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Physical principles of local heat therapy for cancer.

Local hyperthermia therapy for cancer can produce selective heating of solid tumors on the basis of known physical laws. If energy is deposited in the general region of the tumor, temperature tends to develop in the tumor higher than that in surrounding normal tissues. The goal of therapy is to achieve cytotoxic temperature elevations in the tumor for an adequate period of time, without damaging nearby normal tissues. Several modalities exist for local heat treatment, of which radiofrequency and ultrasound offer the most promise for controlled, localized heating at depth. A paucity of blood flow in the tumor compared to that in adjacent normal tissues can enhance selective tumor heating considerably. The tumor types that have reduced flow in their central regions are especially vulnerable to heat therapy, both because they can be heated more efficiently and because hypoxic and acidotic tumor tissues are more susceptible to damage by heat. This effect is more pronounced in larger tumors, which have smaller surface-to-volume ratios and so lose heat less rapidly by thermal diffusion. Selective heat treatment of larger tumor masses with low blood perfusion, therefore, is physically practical and rational therapy. Vigorous research efforts are now underway at many centers to optimize this approach.

Diathermy↗

Anthracycline resistance: the problem and its current definition.

Anthracyclines were introduced for the treatment of breast cancer in the 1970s and were considered the most active single agents until the recent introduction of the taxoids. Although incorporation of anthracyclines into combination regimens has been shown to improve clinical outcomes, the duration of response and survival in women with metastatic disease is still modest, and 50% of women treated with adjuvant chemotherapy eventually relapse. Intrinsic and acquired drug resistance, leading to untreatable disease, are fundamental reasons for clinical failure in breast cancer, but the clinical relevance of the various known mechanisms of drug resistance is not clear. P-glycoprotein (Pgp)-mediated multidrug resistance, the most studied form of anthracycline resistance, can be inhibited by a variety of chemicals. While in vitro studies have demonstrated the efficacy of some Pgp inhibitors, and led to the development of more clinically acceptable agents, clinical studies have not shown a consistent advantage in using Pgp inhibitors. Since Pgp is a physiologic efflux mechanism, consideration also should be given to the possible consequences of its inhibition. Studies with Pgp knock-out transgenic mice suggest that Pgp is not essential for life, but that Pgp inhibition may make some tissues, such as the brain, more vulnerable to cytotoxic drugs. Correlating overexpression of the MDR1 gene in human tumor samples with treatment failure has not proved straightforward, and further studies are needed to clarify the contribution of multidrug resistance mechanisms to clinical anthracycline resistance. Mechanisms other than drug efflux pumps, which may contribute to anthracycline resistance, include changes in topoisomerase II, the major cellular target of anthracyclines. There remains a gulf between the laboratory definitions of drug resistance, which can be elucidated in great detail, and the clinical definition, which is based on the time to treatment failure. New drugs still need to be assessed empirically in the clinic, and these results may then be correlated with laboratory findings. We cannot yet reliably predict clinical efficacy, cross-resistance, or the mechanisms responsible for treatment failure from laboratory studies.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

Distribution and photodynamic effect of disulphonated aluminium phthalocyanine in the pancreas and adjacent tissues in the Syrian golden hamster.

Necrosis of small volumes of tumour tissue with photodynamic therapy (PDT) can be achieved relatively easily. For this to be clinically relevant, it is essential to know what the same treatment parameters do to adjacent normal tissues into which the tumour has spread. For pancreatic cancers, local spread to vital structures is common. We have studied chemical extraction, microscopic fluorescence kinetics and photodynamic effects of disulphonated aluminum phthalocyanine (AlS2Pc) in normal pancreas and adjacent tissues in hamsters. Chemical extraction exhibited a peak duodenal concentration of AlS2Pc 48 h after sensitisation, with levels much higher than in stomach and pancreas. With microscopic fluorescence photometry highest levels were seen in duodenal submucosa and bile duct walls 48 h after photosensitisation. Pancreatic ducts, duodenal mucosa and gastric mucosa and submucosa exhibited intermediate fluorescence with relatively weak fluorescence in pancreatic acinar tissue and the muscle layer of the stomach. As expected, on the basis of fluorescence intensity and chemical extraction studies, the duodenal and bile duct wall were the most vulnerable tissues to photodynamic therapy. When the dose of 5 mumol kg-1 of sensitiser was used, duodenal perforations, gastric ulcers and transudation of bile from the bile duct occurred. However, the lesions in the stomach and bile duct healed without perforation or obstruction, so only the duodenum was at risk of serious, irreversible damage. Using a lower dose of photosensitiser markedly reduced damage.

Animals↗

Psychological adaptation and social support of parents of pediatric cancer patients: a prospective longitudinal study.

OBJECTIVE: To investigate levels of support and the concurrent and prospective effects of support on the psychological functioning of parents of children with cancer in a prospective longitudinal study. METHODS: Parents' (n = 128) self-perceived level of psychological distress, quantity of support, and dissatisfaction with support were assessed, at diagnosis, at 6, and at 12 months. RESULTS: Parents received most support at diagnosis. Self-perceived quantity decreased with time, but parents indicated they remained equally satisfied. Support significantly predicted concurrent and prospective distress of fathers, but not of mothers. Dissatisfaction with support and negative interactions were consistent risk factors for fathers. Mothers who adjusted well psychologically received more support and were less dissatisfied than mothers who remained clinically distressed. Nevertheless, no persisting effect of support was found. CONCLUSIONS: Findings illustrate that social support varies with the stress situation and with gender. Identification of vulnerable parents at diagnosis on the basis of their perception of received quantity of and dissatisfaction with support seems difficult. Intervention efforts aimed at mobilization of needed support may be efficacious.

Adaptation, Psychological↗

Who responds to sugar pills?

Among 288 cancer patients undergoing controlled trials of oral analgesics there were 112 who received 50% or greater pain relief from placebo formulations. Patients who responded to placebo had a greater response rate to active drugs. They also had a higher incidence of central nervous system side effects to placebo. Patient groups showing as increased placebo response included those with a high level of education, farmers, those with a professional occupation, women working outside the home, and patients who were widowed, separated, or divorced. Those resistant to placebo were patients with a low educational level, unskilled workers, housewives, married women without children, and smokers. It is theorized that placebo response is a type of autohypnosis phenomenon resulting from exaggerated oral-dependency needs. Particularly vulnerable to placebo effect is the very self-sufficient individual with heavy responsibilities who is thrust into the unaccustomed dependency of disabling illness.

Aged↗

Perioperative immunotherapy with recombinant interleukin 2 in patients undergoing surgery for colorectal cancer.

Major surgery impairs the cellular immune response. We have therefore studied the immunological effects of low-dose recombinant interleukin 2 given to patients undergoing surgery for colorectal cancer to determine whether this agent has potential in perioperative adjuvant immunotherapy. Patients were randomly allocated to control (n = 13) or treatment groups (n = 12). Immunological studies of both lymphocyte function and subset number were performed preoperatively and on Days 1, 4, 7, and 10. Treatment with recombinant interleukin 2 prevented the postoperative fall in both natural killer and lymphokine-activated killer cell cytotoxicity, clearly demonstrated in the control group. The treatment group also showed in vivo T-cell activation with an initial lymphopenia followed by a rebound lymphocytosis and upregulation of the subset markers CD25 (interleukin 2 receptor) and CD45RO (T-memory cells). These combined effects may have important consequences in controlling metastatic dissemination of tumor during the vulnerable perioperative period.

Aged↗

Influence of cyclosporin A and alpha-difluoromethylornithine, an inhibitor of polyamine biosynthesis, on two rodent T-cell cancers in vivo.

We have examined the influence of cyclosporin A (CsA), administered together with the polyamine antimetabolite, alpha-difluoromethylornithine (DFMO), on growth of the Roser acute T-cell leukaemia in PVG rats and on growth of the EL4 lymphoma in C57BL/6 mice. CsA or DFMO alone, administered from the time of tumour injection, markedly reduced numbers of circulating lymphoblasts in leukaemic rats, although survival was prolonged only in those animals given DFMO. Drug combination further reduced blood-borne tumour cells, but had no additional effects on tumour growth within organs or on host survival, compared to that achieved with DFMO treatment alone. Neither CsA nor DFMO, administered from the time of tumour-cell injection, nor both drugs in combination, affected peritoneal growth of the EL4 lymphoma or organ infiltration. Host survival was prolonged by DFMO. As anticipated, DFMO inhibited polyamine synthesis in vivo, but the observed anti-tumour effect of CsA was not accompanied by an alteration in polyamine biosynthesis. By reducing polyamine synthesis, however, DFMO may enhance the vulnerability of those malignant T cells which are susceptible to the as yet unexplained selective inhibitory action of CsA in vivo.

Animals↗

Colorectal cancer, screening and survival: the influence of socio-economic deprivation.

OBJECTIVES: To determine the extent to which socio-economic deprivation explains colorectal cancer prevalence, subject participation in screening, and postoperative survival and life expectancy. METHODS: Regression analyses of clinical data from a large randomized controlled trial, augmented by geographical-based indices of deprivation. RESULTS: Deprivation appears to exert no significant impact on colorectal cancer prevalence but is a major factor explaining subject participation in screening. Cancer detection at later stages reduces life expectancy at time of treatment. Females from more-deprived areas have poorer post-treatment life expectancies and survival prospects, independently of their screening behaviour. CONCLUSIONS: Screening increases the chances of having a cancer treated at an earlier stage, and treatment at an earlier stage is associated with longer subsequent life expectancy. However, those from more-deprived areas are less likely to accept an invitation to be screened.

Aged↗

West Coast study of childhood brain tumours and maternal use of hair-colouring products.

The immature nervous system of the fetus is characterised by rapid cell growth and division and is particularly vulnerable to carcinogens and mutagens. Several epidemiological studies have reported an increased risk for childhood brain tumours (CBT) associated with exposure to N-nitroso compounds (NOC). Hair-colouring products (hair "dyes") that contain NOC-related aromatic amines have shown mutagenicity in vitro and carcinogenic properties in vivo. The potential public health impact of the relationship between hair dye use and carcinogenesis has prompted epidemiological research, given that a large proportion of American women have used hair dyes. A large population-based case-control study was conducted on the west coast of the USA to investigate risk factors for CBT including exposure to NOC. Eligible CBT patients (<20 years of age and diagnosed between 1984 and 1991) were identified from cancer registries in Los Angeles County, the San Francisco Bay Area in California and the Seattle area in Washington state. A total of 540 biological mothers of these children were interviewed, and 801 control subjects who were frequency matched to the CBT patients on birth year and sex were obtained using random digit dialling. Mothers were asked details about personal use of hair dyes during the index pregnancy including frequency of use, trimester of use and type of dye used. Results from age- and sex-adjusted unconditional logistic regression analyses showed no association between risk for CBT and use of hair dyes 1 month before and/or during pregnancy nor during specific trimesters. A nearly twofold increased risk for CBT was associated with single-interval use during the 1 month before pregnancy, but the confidence interval (CI) was imprecise and the estimate was not different from unity (OR = 1.9, 95% CI [0.5, 7.0]). Exclusive use of permanent dye, temporary dye or hair darkeners was not associated with risk for CBT. A twofold increased risk (OR = 2.0, 95% CI [0.83, 4.7]) was observed with exclusive use of semi-permanent dye during the month before or during pregnancy. Exclusive use of semi-permanent dye during the month before pregnancy and/or first trimester also was associated with an elevated risk for CBT, again not different from unity and with an imprecise CI (OR = 2.5, 95% CI = [0.58, 10.3]). There was no evidence of an association between risk for CBT by histological subtypes and use of hair dyes during the index pregnancy or the month before conception. Together with results from previous studies, these results provide no consistent evidence of an association between risk for CBT and use of hair dyes during pregnancy.

Adolescent↗

The impact of mastectomy on self-concept and social function: a combined cross-sectional and longitudinal study with comparison groups.

Self-concept and social function following radical, modified radical or simple mastectomy for Stage I or II breast cancer, breast biopsy for benign breast disease, cholecystectomy or no operative procedure were measured across a fifteen-month period in a cross-sectional design and across a twelve-month period in a repeated measures design. Women selected for study were without other preexisting mental or physical illness. The degree of disability observed following mastectomy was considerably less than previously reported in uncontrolled studies, with the incidence of actual disturbance extremely small. Women receiving adjuvant therapies following mastectomy, but not women treated by mastectomy alone, reported significantly more body-image dissatisfaction and feminine self-image concerns than the comparison groups. The findings refute previously published impressions of severe psychosocial maladjustments following mastectomy. The study suggests that post-mastectomy women vulnerable to poorer outcome would be those with lower expectations of good quality social support, other present life stressors, other pre-existing chronic diseases, and a disposition to believe in life outcomes as less under their own control.

Adult↗

Gambling with your life: the process of breast cancer treatment decision making in Chinese women.

Treatment decision making (TDM) studies have primarily focused on assessing TDM quality and predominantly presume rational analytic processes as the gold standard. In a grounded theory study of 22 Hong Kong Chinese women following breast surgery who completed an in-depth interview exploring the process of TDM in breast cancer (BC), narrative data showed that discovery of a breast abnormality and emotional responses to BC diagnosis influence the TDM process. Lack of guidance from surgeons impaired TDM. Decisions were, for the most part, made using intuitive, pragmatic and emotionally driven criteria in the absence of complete information. The experience of TDM, which was likened to gambling, did not end once the decision was made but unfolded while waiting for surgery and the post-operative report. In this waiting period, women were emotionally overwhelmed by fear of death and the uncertainty of the surgical outcome, and equivocated over whether they had made the 'right' choice. This suggests that Chinese women feel they are gambling with their lives during TDM. These women are particularly emotionally vulnerable whilst waiting for their surgery and the post-surgical clinical pathology results. Providing emotional support is particularly important at this time when these women are overwhelmed by uncertainty.

Adult↗

A study of the effects of photodynamic therapy on the normal tissues of the rabbit jaw.

Photodynamic therapy (PDT) is an anti-cancer treatment which involves the systemic administration of a photosensitising drug which is preferentially absorbed by tumour tissue. Relatively little drug should be absorbed by the surrounding normal tissues. Tumour destruction is achieved when the tumour is illuminated with light of a wavelength which activates the photosensitising drug thereby inducing a cytotoxic reaction. However studies in many tissues have shown that the hoped for tumour selectivity is rarely achieved. Using the rabbit mandible and gingiva as our models we have studied the effects of various doses of PDT on the tissues of the oral cavity, namely mucosa, bone, muscle and salivary gland. The photosensitiser used was di-sulphonated aluminium phthalocyanine. Results show that whereas bone is extremely resistant to PDT the other tissues are vulnerable to it. In the case of muscle and salivary gland this susceptibility is very much dose related. In salivary tissue necrotising sialometaplasia was observed in areas of the gland adjacent to those that had undergone necrosis. All tissues were noted to heal or regenerate well following PDT injury.

Animals↗

Long-term risk for depressive symptoms after a medical diagnosis.

BACKGROUND: This study examines the risk of development of significant depressive symptoms after a new diagnosis of cancer, diabetes, hypertension, heart disease, arthritis, chronic lung disease, or stroke. METHODS: The study used 5 biennial waves (1992-2000) of the Health and Retirement Study to follow a sample of 8387 adults (aged 51 to 61 years and without significant depressive symptoms in 1992) from 1994 to 2000. Time-dependent Cox regression models estimated adjusted hazard ratios (HRs) for an episode of significant depressive symptoms after a new diagnosis for each of the 7 medical conditions. RESULTS: Within 2 years of initial diagnosis, subjects with cancer had the highest hazard of depressive symptoms (HR, 3.55; 95% confidence interval [CI], 2.79-4.52), followed by subjects with chronic lung disease (HR, 2.21; 95% CI, 1.64-2.79) and heart disease (HR, 1.45; 95% CI, 1.09-1.93). The hazard for depressive symptoms for most of these diseases decreased over time; however, subjects with heart disease continued to have a higher risk for depressive symptoms even 2 to 4 years and 4 to 8 years after diagnosis, and a significantly higher hazard for depressive symptoms developed for persons with arthritis 2 to 4 years after diagnosis (HR, 1.46; 95% CI, 1.11-1.92). CONCLUSION: The findings identify several high-risk patient groups who might benefit from depression screening and monitoring to improve health outcomes in this vulnerable population facing new medical illnesses.

Chronic Disease↗

Nuclear enzymes, fragile sites, and cancer.

The finding of a large number of recurrent fragile sites on human chromosomes provides suggestive evidence for the origin of recurrent chromosomal rearrangements that are a common feature in most neoplasias. These fragile sites can be induced by a wide variety of mutagens and carcinogens that are known to act through different molecular mechanisms. They correlate with two-thirds of the recurrent cancer chromosomal breakpoints known thus far and with the location of most mapped oncogenes and growth factors. Because we have now found that a large number of fragile sites can also be induced by agents such as DNase I and benzo[a]pyrene diol-epoxide (BPDE), which are known to induce hypersensitive chromatin sites, it is possible that a class of fragile sites represents regulatory regions of active genes. We have also introduced restriction enzymes into cultured lymphocytes and found that fragile sites are expressed in a pattern similar to that produced by DNase I and BPDE. Because fragile sites have a higher expression with advancing age, cigarette smoking, and deficiency of folic acid and B12 vitamins, they may represent active genomic sites that are vulnerable to physiological and environmental disturbance.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗

Maryland's Special Populations Cancer Network: cancer health disparities reduction model.

Cancer in Maryland is a serious health concern for minority and underserved populations in rural and urban areas. This report describes the National Cancer Institute (NCI) supported Maryland Special Populations Cancer Network (MSPN), a community-academic partnership. The MSPN's priority populations include African Americans, Native Americans, and other medically underserved residents of rural and urban areas. The MSPN has established a community infrastructure through formal collaborations with several community partners located in Baltimore City, the rural Eastern Shore, and Southern and Western Maryland, and among the Piscataway Conoy Tribe and the other 27 Native American Tribes in Maryland. Key partners also include the University of Maryland Eastern Shore and the University of Maryland Statewide Health Network. The MSPN has implemented innovative and successful programs in cancer health disparities research, outreach, and training; clinical trials education, health disparities policy, and resource leveraging. The MSPN addresses the goal of the NCI and the Department of Health and Human Services (DHHS) to reduce and eventually eliminate cancer health disparities. Community-academic partnerships are the foundation of this successful network.

Black or African American↗

Notch and NOXA-related pathways in melanoma cells.

Notch receptor-mediated intracellular events represent an ancient cell signaling system, and alterations in Notch expression are associated with various malignancies in which Notch may function as an oncogene or less commonly as a tumor suppressor. Notch signaling regulates cell fate decisions in the epidermis, including influencing stem cell dynamics and growth/differentiation control of cells in skin. Because of increasing evidence that the Notch signaling network is deregulated in human malignancies, Notch receptors have become attractive targets for selective killing of malignant cells. Compared with proliferating normal human melanocytes, melanoma cell lines are characterized by markedly enhanced levels of activated Notch-1 receptor. By using a small molecule gamma-secretase inhibitor (GSI) consisting of a tripeptide aldehyde, N-benzyloxycarbonyl-Leu-Leu-Nle-CHO, which can block processing and activation of all four different Notch receptors, we identified a specific apoptotic vulnerability in melanoma cells. GSI triggers apoptosis in melanoma cells, but only G2/M growth arrest in melanocytes without subsequent cell death. Moreover, GSI treatment induced a pro-apoptotic BH3-only protein, NOXA, in melanoma cells but not in normal melanocytes. The use of GSI to induce NOXA induction overcomes the apoptotic resistance of melanoma cells, which commonly express numerous cell survival proteins such as Mcl-1, Bcl-2, and survivin. Taken together, these results highlight the concept of synthetic lethality in which exposure to GSI, in combination with melanoma cells overexpressing activated Notch receptors, has lethal consequences, producing selective killing of melanoma cells, while sparing normal melanocytes. By identifying signaling pathways that contribute to the transformation of melanoma cells (e.g. Notch signaling), and anti-cancer agents that achieve tumor selectivity (e.g., GSI-induced NOXA), this experimental approach provides a useful framework for future therapeutic strategies in cutaneous oncology.

Amyloid Precursor Protein Secretases↗

The carcinogenic effect of inhaled asbestos fibers.

Inhalation of asbestos fibers is associated with high incidence of lung cancers and pleural or peritoneal mesotheliomas in humans. All of these lesions were successfully reproduced in animal experiment, and it was shown that asbestos neoplasm may occur with or without accompanying asbestosis. Incidence of tumors from crocidolite was nearly three times as high as from chrysotile or amosite. It is possible that different carcinogenic entities are responsible for the causation of lung tumors and mesothelial tumors. Lung tumors seem to depend on the adsorptive capacity of asbestos fibers, allowing other carcinogens (heavy metals, polycyclic hydrocarbons, cigarette smoke) to attain a critical focal concentration. Mesothelial tumors, on the other hand, might arise in response to mechanical irritation by fibers which may become lodged during lymphatic spread. Tissues subject to constant respiratory movement (e.g., pleura or peritoneum) are specifically vulnerable to the latter action.

Asbestos↗

The health impact of cigarette smoking in Taiwan.

This study examined mortality attributed to active and passive smoking in Taiwan for the years 1981 and 1990. It was estimated that 19,283 deaths, representing 19% of the total number of deaths in 1990 (almost one out of five deaths in Taiwan), were smoking related. On an average day, 53 people died as a result of cigarette smoking, including 13 deaths from passive smoking. More men died (14,140 deaths) from smoking-related causes than from all cancer deaths combined (13,161 deaths); 91% of lung cancer and 30% of all cancers were due to smoking. In comparison, the smoking attributable mortality was much less for women, with 5,143 deaths. In addition, almost 5,000 deaths can be attributed to passive smoking every year in Taiwan with more deaths from women than from men. The overall prevalence rates for cigarette smoking has changed little in the last 20 years; approximately 60% for men and 4% for women although a consistent increase of one million new smokers was added every decade. Among younger people, the rate increased substantially, while it dropped 10-15% among middle-aged and older persons. Smoking is the largest single source of health risk in Taiwan. It is crucial that strategies to prevent smoking initiation among young people be developed so that the most vulnerable group can receive immediate attention. Despite the recent aggressive smoking cessation campaign by the Department of Health, much work remains. In order to facilitate this work, it is therefore recommended that the government commit to a goal of smoke-free nation by the year 2010.

Adolescent↗