Canadian integrative oncology research priorities: results of a consensus-building process.

BACKGROUND: In Canada, many diverse models of integrative oncology care have emerged in response to the growing number of cancer patients who combine complementary therapies with their conventional medical treatments. The increasing interest in integrative oncology emphasizes the need to engage stakeholders and to work toward consensus on research priorities and a collaborative research agenda. The Integrative Canadian Oncology Research Initiative initiated a consensus-building process to meet that need and to develop an action plan that will implement a Canadian research agenda. METHODS: A two-day consensus workshop was held after completion of a Delphi survey and stakeholder interviews. RESULTS: FIVE INTERRELATED PRIORITY RESEARCH AREAS WERE IDENTIFIED AS THE FOUNDATION FOR A CANADIAN RESEARCH AGENDA: EffectivenessSafetyResource and health services utilizationKnowledge translationDeveloping integrative oncology models Research is needed within each priority area from a range of different perspectives (for example, patient, practitioner, health system) and in a way that reflects a continuum of integration from the addition of a single complementary intervention within conventional cancer care to systemic change. Strategies to implement a Canadian integrative oncology research agenda were identified, and working groups are actively developing projects in line with those strategic areas. Of note is the intention to develop a national network for integrative oncology research and knowledge translation. CONCLUSIONS: The identified research priorities reflect the needs and perspectives of a spectrum of integrative oncology stakeholders. Ongoing stakeholder consultation, including engagement from new stakeholders, is needed to ensure appropriate uptake and implementation of a Canadian research agenda.

Expression of c-fos protein in brain: metabolic mapping at the cellular level.

The proto-oncogene c-fos is expressed in neurons in response to direct stimulation by growth factors and neurotransmitters. In order to determine whether the c-fos protein (Fos) and Fos-related proteins can be induced in response to polysynaptic activation, rat hindlimb motor/sensory cortex was stimulated electrically and Fos expression examined immunohistochemically. Three hours after the onset of stimulation, focal nuclear Fos staining was seen in motor and sensory thalamus, pontine nuclei, globus pallidus, and cerebellum. Moreover, 24-hour water deprivation resulted in Fos expression in paraventricular and supraoptic nuclei. Fos immunohistochemistry therefore provides a cellular method to label polysynaptically activated neurons and thereby map functional pathways.

Cysteamine: a potent and specific depletor of pituitary prolactin.

Cysteamine rapidly reduces the concentration of prolactin in pituitary tissue in vivo and in vitro. The effect is dose-dependent, reversible, and cannot be accounted for by prolactin release. Cysteamine does not appear to exert its effect through dopamine receptors and does not alter lactotrope morphology, as determined by electron microscopy.

MEDiastinal Irradiation and CArdio-Toxic Effects (MEDICATE): Exploring the Relationship between Cardiac Irradiation and High Sensitivity Troponins.

AIMS: Radiation-induced heart disease is a late effect of cardiac irradiation and has been shown in patients with lymphoma and thoracic cancers. There is no established measurement tool to detect acute cardiac damage. However, high sensitivity troponin I and T (HsTnI and HsTnT) and echocardiograms have shown promise in some studies. A pilot trial was conducted to characterise whether these instruments may detect subclinical radiotherapy-induced cardiac damage. MATERIALS AND METHODS: Eligible patients received high cardiac doses defined by either at least 30 Gy to 5% of cardiac volume or a mean dose of 4 Gy. HsTnI and HsTnT were measured before radiotherapy and after 2 and 4 weeks of radiotherapy; three-dimensional echocardiograms were completed before and 1 year after radiotherapy. RESULTS: Of 19 patients, the median 'mean left ventricular dose' was 3.1 Gy and the 'mean cardiac dose' was 8.6 Gy. Significant positive associations between HsTnI and HsTnT were observed at all time points, but there was no significant association with cardiac dose. The mean left ventricular dose and the maximum left ventricular dose were, however, associated with a decrease in ejection fraction (P = 0.054, 0.043) as well as an increase in left ventricular strain (P = 0.058). CONCLUSION: This study suggests that HsTnI and HsTnT are intimately related, but detection of acute cardiac damage was not shown, potentially due to limitations of these markers or low radiotherapy doses using conformal techniques. Our results also suggest subacute damage at 1 year may depend on the dose to the left ventricle. Further studies are needed, as identification of early damage could facilitate the ability to closely monitor and intervene in patients at risk for radiation-induced heart disease.

How do we evaluate outcome in an integrative oncology program?

Integrative oncology focuses on the roles of complementary therapies to increase the effectiveness of conventional cancer treatment programs by improving defined outcomes such as symptom control, quality of life, rehabilitation, and prevention of recurrence. Implementation of integrative oncology programs should be based on the best evidence and must continually be evaluated to ensure quality, optimization of techniques, collection of new data, and cost-effectiveness. Useful domains that can be evaluated include symptom control, adherence to treatment protocols, quality of life, individual outcomes, prevention, rehabilitation, potential advantages of a whole-systems health approach, and economics of health services.

Chinese medicine and biomodulation in cancer patients--Part one.

Traditional Chinese Medicine (tcm) may be integrated with conventional Western medicine to enhance the care of patients with cancer. Although tcm is normally implemented as a whole system, recent reductionist research suggests mechanisms for the effects of acupuncture, herbs, and nutrition within the scientific model of biomedicine. The health model of Chinese medicine accommodates physical and pharmacologic interventions within the framework of a body-mind network. A Cartesian split does not occur within this model, but to allow for scientific exploration within the restrictions of positivism, reductionism, and controls for confounding factors, the components must necessarily be separated. Still, whole-systems research is important to evaluate effectiveness when applying the full model in clinical practice. Scientific analysis provides a mechanistic understanding of the processes that will improve the design of clinical studies and enhance safety. Enough preliminary evidence is available to encourage quality clinical trials to evaluate the efficacy of integrating tcm into Western cancer care.

Research and regulatory issues for integrative oncology.

Many oncology patients are empowering themselves to self-treat with herbs, nutritional supplements, and mind-body techniques. Other practitioners, such as acupuncturists, are becoming involved in the supportive care of cancer patients. Government research agencies are supporting studies that evaluate complementary therapies. This educational article provides an overview of the challenges in designing appropriate studies of complementary and alternative therapies, evaluating the results, and regulating implementation of useful therapies.

Massage therapy for cancer patients: a reciprocal relationship between body and mind.

Some cancer patients use therapeutic massage to reduce symptoms, improve coping, and enhance quality of life. Although a meta-analysis concludes that massage can confer short-term benefits in terms of psychological wellbeing and reduction of some symptoms, additional validated randomized controlled studies are necessary to determine specific indications for various types of therapeutic massage. In addition, mechanistic studies need to be conducted to discriminate the relative contributions of the therapist and of the reciprocal relationship between body and mind in the subject. Nuclear magnetic resonance techniques can be used to capture dynamic in vivo responses to biomechanical signals induced by massage of myofascial tissue. The relationship of myofascial communication systems (called "meridians") to activity in the subcortical central nervous system can be evaluated. Understanding this relationship has important implications for symptom control in cancer patients, because it opens up new research avenues that link self-reported pain with the subjective quality of suffering. The reciprocal body-mind relationship is an important target for manipulation therapies that can reduce suffering.

Natural health products that inhibit angiogenesis: a potential source for investigational new agents to treat cancer-Part 1.

An integrative approach for managing a patient with cancer should target the multiple biochemical and physiologic pathways that support tumour development and minimize normal-tissue toxicity. Angiogenesis is a key process in the promotion of cancer. Many natural health products that inhibit angiogenesis also manifest other anticancer activities. The present article focuses on products that have a high degree of anti-angiogenic activity, but it also describes some of the many other actions of these agents that can inhibit tumour progression and reduce the risk of metastasis. Natural health products target molecular pathways other than angiogenesis, including epidermal growth factor receptor, the HER2/neu gene, the cyclooxygenase-2 enzyme, the nuclear factor kappa-B transcription factor, the protein kinases, the Bcl-2 protein, and coagulation pathways. The herbs that are traditionally used for anticancer treatment and that are anti-angiogenic through multiple interdependent processes (including effects on gene expression, signal processing, and enzyme activities) include Artemisia annua (Chinese wormwood), Viscum album (European mistletoe), Curcuma longa (curcumin), Scutellaria baicalensis (Chinese skullcap), resveratrol and proanthocyanidin (grape seed extract), Magnolia officinalis (Chinese magnolia tree), Camellia sinensis (green tea), Ginkgo biloba, quercetin, Poria cocos, Zingiber officinalis (ginger), Panax ginseng, Rabdosia rubescens hora (Rabdosia), and Chinese destagnation herbs. Quality assurance of appropriate extracts is essential prior to embarking upon clinical trials. More data are required on dose-response, appropriate combinations, and potential toxicities. Given the multiple effects of these agents, their future use for cancer therapy probably lies in synergistic combinations. During active cancer therapy, they should generally be evaluated in combination with chemotherapy and radiation. In this role, they act as modifiers of biologic response or as adaptogens, potentially enhancing the efficacy of the conventional therapies.

Natural health products that inhibit angiogenesis: a potential source for investigational new agents to treat cancer-Part 2.

The herbalist has access to hundreds of years of observational data on the anticancer activity of many herbs. Laboratory studies are expanding the clinical knowledge that is already documented in traditional texts. The herbs that are traditionally used for anti-cancer treatment and that are anti-angiogenic through multiple interdependent processes (including effects on gene expression, signal processing, and enzyme activities) include Artemisia annua (Chinese wormwood), Viscum album (European mistletoe), Curcuma longa (curcumin), Scutellaria baicalensis (Chinese skullcap), resveratrol and proanthocyanidin (grape seed extract), Magnolia officinalis (Chinese magnolia tree), Camellia sinensis (green tea), Ginkgo biloba, quercetin, Poria cocos, Zingiber officinalis (ginger), Panax ginseng, Rabdosia rubescens hora (Rabdosia), and Chinese destagnation herbs. Natural health products target molecular pathways other than angiogenesis, including epidermal growth factor receptor, the HER2/neu gene, the cyclo-oxygenase-2 enzyme, the nuclear factor kappa-B transcription factor, the protein kinases, the Bcl-2 protein, and coagulation pathways. Quality assurance of appropriate extracts is essential prior to embarking upon clinical trials. More data are required on dose-response, appropriate combinations, and potential toxicities. Given the multiple effects of these agents, their future use for cancer therapy probably lies in synergistic combinations. During active cancer therapy they should generally be evaluated in combination with chemotherapy and radiation. In this role, they act as modifiers of biologic response or as adaptogens, potentially enhancing the efficacy of the conventional therapies or reducing toxicity. Their effectiveness may be increased when multiple agents are used in optimal combinations. New designs for trials to demonstrate activity in human subjects are required. Although controlled trials may be preferable, smaller studies with appropriate endpoints and surrogate markers for anti-angiogenic response could help to prioritize agents for larger, resource-intensive phase iii trials.

The mechanism of action of cysteamine in depleting prolactin immunoreactivity.

The thiol reagent cysteamine (CSH) depletes anterior pituitary cells of immunoreactive PRL both in vivo and in vitro. We examined the hypothesis that CSH affects either the solubility or immunoreactivity of PRL through a mechanism involving thiol-disulfide exchange. Adult female rats were treated with either CSH (300 mg/kg, sc) or an equimolar dose of ethanolamine as a control. Anterior pituitary glands were extracted in 0.1 M sodium borate buffer, pH 9.0. Treatment of pituitary extracts with beta-mercaptoethanol (BME) destroys the immunoreactivity of PRL. However, extraction in the presence of reduced glutathione or CSH of pituitaries of rats treated with CSH restores immunoreactive PRL to control levels. Extracts were also subjected to polyacrylamide gel electrophoresis (PAGE). On gels of pituitary extracts of CSH-treated rats, the band that comigrates with purified PRL is diminished compared to that in ethanolamine-treated controls. This is found regardless of whether the borate extracts are treated with BME. However, extraction of the pituitaries in sodium dodecyl sulfate-containing buffer followed by chemical reduction with BME restores the PRL band. Therefore, CSH acts on PRL through a thiol-related mechanism to yield a product that is poorly soluble in aqueous buffer at pH 9 and is poorly immunoreactive. Dispersed anterior pituitary cells in tissue culture were incubated with L-[35S]methionine to radiolabel newly synthesized peptides. These cultures were incubated in the presence of either CSH or ethanolamine. PAGE followed by autoradiography confirmed the above results obtained in vivo. Also, extracts of CSH-treated cultures were subjected to gel permeation chromatography. As determined by PAGE, at least some of the radiolabeled PRL can be recovered from void volume fractions by reduction with BME, indicating that CSH induces the formation, through disulfide exchange, of a high mol wt form of PRL, possibly PRL oligomers.

Cysteamine depletes prolactin in young and old hyperprolactinemic rats.

Studies were undertaken to evaluate the effects of cysteamine on serum and anterior pituitary concentrations of prolactin in hyperprolactinemic female rats. Serum prolactin was elevated in young (4 to 5 months old) rats by implantation of 17 beta-estradiol while 26- to 28-month-old rats were in constant estrus and exhibited an age-related hyperprolactinemia. At 4 h after treatment with cysteamine (90 mg/kg body wt) serum and anterior pituitary prolactin concentrations were reduced in young animals by 98 and 85%, respectively. In old constant-estrous rats, cysteamine reduced serum prolactin by 92% and anterior pituitary prolactin by 82%. In young pseudopregnant rats, cysteamine induced a prompt resumption of estrous cycles. These studies indicate that cysteamine is an effective depletor of serum and pituitary prolactin in hyperprolactinemic rats.

Evidence that reduced growth hormone secretion observed in monosodium glutamate-treated rats is the result of a deficiency in growth hormone-releasing factor.

The present experiments were designed to examine various aspects of GH secretion in adult male rats given monosodium glutamate (MSG; 4 mg/g BW, sc) during the neonatal period. MSG-treated animals sustained lesions localized to the hypothalamic arcuate nuclei (ARC) and had reduced nasal-anal lengths and body weights. Anterior pituitary (AP) weights were decreased, but AP concentrations of GH and PRL were not significantly altered. Analysis of pulsatile GH secretion showed depressed GH pulses and prolonged GH trough periods. Mean 5-h plasma GH levels were reduced, whereas PRL levels were not affected. Morphine sulfate (MS) at doses of 0.01, 0.1, 1.0, and 3.0 mg/kg induced a prompt rise in GH during the 45 min after drug administration in controls. MSG-treated animals showed a significant rise in GH only with 1.0 and 3.0 mg/kg MS. A significant elevation in PRL was found in both control and MSG-treated animals after 1.0 and 3.0 mg/kg MS. The pentobarbital-induced rise in GH was also blunted in MSG-treated animals. MSG-treated animals which were administered antisomatostatin serum showed elevated GH trough and mean GH levels, with no apparent effect on GH peak levels. In view of the mechanisms by which MS and pentobarbital act to increase GH secretion, the present data suggest that the GH regulatory deficit observed in MSG-treated rats is due to a relative loss of GH-releasing factor secondary to ARC damage.

Cysteamine depletes prolactin (PRL) but does not alter the structure of PRL-containing granules in the anterior pituitary.

Cysteamine causes a profound depletion of PRL in the anterior pituitary and in the systemic circulation, as measured by RIA and bioassay. However, electron microscopic study of PRL-containing cells in rat anterior pituitary does not reveal changes in secretory granule or cytoplasmic structure during the interval of depressed PRL content and of subsequent recovery to normal levels. In contrast to the results obtained by RIA, PRL-like immunoreactivity as detected by immunocyto-chemistry is present and similar to that of control preparations after cysteamine administration. We suggest that cysteamine alters PRL structure in secretory granules, probably by interacting with the disulfide bonds of PRL, thereby altering bioactivity and immunoreactivity. The presence of cysteamine-altered PRL in secretory granules does not seem to trigger degradation of granules by the lysosomal system.

Cysteamine induces depletion of both immunological and biological prolactin activity in the anterior pituitary and blood of the rat.

Previous studies have shown that cysteamine [2-aminoethanethiol (CSH)], given in vivo or in vitro, rapidly but reversibly depletes immunoreactive PRL from the anterior pituitary (AP) through a mechanism which, in vitro, does not appear to involve the dopamine (DA) receptor. In the present investigation, these effects of CSH were explored further with emphasis on determining whether CSH; (1) depletes biological as well as immunological PRL activity from the AP and blood, (2) has effects on plasma PRL in chronically cannulated male rats, (3) alters the PRL response to drugs which stimulate the secretion of the hormone, and (4) acts in vivo via DA receptors to deplete PRL. CSH produced a dose-dependent depletion of both immunological and biological PRL activity from the AP and blood. In chronically cannulated animals, PRL levels in the plasma were undetectable 90 min after CSH administration and remained so for 4 h. However, by 24 h plasma PRL in treated animals had returned to control levels. The PRL response to both domperidone and morphine was virtually abolished in CSH-treated animals. Blockade of DA receptors by pretreatment with domperidone did not alter the ability of CSH to reduce AP PRL stores. These results indicate that CSH: 1) alters both biological and immunological PRL activity by a rapid but reversible effect, and 2) circumvents the DA receptor to deplete pituitary PRL content. Thus, CSH or similar compounds may serve as a prototype for a new class of drugs which can be used in the treatment of hyperprolactinemia.

The effects of cysteamine on thyrotropin and immunoreactive beta-endorphin secretion in the rat.

We examined the effects of the thiol agent cysteamine (CSH), which is known to deplete the hypothalamus of immunoreactive somatostatin, on physiological TSH and beta- endorphin secretion in the adult male rat. CSH at doses of 90 and 300 mg/kg CSH produced a rapid decline in plasma TSH, whereas a dose of 30 mg/kg did not alter plasma TSH levels. After the higher doses of CSH, TSH levels in the blood remained lower than control values on day 2, but returned to normal by 1 week. This decrease in TSH within the plasma was not associated with a reduction in hypothalamic TRH concentrations. The TSH response to 500 ng/kg TRH was normal in CSH-treated animals. Blockade of norepinephrine synthesis with diethyldithiocarbamate (500 mg/kg) or fusaric acid (100 mg/kg) inhibited TSH secretion in a manner similar to that of CSH. beta-Endorphin-like immunoreactivity (bet-End-LI) was elevated in the plasma immediately after CSH (300 mg/kg) administration. This was associated with a 58% reduction in anterior pituitary beta-End-LI and no change in hypothalmic beta-End-LI. Plasma beta-End-LI returned to normal on day 2. The increase in plasma beta-End-LI induced by immobilization stress was not compromised by CSH treatment. The observed effects of CSH on both TSH and beta-End-LI are consistent with a reduction in central norepinephrine neurotransmission through the known actin of CSH to inhibit dopamine-beta-hydroxylase. Acute stress may play a role as well in the observed changes in TSH and beta-End-LI secretion.

Integration of Chinese medicine into supportive cancer care: a modern role for an ancient tradition.

Recent evidence suggests that many traditional Chinese medical therapies are effective for the supportive care of cancer patients. This is a review of some of the published literature (indexed in Medline) and our own practical experience. It is not intended to be a systematic review, but does provide various levels of evidence which support further research into a developing model of integrative care. The holistic approach of Traditional Chinese Medicine (TCM) may be integrated into conventional Western Medicine to supplement deficiencies in the current biomedical model. The philosophy of TCM proposes novel hypotheses which will support the development of a science-based holistic medicine.

Induction of c-fos, junB, c-jun, and hsp70 mRNA in cortex, thalamus, basal ganglia, and hippocampus following middle cerebral artery occlusion.

Middle cerebral artery (MCA) occlusion in halothane-anesthetized rats induced c-fos, junB, and c-jun immediate early gene mRNAs and hsp70 heat shock gene mRNA in brain. In situ hybridization studies showed that c-fos and junB were induced throughout all of the cortex at 1 and 4 h following MCA occlusion. hsp70 was induced in the core and margins of the MCA ischemia. By 24 h, there was little expression of c-fos, junB, c-jun, and hsp70 in the core of the MCA infarct; there was modest induction of hsp70 at the margins of the infarct; and there was diffuse induction of c-fos, junB, and c-jun in all of the cortex outside the infarct. MCA occlusion also induced these genes in subcortical structures. c-fos, junB, and hsp70 were induced in ipsilateral medial striatum, most of thalamus including medial and lateral geniculate nuclei, substantia nigra, and hippocampus. Most of these structures, except for the striatum, are not supplied by the MCA. These data show that changes in gene expression can occur in regions remote from an infarction.

Induction of 70-kDa heat shock protein and hsp70 mRNA following transient focal cerebral ischemia in the rat.

Induction of the 70-kDa heat shock protein (HSP70) was demonstrated immunocytochemically in adult rats 4 h to 7 days following temporary middle cerebral artery (MCA) occlusions lasting 30, 60, or 90 min. Maximal HSP70 induction occurred approximately 24 h following ischemia. Thirty minutes of ischemia induced HSP70 in neurons throughout the cortex in the MCA distribution, whereas 90 min of ischemia induced HSP70 in neurons in the penumbra. HSP70 protein was induced in endothelial cells in infarcted neocortex following 60-90 min of MCA occlusion, and HSP70 was induced in endothelial cells in infarcted regions of lateral striatum following 30-90 min of MCA occlusion. hsp70 mRNA was induced in the MCA distribution in cortex and to a lesser extent in striatum at 2 h to 3 days following 60 min of ischemia. It is proposed that brief ischemia induces hsp70 mRNA and HSP70 protein in the cells most vulnerable to ischemia--the neurons. HSP70 protein is not induced in most neurons and glia following 60-90 min of ischemia in areas destined to infarct, whereas it is induced in vascular endothelial cells.

NADPH-diaphorase reactive neurons of the rabbit retina: differential sensitivity to excitotoxins and unusual morphologic features.

Various populations of retinal and brain neurons display different degrees of sensitivity to the toxic effects of excitatory amino acid agonists. To further define this phenomenon, the effects of intravitreal injections of kainic acid, N-methyl-D-aspartate (NMDA), quinolinic acid, and ibotenic acid on NADPH-diaphorase (NADPHd) reactive cells of the rabbit retina were examined. In normal rabbit retinas, NADPHd histochemistry selectively stains two populations of cells at the inner margin of the inner plexiform layer: large densely staining (Type I) and more numerous, smaller and lightly staining (Type II) cells. All of the toxins studied destroy both cell types at high doses. Kainic acid, however, at low doses destroys Type I cells but selectively spares Type II cells. NMDA injections result in a more complex and less consistent pattern of cell loss; overall, the Type I cells are perhaps slightly resistant to this agent as compared to Type II cells. The Type I neurons in this respect are analogous to striatal NADPHd-reactive neurons, which have, at most, a slight relative resistance to NMDA neurotoxicity. The excitotoxin lesions reduce the complexity of the fiber plexus in the inner plexiform layer and thereby reveal anatomic features of surviving NADPHd reactive neurons that are not apparent in normal retinas. In particular, each Type I cell gives off several fine, straight, beaded processes that emanate from dendrites and run several millimeters in the inner plexiform layer. These processes are presumably involved in long-distance interactions within the retina. Excitotoxin lesions may provide a generally useful anatomic tool for elucidating morphological features of neurons stained by histochemical and immunohistochemical methods.