Neuroendocrine neoplasms of the GI tract : the role of cytotoxic chemotherapy

Neuroendocrine neoplasms (NENs) comprise a heterogeneous group of neoplasms derived from peptide- and amine-secreting cells of the neuroendocrine system. NENs commonly arise in the GI tract but can arise in most organs of the body. NENs in different organs share many common pathologic features. Although the incidence of NENs is not high, the prevalence is not low because many patients may live relatively long periods without major symptoms from the disease. While many of these tumors lead an indolent clinical course, they constitute a therapeutic challenge when they progress, metastasize and become symptomatic. Treatment requires a multidisciplinary approach including cytotoxic chemotherapy. Almost all clinical trials investigating cytotoxic chemotherapy in NENs are small single-arm studies and guidelines are derived from expert opinion and from extrapolating results from small cell lung cancer studies. This article briefly reviews NENs before focusing on reviewing data on the role of cytotoxic chemotherapy studies in NENs.

Pain during mammography: implications for breast screening programmes

Pain experienced during mammography can deter women from attending for breast cancer screening. Review of the current literature on pain experienced during mammography reveals three main areas of interest: reports of the frequency of pain, identification of predictors of pain and strategies for responding to pain. Implications of this literature for breast screening programmes include the need for appropriate measurements of pain during mammography that are valid for screening populations, a further understanding of organizational factors involved in screening programmes that may be predictors of pain and for the development of valid strategies for responding to pain within breast screening programmes.

Induction of epithelial to mesenchymal transition in PMC42-LA human breast carcinoma cells by carcinoma-associated fibroblast secreted factors

Background
Breast carcinoma is accompanied by changes in the acellular and cellular components of the microenvironment, the latter typified by a switch from fibroblasts to myofibroblasts.


Methods
We utilised conditioned media cultures, Western blot analysis and immunocytochemistry to investigate the differential effects of normal mammary fibroblasts (NMFs) and mammary cancer-associated fibroblasts (CAFs) on the phenotype and behaviour of PMC42-LA breast cancer cells. NMFs were obtained from a mammary gland at reduction mammoplasty, and CAFs from a mammary carcinoma after resection.


Results
We found greater expression of myofibroblastic markers in CAFs than in NMFs. Medium from both CAFs and NMFs induced novel expression of α-smooth muscle actin and cytokeratin-14 in PMC42-LA organoids. However, although conditioned media from NMFs resulted in distribution of vimentin-positive cells to the periphery of PMC42-LA organoids, this was not seen with CAF-conditioned medium. Upregulation of vimentin was accompanied by a mis-localization of E-cadherin, suggesting a loss of adhesive function. This was confirmed by visualizing the change in active β-catenin, localized to the cell junctions in control cells/cells in NMF-conditioned medium, to inactive β-catenin, localized to nuclei and cytoplasm in cells in CAF-conditioned medium.


Conclusion
We found no significant difference between the influences of NMFs and CAFs on PMC42-LA cell proliferation, viability, or apoptosis; significantly, we demonstrated a role for CAFs, but not for NMFs, in increasing the migratory ability of PMC42-LA cells. By concentrating NMF-conditioned media, we demonstrated the presence of factor(s) that induce epithelial-mesenchymal transition in NMF-conditioned media that are present at higher levels in CAF-conditioned media. Our in vitro results are consistent with observations in vivo showing that alterations in stroma influence the phenotype and behaviour of surrounding cells and provide evidence for a role for CAFs in stimulating cancer progression via an epithelial-mesenchymal transition. These findings have implications for our understanding of the roles of signalling between epithelial and stromal cells in the development and progression of mammary carcinoma.

α-linolenic acid and the risk of prostate cancer. What is the evidence?

Purpose
Several studies have examined the association between polyunsaturated fatty acids and prostate cancer risk. We evaluated the evidence on the association between the essential polyunsaturated fatty acid, known as α-linolenic acid, and the risk of prostate cancer in humans.
Materials and Methods
We comprehensively reviewed published studies on the association between α-linolenic acid and the risk of prostate cancer using MEDLINE.
Results
A number of studies have shown a positive association between dietary, plasma or red blood cell levels of α-linolenic acid and prostate cancer. Other studies have demonstrated either no association or a negative association. The limitations of these studies include the assumption that dietary or plasma α-linolenic acid levels are positively associated with prostate tissue α-linolenic acid levels, and measurement errors of dietary, plasma and red blood cell α-linolenic acid levels.
Conclusions
More research is needed in this area before it can be concluded that there is an association between α-linolenic acid and prostate cancer.

Burden of disease and injury in Aboriginal and non-Aboriginal populations in the Northern Territory

Objective:
To quantify the burden of disease and injury for the Aboriginal and non-Aboriginal populations in the Northern Territory.

Design and setting:
Analysis of Northern Territory data for 1 January 1994 to 30 December 1998 from multiple sources.

Main outcome measures:
Disability-adjusted life-years (DALYs), by age, sex, cause and Aboriginality.

Results:
Cardiovascular disease was the leading contributor (14.9%) to the total burden of disease and injury in the NT, followed by mental disorders (14.5%) and malignant neoplasms (11.2%). There was also a substantial contribution from unintentional injury (10.4%) and intentional injury (4.9%). Overall, the NT Aboriginal population had a rate of burden of disease 2.5 times higher than the non-Aboriginal population; in the 35-54-year age group their DALY rate was 4.1 times higher. The leading causes of disease burden were cardiovascular disease for both Aboriginal men (19.1%) and women (15.7%) and mental disorders for both non-Aboriginal men (16.7%) and women (22.3%).

Conclusions:
A comprehensive assessment of fatal and non-fatal conditions is important in describing differentials in health status of the NT population. Our study provides comparative data to identify health priorities and facilitate a more equitable distribution of health funding.

Television viewing time and weight gain in colorectal cancer survivors : a prospective population-based study

Objective To investigate the prospective relationships between television viewing time and weight gain in the 3 years following colorectal cancer diagnosis for 1,867 colorectal cancer survivors (body mass index (BMI) ≥ 18.5 kg/m2).

Methods BMI, television viewing time, physical activity, and socio-demographic and clinical covariates were assessed at baseline (5 months), 24 months and 36 months post-diagnosis. Multiple linear regression was used to study independent associations between baseline television viewing time and BMI at 24 and 36 months post-diagnosis.

Results At both follow-up time points, there was a significant increase in mean BMI for participants reporting ≥5 h/day of television viewing compared to those watching <3 h/day at baseline (24 months: 0.72 kg/m2 (0.31, 1.12), p < 0.001; 36 months: 0.61 kg/m2 (0.14, 1.07), p = 0.01), independent of baseline BMI, gender, age, education, marital status, smoking, cancer site, cancer disease stage, treatment mode and co-morbidities. Additional adjustment for baseline physical activity did not change results.

Conclusions These findings suggest that a greater emphasis on decreasing television viewing time could help reduce weight gain among colorectal cancer survivors. This, in turn, could contribute to a risk reduction for co-morbid conditions such as type 2 diabetes and cardiovascular disease.

Studies on dietary fibre : analysis, epidemiological and physiological aspects

This thesis involves an investigation in three areas; first, a study of an enzymatic-gravimetric method for the analysis of dietary fibre; second, a survey of dietary fibre intake in an area of a developing country, and finally, some observations on the functional aspects of gel-forming dietary fibre in the rat. A simple and rapid enzymatic-gravimetric assay for both soluble and insoluble dietary fibre has been critically investigated. Reference samples were also analysed by a more comprehensive, enzymatic gas chromatographic method to allow testing of the relative accuracy of the enzymatic-gravimetric method. The enzymatic-gravimetric method was found to be highly reproducible but gave a slightly higher value for total dietary fibre than the more comprehensive method. This discrepancy is probably due to the presence of small quantities of resistant starch and protein residue which are recovered in the enzymatic-gravimetric method. In the enzymatic-gas chromatographic method, protein residue is not measured, and resistant starch is estimated, but not counted as dietary fibre. The enzymatic-gravimetric method was applied to the analysis of foods commonly consumed in the Padang region of West Sumatra in Indonesia, in order to estimate dietary fibre intake in the region. Daily intakes of usual foods were estimated by use of a 24-hour recall procedure aided by food photographs to assist in the estimation of portion size. Samples of approximately 60 of the most commonly consumed foods were collected and analysed for dietary fibre. These appear to be the first data which report values for dietary fibre in Indonesion foods and they represent a significant improvement upon the existing data on crude fibre content. Knowledge of the amounts of foods usually consumed and their dietary fibre content allowed an estimation of usual intakes of dietary fibre. Fibre intake was found to be lower than in the developing countries of Africa and was comparable to intakes measured in the U.K. This is the first study to show that in this part of South East Asia, a developing country area using polished rice as a staple food, dietary fibre intakes are as low as in Western countries. Low intakes of fibre are believed to be related to the prevalence of a range of diseases and, in this study, preliminary data on the rates of non-infective, chronic diseases were collected from the two main hospitals in West Sumatra. Chronic, non-infectious diseases such as inguinal hernia, appendicitis, haemorrhoids, diabetes mellitus, hypertension and malignant neoplasms of the rectum are relatively frequent in West Sumatra. While no firm conclusions can be drawn from these data, they do show the possibility of a relationship between low intakes of dietary fibre and the prevalence of these diseases, and suggest that further investigation is necessary. Some observations were made of the effect of gel-forming dietary fibre on stomach emptying and intestinal transit rate in the rat. Xanthan gum was added to iso-osmotic solutions to produce increased viscosity and phenol sulphonphthalein (phenol red) was used as a non-absorbable marker. Gavage feeding of solutions with a range of viscosities was used to study the effect of viscosity on the rate of stomach emptying and intestinal transit. Increased viscosity was observed to slow gastro-intestinal transit and this provides one mechanism by which dietary fibre of the gel-forming type ray improve glucose tolerance.

Regressive logistic and proportional hazards disease models for within-family analyses of measured genotypes, with application to a CYP17 polymorphism and breast cancer

Various statistical methods have been proposed to evaluate associations between measured genetic variants and disease, including some using family designs. For breast cancer and rare variants, we applied a modified segregation analysis method that uses the population cancer incidence and population-based case families in which a mutation is known to be segregating. Here we extend the method to a common polymorphism, and use a regressive logistic approach to model familial aggregation by conditioning each individual on their mother's breast cancer history. We considered three models: 1) class A regressive logistic model; 2) age-of-onset regressive logistic model; and 3) proportional hazards familial model. Maximum likelihood estimates were calculated using the software MENDEL. We applied these methods to data from the Australian Breast Cancer Family Study on the CYP17 5UTR TC MspA1 polymorphism measured for 1,447 case probands, 787 controls, and 213 relatives of case probands found to have the CC genotype. Breast cancer data for first- and second-degree relatives of case probands were used. The three methods gave consistent estimates. The best-fitting model involved a recessive inheritance, with homozygotes being at an increased risk of 47% (95% CI, 28-68%). The cumulative risk of the disease up to age 70 years was estimated to be 10% or 22% for a CYP17 homozygote whose mother was unaffected or affected, respectively. This analytical approach is well-suited to the data that arise from population-based case-control-family studies, in which cases, controls and relatives are studied, and genotype is measured for some but not all subjects.

Genome - wide association study identifies novel breast cancer susceptibility loci

Breast cancer exhibits familial aggregation, consistent with variation in genetic susceptibility to the disease. Known susceptibility genes account for less than 25% of the familial risk of breast cancer, and the residual genetic variance is likely to be due to variants conferring more moderate risks. To identify further susceptibility alleles, we conducted a two-stage genome-wide association study in 4,398 breast cancer cases and 4,316 controls, followed by a third stage in which 30 single nucleotide polymorphisms (SNPs) were tested for confirmation in 21,860 cases and 22,578 controls from 22 studies. We used 227,876 SNPs that were estimated to correlate with 77% of known common SNPs in Europeans at r² > 0.5. SNPs in five novel independent loci exhibited strong and consistent evidence of association with breast cancer (P < 10^-7). Four of these contain plausible causative genes (FGFR2, TNRC9, MAP3K1 and LSP1). At the second stage, 1,792 SNPs were significant at the P < 0.05 level compared with an estimated 1,343 that would be expected by chance, indicating that many additional common susceptibility alleles may be identifiable by this approach.

Recent advances on the roles of NO in cancer and chronic inflammatory disorders

Nitric oxide (NO) is a short-life molecule produced by the enzyme known as the nitric oxide synthase (NOS), in a reaction that converts arginine and oxygen into citrulline and NO. There are three isoforms of the enzyme: neuronal NOS (nNOS, also called NOS1), inducible NOS (iNOS or NOS2), and endothelial NOS (eNOS or NOS3). It is now known that each of these isoforms may be expressed in a variety of tissues and cell types. This paper is a review of the current knowledge of various functions of NO in diseases. We discuss in more detail its role in Cancer, the role of NO in myocardial pathophysiology, in central nervous system (CNS) pathologies. Other diseases such as inflammation, asthma, in chronic liver diseases, inflammatory bowel disease (IBD), arthritis, are also discussed. This review also covers the role of NO in cardiovascular, central nervous, pancreas, lung, gut, kidney, myoskeletal and chronic liver diseases (CLD). The ubiquitous role that the simple gas nitric oxide plays in the body, from maintaining vascular homeostasis and fighting infections to acting as a neurotransmitter and its role in cancer, has spurred a lot of interest among researchers all over the world. Nitric oxide plays an important role in the physiologic modulation of coronary artery tone and myocardial function. Nitric oxide from iNOS appears to be a key mediator of such glial-induced neuronal death. The high sensitivity of neurons to NO is partly due to NO causing inhibition of respiration, rapid glutamate release from both astrocytes and neurons, and subsequent excitotoxic death of the neurons.

Obstructive jaundice secondary to neuroendocrine tumour in a patient with von Recklinghausen's disease

Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder, with variable clinical manifestations and unpredictable course, associated with an increased incidence of various tumours. Plexiform neurofibromas are hallmark lesions of NF1; they are slow-growing tumours, which account for substantial morbidity, including disfigurement and functional impairment, and may even be life-threatening. Neuroendocrine tumours (NETs), a rare diverse group of neoplasms, are occasionally associated with neurofibromatosis. Pancreatic NETs are tumours with an incidence of less than 1/100 000 population/year and complex patterns of behaviour, which often need complicated strategies for optimal management. We present the case of a young adult with NF1, having a unique concurrence of plexiform neurofibroma involving the liver with an ampullary NET, and we discuss step by step the management in a specialist centre.

Immune thrombocytopenic purpura (ITP) and breast cancer. Does adjuvant therapy for breast cancer improve platelet counts in ITP?

Although both breast cancer and immune thrombocytopenic purpura (ITP) are common conditions, the simultaneous coexistence of these two diseases is rare. ITP is an autoimmune disease in which the presence of autoantibodies against platelets results in splenic sequestration and thrombocytopenia that may be associated with lymphoid neoplasms [1]. Except for an observational case series of 10 patients [2], only a few individual case reports of ITP coinciding with breast cancer have been reported [3–8]. We are reporting two cases with simultaneous confirmed ITP and breast cancer. The platelet counts in both women have improved during adjuvant breast cancer chemotherapy.

Neuro-oncology : late neurocognitive decline after radiotherapy for low-grade glioma

Radiotherapy is administered to most patients with low-grade glioma. A well-designed, retrospective study assessed neurocognitive function in patients who had received radiotherapy for low-grade gliomas versus those who had not. Cognitive function did not differ markedly between groups after 6 years, but by 12 years this feature was worse in the group that received radiotherapy.

Neurological complication of systemic cancer

Neurological complications of systemic cancer—those arising outside the nervous system—can be distressing, disabling, and sometimes fatal. Diagnosis is often difficult because different neurological disorders may present with similar signs and symptoms. Furthermore, comorbid neurological illnesses, common in elderly patients with cancer, can complicate diagnosis. Early diagnosis and aggressive treatment can improve neurological symptoms and can substantially enhance a patient's quality of life. We approach the problem of neurological complications of systemic cancer as would a neurologist: first by identifying the anatomical area or areas that are affected (ie, brain, spinal cord, peripheral nerve), then by evaluating the diagnostic approach, considering the symptoms and signs and including appropriate laboratory tests, and finally, by recommending treatment. We focus on disorders that are difficult to diagnose, need neurological consultation, and for which effective treatments exist.

Cost-effectiveness of mammographic screening in Australia

The purpose of this research was to estimate the cost-effectiveness of mammographic screening to supplement the results of the National Evaluation of Breast Cancer Screening which identified the mortality benefit as the most sensitive parameter. This appraisal used a different computer model, MISCAN, which models the effects of introducing a national screening program into a previously unscreened population, rather than basing estimates on the assumption of a fully established program. For the 40 to 49 age group a mortality reduction of 8 per cent was assumed, rather than the 30 per cent estimate utilised in the National Evaluation. The revised estimate is based on the two Swedish trials (Malmo and WE). New estimates for treatment costs were also incorporated into the MISCAN model. The cost-effectiveness of the policy recommended in the National Evaluation Report, $11 000 per life year saved with two-yearly screening of women over 40, is estimated by the MISCAN model to be $20 300. These differences arise partly from the difference in mortality effects for the 40 to 49 age group, but also from differences inherent in the steady-state and dynamic population approaches to modelling premature deaths averted. The MISCAN results confirm that screening for women over 50 is more cost-effective than screening women under 50. Screening all women aged 50 to 69 every two to three years is reasonable value for money. For women aged 40 to 49 the mortality benefit and cost-effectiveness is less clear, and it would be prudent to allow screening in this group until further evidence is available.