Perioperative biobehavioral interventions to prevent cancer recurrence through combined inhibition of β-adrenergic and cyclooxygenase 2 signaling

Evidence suggests that excess perioperative activation of the sympathetic nervous system and the consequent release of catecholamines (ie, epinephrine and norepinephrine) in the context of cancer surgery and inflammation may significantly facilitate prometastatic processes. This review first presents biomedical processes that make the perioperative timeframe pivotal in determining long-term cancer outcomes nonproportionally to its short duration (days to weeks). Then, it analyzes the various mechanisms via which the excess release of catecholamines can facilitate the progression of cancer metastases in this context by directly affecting the malignant tissues and by regulating, via indirect pathways, immunological and other mechanisms that affect metastatic progression in the tumor microenvironment and systemically. In addition, this review addresses the need to supplement β-adrenoreceptor blockade with cyclooxygenase 2 inhibition, especially during surgery and shortly thereafter, because similar mechanisms are simultaneously activated by surgery-induced inflammatory responses. Importantly, this review presents translational and clinical evidence showing that perioperative β-adrenoreceptor blockade and cyclooxygenase 2 inhibition can reduce the prometastatic process and cancer recurrence, and the clinical feasibility and safety of this approach are demonstrated as well. Lastly, alternative psychophysiological approaches to the use of β-adrenergic blockers are presented because a substantial portion of patients have medical contraindications to this pharmacological treatment. The adaptation of existing psychophysiological interventions to the perioperative period and principles for constructing new approaches are discussed and exemplified. Overall, pharmacobehavioral interventions, separately or in combination, could transform the perioperative timeframe from being a prominent facilitator of metastatic progression to an opportunity for arresting or eliminating residual disease, potentially improving long-term survival rates in cancer patients.     

Considerations for Hartmann’s reversal and Hartmann’s reversal outcomes—a multicenter study

Purpose

Hartmann’s procedure is commonly practiced in emergent cases with the restoration of bowel continuity planned at a second stage. This study assessed the rate of restorations following Hartmann’s procedure and evaluated factors affecting decision-making.

Methods

Data on patient demographics, comorbidities, causes for Hartmann’s procedure, reversal rate, and complications were collected in a multicenter retrospective cohort study of patients who underwent Hartmann’s procedure in five medical centers.

Results

Six hundred forty patients underwent Hartmann’s procedure for diverticular disease (36.1%), obstructing malignancy (31.8%), benign obstruction (5%), and other reasons (23.1%). Overall, 260 (40.6%) patients underwent subsequent restoration of bowel continuity. One hundred twenty-one (46.5%) patients had post-reversal complications, with an average Clavien-Dindo score of 1.4 and a mortality rate of 0.77%. Decision to avoid reversal was mostly related to comorbidities (49.7%) and metastatic disease (21.6%). Factors associated with the decision to restore bowel continuity included male gender (P = 0.02), patient age (62.3 years in Hartmann’s reversal patients vs 73.5 years in non-reversal patients; P < 0.0001), number of comorbidities (1.1 vs 1.58; P < 0.001), average Charlson score (1.93 vs 3.44; P < 0.001), and a neoplastic etiology (P < 0.0001). A sub-analysis excluding all patients who died in the 30 days following Hartmann’s procedure showed similar factors associated with ostomy closure.

Conclusion

Many patients do not have restoration of bowel continuity after undergoing Hartmann’s procedure. Hartmann’s reversal is associated with a significant postoperative morbidity. Surgeons and patients should be aware of the possibility that the colostomy might become permanent.

     

Nitric oxide signals that aplysia have attempted to eat, a necessary component of memory formation after learning that food is inedible

Inhibiting nitric oxide (NO) synthesis during learning that food is inedible in Aplysia blocks subsequent memory formation. To gain insight into the function of NO transmission during learning we tested whether blocking NO synthesis affects aspects of feeding that are expressed both in a nonlearning context and during learning. Inhibiting NO synthesis with L-NAME and blocking guanylyl cyclase with methylene blue decreased the efficacy of ad libitum feeding. D-NAME had no effect. L-NAME also decreased rejection responses frequency, but did not affect rejection amplitude. The effect of L-NAME was explained by a decreased signaling that efforts to swallow are not successful, leading to a decreased rejection rate, and a decreased ability to reposition and subsequently consume food in ad libitum feeding. Signaling that animals have made an effort to swallow is a critical component of learning that food is inedible. Stimulation of the lips with food alone did not produce memory, but stimulation combined with the NO donor SNAP did produce memory. Exogenous NO at a concentration causing memory also excited a key neuron responding to NO, the MCC. Block of the cGMP second-messenger cascade during training by methylene blue also blocked memory formation after learning. Our data indicate that memory arises from the contingency of three events during learning that food is inedible. One of the events is efforts to swallow, which are signaled by NO by cGMP.     

p53 Regulates insulin-like growth factor-I receptor gene expression in uterine serous carcinoma and predicts responsiveness to an insulin-like growth factor-I receptor-directed targeted therapy

The role of the insulin-like growth factors (IGF) in endometrial cancer has been well established. The IGF-I receptor (IGF-IR), which mediates the biological actions of IGF-I, is usually overexpressed in endometrial tumours. Uterine serous carcinoma (USC) constitutes a defined histological category among endometrial cancers. Mutation of the p53 gene appears early in the course of the disease and is considered a key event in the initiation of USC. The aim of the present study was to evaluate the potential interactions between p53 and the IGF-IR in USC. In addition, we investigated the role of p53 as a biomarker in IGF-IR targeted therapies. Immunohistochemical analysis in a collection of 35 USC specimens revealed that IGF-IR is highly expressed in primary and metastatic USC. Likewise, p53 was expressed in 85.7% of primary tumours and 100% of metastases. A significant negative correlation between p53 expression and survival was noticed. In addition, using USC-derived cell lines we provide evidence that p53 regulates IGF-IR gene expression via a mechanism that involves repression of the IGF-IR promoter. We show that the mechanism of action of p53 involves interaction with zinc finger protein Sp1, a potent transactivator of the IGF-IR gene. Finally, we demonstrate that USC tumours overexpressing p53 are more likely to benefit from anti-IGF-IR therapies. In summary, we provide evidence that p53 regulates IGF-IR gene expression in USC cells via a mechanism that involves repression of the IGF-IR promoter. The interplay between the p53 and IGF-I signalling pathways is of major basic and translational relevance.     

A new approach to reducing postsurgical cancer recurrence: perioperative targeting of catecholamines and prostaglandins

Surgery is a crucial intervention in most cancer patients, but the perioperative period is characterized by increased risks for future outbreak of preexisting micrometastases and the initiation of new metastases-the major cause of cancer-related death. Here we argue that the short perioperative period is disproportionately critical in determining long-term recurrence rates, discuss the various underlying risk factors that act synergistically during this period, and assert that this time frame presents an unexplored opportunity to reduce long-term cancer recurrence. We then address physiologic mechanisms that underlie these risk factors, focusing on excess perioperative release of catecholamines and prostaglandins, which were recently shown to be prominent in facilitating cancer recurrence through their direct impact on the malignant tissue and its microenvironment, and through suppressing antimetastatic immunity. The involvement of the immune system is further discussed in light of accumulating evidence in cancer patients, and given the recent identification of endogenously activated unique leukocyte populations which, if not suppressed, can destroy autologous "immune-resistant" tumor cells. We then review animal studies and human correlative findings, suggesting the efficacy of blocking catecholamines and/or prostaglandins perioperatively, limiting metastasis and increasing survival rates. Finally, we propose a specific perioperative pharmacologic intervention in cancer patients, based on simultaneous β-adrenergic blockade and COX-2 inhibition, and discuss specific considerations for its application in clinical trials, including our approved protocol. In sum, we herein present the rationale for a new approach to reduce long-term cancer recurrence by using a relatively safe, brief, and inexpensive intervention during the perioperative period. Clin Cancer Res; 18(18); 4895-902. ?2012 AACR.     

Causes of near misses in critical care of neonates and children

AIM: The primary goal of this study was to examine the nature and causes of medical errors known as almost adverse events (AAEs) and potential adverse events (PAEs) in intensive care units. METHODS: Observations were conducted in the Neonatal Intensive Care Unit and in the Pediatric Intensive Care Unit in a large hospital in Israel. The AAEs and PAEs were classified into three main categories: environmental, system and human factors. Data encoding and analysis was based on a Bayesian model previously developed to analyse causes of traffic accidents, and the categories were based on systems and ergonomics approaches. RESULTS: 'Workload' (a system factor) was the main cause of AAEs and 'communication failures' (a human factor) was the second main cause of AAEs. Among the environmental factors, 'failures in medical devices' was the most cited cause of AAEs. Environmental factors accounted for most of PAEs and among them 'form failures' was the most 'AAE'-prone factor. CONCLUSIONS: Environmental factors (mainly 'failures in medical device') and system factors (mainly 'workload') accounted for most of AAEs in the intensive care units studied. The systems and the ergonomics approaches to error analysis can be useful in creating a comprehensive error management programme in order to minimize the gap between work demands and individual capabilities.     

Radiology department,human factors and organizational perspectives: using action research to improve patient safety

Background

Action research is a participatory research method based on active cooperation between researchers and subjects. In clinical practice, action research enables active involvement of workers in developing and implementing actions promoting patient safety. This article describes a participatory action research project that was conducted in the radiology department of a tertiary care university hospital. The main objectives were: identifying potential adverse events in the department of radiology, and offering a proactive approach to improving patient safety.

Methods

Phase one of the study included observing 100 patients in three units of the department and identifying potential adverse events using an observation form. According to the data obtained from the observations, multidisciplinary research teams developed and initiated, together with front-line workers, four types of interventions: ergonomic interventions in work environment design, interventions in work procedure and task design, training and guidance, and managerial interventions. Phase two included evaluation of the interventions after six months of implementation.

Results

Results showed different weaknesses in each of the three radiology units tested, including incomplete medical information necessary for performing the radiological procedure, and discontinuity of care. Post-intervention observations showed a significant reduction in the prevalence of potential adverse events. At the Angiography unit, potential adverse events related to incomplete medical information dropped from 50% to 32%, and at the CT unit they dropped from 70% to 23%. At the MRI unit potential adverse events related to discontinuity of care dropped from 61% to 19%.

Conclusions

The current study demonstrates the value of action research in non-hospitalizing health units and the benefits of cooperation between medical teams and human factor professionals in promoting patient safety. Methods similar to those described in the current paper are applicable to medical work teams in a broad range of practices.

     

Pulsatile ocular blood flow: relationship with flow velocities in vessels supplying the retina and choroid

BACKGROUND: Although ocular tonography measures a pulsatile component of the ocular perfusion, the retinal and/or choroidal components of this pulsatile flow remain undefined. AIM: To compare ocular tonography with the assessment of flow velocities in arteries supplying the retina, choroid and entire orbit. METHODS: 22 normal eyes from 11 subjects were studied. Pulsatile ocular blood flow (POBF) was measured using the ocular blood flow tonograph, and flow velocities in the ophthalmic, central retinal (CRA) and temporal short posterior ciliary arteries (TSPCA) using colour Doppler imaging. The correlation between POBF and retrobulbar flow velocities was determined. RESULTS: POBF correlated significantly with peak systolic velocity (PSV) of the CRA (r = 0.56, p = 0.007) and the TSPCA (r = 0.48, p = 0.02), and with the resistive index of the TSPCA (r = 0.45, p = 0.04). Additionally, pulse amplitude (PSV-end diastolic velocity) in the CRA and the TSPCA correlated significantly with POBF measurements (each p<0.05). However, POBF did not correlate with any flow velocity indices in the ophthalmic artery. CONCLUSION: POBF is associated with systolic and pulsatile components of blood flow velocities in both the CRA and the TSPCA. This result suggests that POBF determinations are influenced by the pulsatile components of both choroidal and retinal perfusion.