun to show the role of the activity of the vagus nerve in cancer prognosis. However, it remains unknown whether cancer severity can impair vagal nerve activity. This study combined data (N=657) of five different cancers (colorectal, pancreas, prostate, lung and ovarian) concerning patients' Heart Rate Variability (HRV), a vagal nerve activity index. These data were compared to HRV levels of a healthy sample in another study. In addition, we examined the moderating effects of age, gender and cancer stage on HRV. The mean HRV of the cancer patients sample was significantly lower (HRV=22 ms) compared to the healthy sample (HRV=50 ms) (p<0.000001). While age and gender did not significantly affect HRV, cancer patients with advanced stages had significantly lower HRV than those with early stages (p=0.011). A possible bi-directional relation between cancer and vagal nerve activity is discussed. These findings are of importance for prognostication since they provide researchers and clinicians with expected values of vagal nerve activity in cancer patients.

Immune system function, stress, exercise and nutrition profile can affect pregnancy outcome: Lessons from a Mediterranean cohort.

Pregnancy is associated with major physiological and future psychosocial changes, and maternal adaptation to these changes is crucial for normal foetal development. Psychological stress in pregnancy predicts an earlier birth and lower birth weight. Pregnancy-specific stress contributes directly to preterm delivery. The importance of nutrition and exercise during pregnancy with regard to pregnancy outcome has long been acknowledged. This importance has only been further emphasized by the recent changes in food quality and availability, lifestyle changes and a new understanding of foetal programming's effects on adult outcomes. We hypothesised that for a successful pregnancy certain events at a nutritional, immune, psycho-emotional and genetic level should be tightly linked. Therefore, in this study we followed an 'integrative' approach to investigate how maternal stress, nutrition, pregnancy planning and exercise influence pregnancy outcome. A key finding of our study is that there was a significant reduction in the intake of alcohol, caffeine-containing and sugary drinks during pregnancy. However, passive smoking in the household remained unchanged. In terms of immune profile, a significant inverse correlation was noted between difficulty to 'fight' an infection and number of colds (r=-0.289, P=0.003) as well as the number of infections (r=-0.446, P<0.0001) during pregnancy. The vast majority of the pregnant women acquired a more sedentary lifestyle in the third trimester. In planned, but not in unplanned, pregnancies stress predicted infant weight, independent of age and body mass index (BMI). Notably, in mothers with negative attitudes towards the pregnancy, those with an unplanned pregnancy gave birth to infants with significantly higher weights than those with planned pregnancies. Collectively these data suggest that there is a higher order of complexity, possibly involving gene-environment interactions that work together to ensure a positive outcome for the mother as well as the foetus.

The Effects of Psychological Inoculation on Cognitive Barriers Against Condom Use in Women with HIV: A Controlled Pilot Study

Past studies have shown that in attempts to prevent HIV; health education yields little change in condom use. The reason may be that education fails to target barriers for changing behaviour. The present controlled pilot study tested whether psychological inoculation (PI) reduces such barriers for using male condoms. Twenty-two Nigerian women with HIV were randomly assigned to receive PI or health education (control). In the PI condition; women learned to refute sentences reflecting barriers against condom use; while controls learned how to use condoms and the consequences of their non-use. Barriers for condom use; self-efficacy to negotiate condom use with partners and actual condom use were self-reported before and one week after interventions. Results revealed that only in the PI group were there statistically significant increases in condom use negotiating self-efficacy and reductions in barriers concerning motivation; sexual satisfaction and partners. Controls reported no statistically significant changes. However; actual reported condom use was unchanged in both groups. Thus; it is feasible to conduct PI interventions in an African sample of HIV patients. Furthermore; PI can reduce cognitive barriers for condom use; while health education yields little changes in such outcomes over time. If replicated in larger samples with longer follow-ups; these findings could eventually have implications for HIV prevention in several world regions

Hippocampal microinfusion of oxytocin attenuates the behavioural response to stress by means of dynamic interplay with the glucocorticoid-catecholamine responses.

The neurohypophysial hormone oxytocin acts as a central nervous system neurotransmitter/neuromodulator. We evaluated the effects of oxytocin on behavioural responses to stress, as well as associated biophysiological responses, in a controlled, prospective animal model. The long-term effects of exogenous oxytocin microinjected to the hippocampus of male rats were assessed. Animals were exposed to predator scent stress and treated 1 h or 7 days later with oxytocin or vehicle. Behaviours were assessed with the elevated plus-maze and acoustic startle response tests, 7 days after microinjection and freezing behaviour upon exposure to a trauma-related cue on day 8. These data served for classification into behavioural response groups. Trauma cue response, circulating corticosterone and oxytocin, hippocampal expression of glucocorticoid and mineralocorticoid receptors, and oxytocin receptor mRNA levels were assessed. The interplay between oxytocin, corticosterone and norepinephrine was assessed. Microinfusion of oxytocin both immediately after predator scent stress exposure or 7 days later, after exposure to trauma cue significantly reduced the prevalence rates of extreme responders and reduced trauma cue freezing responses. Post-exposure treatment with oxytocin significantly corrected the corticosterone stress response, decreased glucocorticoid receptor expression and increased mineralocorticoid receptor expression in the hippocampus compared to vehicle treatment. High-dose corticosterone administration together with norepinephrine caused release of plasma oxytocin and hippocampal oxytocin receptor. Oxytocin is actively involved in the neurobiological response to predator scent stress processes and thus warrants further study as a potential therapeutic avenue for the treatment of anxiety-related disorders.

Psychological interactions with infertility among women.

Despite the fact that various studies have demonstrated the importance of the mind-body connection and fertility, the psychosocial aspects of infertility have not been adequately addressed. Fertility treatments, ranging from medical monitoring, to hormonal remedies and in vitro fertilization (IVF), are both a physical and emotional burden on women and their partners. Psychological factors such as depression, state-anxiety, and stress-induced changes in heart rate and cortisol are predictive of a decreased probability of achieving a viable pregnancy. A couple that is trying to conceive will undoubtedly experience feelings of frustration and disappointment if a pregnancy is not easily achieved. However, if the difficulties progress and the man and or woman are labelled as having fertility problems, then this may result in a severe insult to self-esteem, body image, and self-assessed masculinity or femininity. Three types of relationships have been hypothesized between psychological factors and infertility. These include: (1) psychological factors are risk factors of subsequent infertility; (2) the experience of the diagnosis and treatment of infertility causes subsequent psychological distress; (3) a reciprocal relationship exists between psychological factors and infertility. The evidence for these three relationships is reviewed and an alternative approach to the treatment of infertility including stress evaluation that precedes or is concurrent to fertility treatment is suggested.

High incidence of severe twin hemodialysis catheter infections in elderly women. Possible roles of insufficient nutrition and social support.

BACKGROUND: Cuffed-tunneled hemodialysis (HD) catheters are recommended as a bridging therapy until peripheral access is available, but their long-term use is controversial. AIM: To evaluate the complications and lifetime of twin-tunneled HD catheters and to identify parameters which could predict their outcome. METHODS: 29 chronic HD patients (19 female and 10 male) were inserted with twin hemodialysis catheters (28 Tesio, 1 Schon Duoflow), followed for up to 9 months or until catheter loss, and evaluated for severe catheter-related complications necessitating catheter removal. Since the most common severe complication was catheter-related infection, we retrospectively examined whether parameters such as age, gender, duration of end-stage renal disease, delivered dose of dialysis, nutrition, diabetes and indices of social support correlate with this outcome. RESULTS: Severe catheter infection requiring catheter removal occurred in 11 patients (10 female). Of these infected female patients, 9 were elderly (> or =67 years) and in 6 of those, catheter infection was fatal (54% of infected cases). At 9 months, severe catheter infection and related patient death rates were 38 and 21%, respectively. Severe catheter infection was significantly related to less social support (p < 0.005), older age, female gender, lower nPCR (all p < 0.05), and tended to be related to shorter end-stage renal disease duration prior to catheter insertion (p = 0.06). CONCLUSION: This study demonstrated that twin HD catheters are associated with a high incidence of severe catheter-related infections which was most significantly related to social-support as well as inadequate nutrition, older age and female gender. Therefore, we suggest early removal of the catheter, enhancement of social support and dietary counseling for the elderly and lonely HD patients using this type of catheter.

Development and cross-cultural and clinical validation of a brief comprehensive scale for assessing hostility in medical settings.

This study presents the development and validation of a brief comprehensive hostility scale. Two items of each subscale from the Buss-Perry (1992) Aggression Questionnaire, most strongly correlated with their subscale score, were selected, yielding the eight-item New-Buss. Internal reliability was .66 to .81, and full and brief scales correlated r = .92 to .94. In Study 1 (95 Israeli students), New-Buss scores were significantly higher in self-rated deviant or speeding drivers than nondeviant or nonspeeding drivers, respectively. In Study 2 (279 American students), New-Buss scores correlated significantly with Barefoot's Ho, Anger-Out, Anger-In, and Agreeableness. In Study 3 (79 Israeli patients undergoing angiography), New-Buss scores were significantly correlated with coronary artery disease severity independent of SBP in men below age 60 alone but not in women. Our findings support the cross-cultural feasibility, reliability, and concurrent, construct, and criterion validity of the New-Buss.

Translating research findings to PTSD prevention: results of a randomized-controlled pilot study.

Based on therapeutic studies revealing positive prognostic factors and on research findings revealing how trauma is processed, we developed the memory structuring intervention (MSI) in attempt to prevent posttraumatic stress disorder (PTSD). The MSI attempts to shift processing of traumatic memory from uncontrollable somatosensory and affective processes to more controlled linguistic and cognitive processes by providing patients organization, labeling, and causality. In a single-blind randomized-controlled pilot study, 17 traffic accident victims at risk for PTSD (heart rate >94 BPM) were assigned to two MSI or two supportive-listening control sessions. Three months later, MSI patients reported significantly less frequent intrusive, arousal, and total PTSD symptoms than controls. A replication study with a larger sample is underway.

The short-term effects of a hostility-reduction intervention on male coronary heart disease patients.

This preliminary study examined the effects of a hostility-reduction intervention on patients with coronary heart disease (CHD). Twenty-two high-hostile CHD men were matched on age and hostility and then randomly assigned to a hostility intervention (N = 10) or an information-control group (N = 12). Patients were reassessed immediately and 2 months posttreatment on hostility (with self-report and structured interview) and resting blood pressure. The intervention's overall effect size was moderately strong (d' = .62). Intervention patients reported at both reassessments and were observed at follow-up to be less hostile than controls. At follow-up, intervention patients had significantly lower diastolic blood pressure (DBP) than controls. Finally, reductions in hostility were significantly and positively correlated with reductions in DBP. Replication with a larger sample and CHD outcomes is recommended.

Bus commuters' coping strategies and anxiety from terrorism: an example of the Israeli experience.

This study examined the use of three coping strategies: (1) emotion-focused coping (calming-distraction); (2) problem-focused coping (checking-behavior); and (3) denial (reduced perceived vulnerability), and their relationship to anxiety from terrorism among 50 Israeli bus commuters. Their mean age was 31 years (60% females). Commuting frequency was negatively correlated, and problem-focused coping was positively correlated with anxiety from terrorism. Ratios of problem-focused coping/denial and of problem-focused/emotion-focused coping were each positively correlated with anxiety from terrorism. Coping ratios accounted for 15% of the variance in anxiety from terrorism, after considering commuting frequency. Combining minimal problem-focused preventative acts with distraction and reduced perceived vulnerability may be beneficial.

Increasing constructive anger verbal behavior decreases resting blood pressure: a secondary analysis of a randomized controlled hostility intervention.

We hypothesized that increasing anger verbal behavior in an assertive, constructively motivated style should decrease resting blood pressure (BP) and that this behavior may be one mechanism through which hostility relates to BP. We tested this hypothesis by conducting secondary analyses on a single-blind, matched, randomized controlled study of hostility modification and BP. A total of 22 high-hostile male patients with coronary heart disease were matched on age and hostility level and were randomly assigned to either an 8-week cognitive-behavioral hostility treatment (n = 10) or an information-control group (n = 12). Patients were reassessed after treatment and at 2-month follow-up on hostility, observed anger expression, and resting BP. We found that decreases in hostility predicted increases in constructive anger behavior-verbal component, which in turn predicted decreases in resting BP at follow-up. Thus, one of the mechanisms underlying the hostility-BP association may be the lack of constructive anger expression.

Development and preliminary testing of a brief intervention for modifying CHD-predictive hostility components.

Hostility is an independent risk factor for coronary heart disease (CHD), and certain hostility subscales (e.g., Barefoot's refined Ho) predict CHD and mortality more powerfully than global hostility measures. An intervention for modifying CHD-predictive hostility components was developed and tested. Twenty-two healthy, high-hostile males, who were matched on age and hostility level, were randomly assigned to either an experimental hostility-reduction treatment group or an information-control group. The experimental group received eight 90-min weekly sessions for altering antagonism, cynicism, and anger reactions. After controlling for pretreatment levels, subjects' group status accounted for an additional and significant 28 and 19% of the variance in improvement of observed Anger-Out scores and Barefoot's refined Ho scores, respectively. Thus, this treatment may reduce CHD-predictive and mortality-predictive hostility levels. The possible clinical significance of these results was tested, and future large-scale and long-term trials are recommended.

The physical and psychosocial predictors of adolescents' recovery from oral surgery.

The purpose of this study was to expand medical models of recovery from surgery in adolescents. Sixty-seven adolescents undergoing third molar surgery and their parents participated. Adolescents' negative affectivity, expectancies about recovery, coping styles, and parents' anticipated encouragement of illness behavior were assessed preoperatively. Extent of surgery was assessed by the oral surgeon. Outcome measures included mouth opening, disability, and pain. Extent of surgery did not predict recovery. After controlling for extent of surgery, the psychosocial parameters accounted for an additional 19% of the variance in mouth opening and 21% of the variance in disability. Adolescents' expectancies about recovery and parents' anticipated "pampering" responses predicted mouth opening. Adolescents' expectancies predicted disability. Expectancies about recovery and parental encouragement of illness behavior add predictive power to models of adolescents' recovery from surgery. Limitations of the study, future research directions, and clinical implications are discussed.