Chemotherapy for upper gastrointestinal tumours

The aim of this review is to identify current chemotherapy treatment for tumours of the oesophagus, stomach, pancreas, and liver. The role of both neoadjuvant, adjuvant, and palliative chemotherapy regimens will be discussed. This review will be of interest to oncologists in clarifying current issues regarding chemotherapy, and to physicians in other medical specialties, to increase their general understanding of benefits and drawbacks of chemotherapy in this patient group.

Experiences with control of evaporators using extensive vapour bleeding

FOR SUGAR factories with cogeneration plants major changes to the process stations have been undertaken to reduce the consumption of exhaust steam from the turbines and maximise the generated power. In many cases the process steam consumption has been reduced from greater than 52% on cane to ~40% on cane. The main changes have been to install additional evaporation area at the front of the set, operate the pan stages on vapour from No 1 or No 2 effects and undertake juice heating using vapour bleed from evaporators as far down the set as the penultimate stage. Operationally, one of the main challenges has been to develop a control system for the evaporators that addresses the objectives of juice processing rate (throughput) and steam economy, while producing syrup consistently at the required brix and providing an adequate and consistent vapour pressure for the pan stage operations. The cyclic demand for vapour by batch pans causes process disturbances through the evaporator set and these must be regulated in an effective manner to satisfy the above list of objectives for the evaporator station. The impact of the cyclic pan stage vapour demand has been modelled to define the impact on juice rate, steam economy, syrup brix and head space pressures in the evaporators. Experiences with the control schemes used at Pioneer and Rocky Point Mills are discussed. For each factory the paper provides information on (a) the control system used, the philosophy behind the control system and experiences in reaching the current system for control (b) the performance of the control system to handle the disturbances imposed by the pan stage and operate within other constraints of the factory (c) deficiencies in the current system and plans for further improvements. Other processing changes to boost the performance of the evaporators are also discussed.

Postprocedural effects of gastrointestinal endoscopy performed as a day case procedure in children : implications for patient and family education

A prospective design that included a survey tool, nursing care records, and telephone interview was used to determine postprocedural effects experienced by children and families following gastrointestinal endoscopy performed as a day procedure. One hundred twenty-one children attending a pediatric gastroenterology unit for endoscopy under general anesthesia participated in the study. Physical symptoms, day care/school attendance, behavioral issues, and economic factors in the 72 hours post procedure were identified. Over half the children (n = 69, 57%) experienced pain in the hospital post procedure. Pain was reported by 73 children (60%) at home on the day of the procedure, by 55 children (45%) on Day 1 post procedure, and by 37 children (31%) on Day 2 post procedure. The throat was the most common site of pain. Nausea or vomiting was experienced by 37 children (31%) at some time following their procedure but was not associated with procedure type, age, or fasting time. Over half the children (n = 53, 51%) who usually attended day care or school did not attend the day following their procedure. Twenty-four parents (40%) who would normally have worked on the day after the procedure did not attend employment. These findings have been used to improve the preprocedural information and discharge management of patients treated in a pediatric gastroenterology ambulatory setting. © The Society of Gastroenterology Nurses & Associates 2007. All Rights Reserved.

Perinatal nutrition and gastrointestinal disorders : Working Group Report of the Second World Congress of Pediatric Gastroenterology, Hepatology, and Nutrition

Metabolic programming during the perinatal period as a consequence of early nutrition is an emerging area of great interest. This concept is known as the "fetal origins of adult disease" theory (1). Numerous epidemiological studies published over the past 20 years or so have suggested that small body size at birth and during infancy and, more specifically, intrauterine growth retardation are associated later in life with lowered cognitive performance and increased rates of coronary heart disease and its major biological risk factors, ie, raised blood pressure, insulin resistance, coronary artery disease, and abnormalities in lipid metabolism. The molecular mechanisms that govern this phenomenon in humans, however, are unknown and need to be elucidated.

Cloning and gastrointestinal expression of rat hephaestin: Relationship to other iron transport proteins

The membrane-bound ceruloplasmin homolog hephaestin plays a critical role in intestinal iron absorption. The aims of this study were to clone the rat hephaestin gene and to examine its expression in the gastrointestinal tract in relation to other genes encoding iron transport proteins. The rat hephaestin gene was isolated from intestinal mRNA and was found to encode a protein 96% identical to mouse hephaestin. Analysis by ribonuclease protection assay and Western blotting showed that hephaestin was expressed at high levels throughout the small intestine and colon. Immunofluorescence localized the hephaestin protein to the mature villus enterocytes with little or no expression in the crypts. Variations in iron status had a small but nonsignificant effect on hephaestin expression in the duodenum. The high sequence conservation between rat and mouse hephaestin is consistent with this protein playing a central role in intestinal iron absorption, although its precise function remains to be determined.

Behçet's syndrome involving the gastrointestinal tract: a diagnostic dilemma in childhood

Behçet's syndrome is very rare in children, especially those under 10 years of age. Clinical and radiological features are described in 4 children, including 2 under the age of 5 years, with the syndrome. As in other pediatric cases reported, the incomplete form of Behçet's syndrome was present in each case. All 4 patients had oral and genital mucosal effects, arthritis and gastrointestinal and dermatological manifestations. Ophthalmological symptoms occurred in only 1 patient. Radiologically, the 4 cases demonstrated the spectrum of gastrointestinal involvement, from minimal irregularity and thickening of the terminal ileum to gross irregularity and deformity of the terminal ileum and cecum. Because of the difficulty in differentiating Behçet's syndrome from other forms of inflammatory bowel disease it is suggested that in children with gastrointestinal involvement, 3 major criteria be present before the diagnosis of Behçet's syndrome is made.

Effect of changes in hook pattern and size on catch rate, hooking location, injury and bleeding for a number of tropical reef fish species

The Queensland Great Barrier Reef line fishery in Australia is regulated via a range of input and output controls including minimum size limits, daily catch limits and commercial catch quotas. As a result of these measures a substantial proportion of the catch is released or discarded. The fate of these released fish is uncertain, but hook-related mortality can potentially be decreased by using hooks that reduce the rates of injury, bleeding and deep hooking. There is also the potential to reduce the capture of non-target species though gear selectivity. A total of 1053 individual fish representing five target species and three non-target species were caught using six hook types including three hook patterns (non-offset circle, J and offset circle), each in two sizes (small 4/0 or 5/0 and large 8/0). Catch rates for each of the hook patterns and sizes varied between species with no consistent results for target or non-target species. When data for all of the fish species were aggregated there was a trend for larger hooks, J hooks and offset circle hooks to cause a greater number of injuries. Using larger hooks was more likely to result in bleeding, although this trend was not statistically significant. Larger hooks were also more likely to foul-hook fish or hook fish in the eye. There was a reduction in the rates of injuries and bleeding for both target and non-target species when using the smaller hook sizes. For a number of species included in our study the incidence of deep hooking decreased when using non-offset circle hooks, however, these results were not consistent for all species. Our results highlight the variability in hook performance across a range of tropical demersal finfish species. The most obvious conservation benefits for both target and non-target species arise from using smaller sized hooks and non-offset circle hooks. Fishers should be encouraged to use these hook configurations to reduce the potential for post-release mortality of released fish.

Reduced efficacy of macrocyclic lactone treatments in controlling gastrointestinal nematode infections of weaner dairy calves in subtropical eastern Australia.

Faecal Egg Count Reduction Tests (FECRTs) for macrocyclic lactone (ML) and levamisole (LEV) drenches were conducted on two dairy farms in the subtropical, summer rainfall region of eastern Australia to determine if anthelmintic failure contributed to severe gastrointestinal nematode infections observed in weaner calves. Subtropical Cooperia spp. were the dominant nematodes on both farms although significant numbers of Haemonchus placei were also present on Farm 2. On Farm 1, moxidectin pour-on (MXD) drenched at 0.5 mg kg-1 liveweight (LW) reduced the overall Cooperia burden by 82% (95% confidence limits, 37-95%) at day 7 post-drench. As worm burdens increased rapidly in younger animals in the control group (n = 4), levamisole was used as a salvage drench and these calves withdrawn from the trial on animal welfare grounds after sample collection at day 7. Levamisole (LEV) dosed at 6.8 mg kg-1 LW reduced the worm burden in these calves by 100%, 7 days after drenching. On Farm 2, MXD given at 0.5 mg kg-1 LW reduced the faecal worm egg count of cooperioids at day 8 by 96% (71-99%), ivermectin oral (IVM) at 0.2 mg kg-1 LW by 1.6% (-224 to 70%) and LEV oral at 7.1 mg kg-1 LW by 100%. For H. placei the reductions were 98% (85-99.7%) for MXD, 0.7% (-226 to 70%) for IVM and 100% for LEV. This is the first report in Australia of the failure of macrocyclic lactone treatments to control subtropical Cooperia spp. and suspected failure to control H. placei in cattle.

Improving oncolytic adenoviral therapies for gastrointestinal cancers and tumor initiating cells

Although the treatment of most cancers has improved steadily, only few metastatic solid tumors can be cured. Despite responses, refractory clones often emerge and the disease becomes refractory to available treatment modalities. Furthermore, resistance factors are shared between different treatment regimens and therefore loss of response typically occurs rapidly, and there is a tendency for cross-resistance between agents. Therefore, new agents with novel mechanisms of action and lacking cross-resistance to currently available approaches are needed. Modified oncolytic adenoviruses, featuring cancer-celective cell lysis and spread, constitute an interesting drug platform towards the goals of tumor specificity and the implementation of potent multimodal treatment regimens. In this work, we demonstrate the applicability of capsid-modified, transcriptionally targeted oncolytic adenoviruses in targeting gastric, pancreatic and breast cancer. A variety of capsid modified adenoviruses were tested for transductional specificity first in gastric and pancreatic cancer cells and patient tissues and then in mice. Then, oncolytic viruses featuring the same capsid modifications were tested to confirm that successful transductional targeting translates into enhanced oncolytic potential. Capsid modified oncolytic viruses also prolonged the survival of tumor bearing orthotopic models of gastric and pancreatic cancer. Taken together, oncolytic adenoviral gene therapy could be a potent drug for gastric and pancreatic cancer, and its specificity, potency and safety can be modulated by means of capsid modification. We also characterized a new intraperitoneal virus delivery method in benefit for the persistence of gene delivery to intraperitoneal gastric and pancreatic cancer tumors. With a silica implant a steady and sustained virus release to the vicinity of the tumor improved the survival of the orthotopic tumor bearing mice. Furthermore, silica gel-based virus delivery lowered the toxicity mediating proimflammatory cytokine response and production of total and anti-adenovirus neutralizing antibodies (NAbs). On the other hand, silica shielded the virus against pre-excisting NAbs, resulting in a more favourable biodistribution in the preimmunized mice. The silica implant might therefore be of interest in treating intraperitoneally disseminated disease. Cancer stem cells are thought to be resistant to conventional cancer drugs and might play an important role in cancer relapse and the formation of metastasis. Therefore, we examined if transcriptionally modified oncolytic adenoviruses are able to kill these cells. Complete eradication of CD44+CD24-/low putative breast cancer stem cells was seen in vitro, and significant antitumor activity was detected in CD44+CD24-/low –derived tumor bearing mice. Thus, genetically engineered oncolytic adenoviruses have potential in destroying cancer initiating cells, which may have relevance for the elimination of cancer stem cells in humans.

Anthelmintic resistance in ovine gastrointestinal nematodes in inland southern Queensland

Objective To establish the prevalence of anthelmintic resistance in ovine gastrointestinal nematodes in southern Queensland. Design An observational parasitological study using the faecal egg count reduction test. Methods Sheep farms (n = 20) enrolled in this study met the twin criteria of using worm testing for drench decisions and having concerns about anthelmintic efficacy. On each farm, 105 sheep were randomly allocated to one of six treatment groups or an untreated control group. Faecal samples were collected on day 0 and days 10–14 for worm egg counts and larval differentiation. Single- and multi-combination anthelmintics, persistent and non-persistent, oral liquid or capsule, pour-on and injectable formulations were tested. Monepantel was not tested. Farmers also responded to a questionnaire on drenching practices. Results Haemonchus contortus was the predominant species. Efficacy <95% was recorded on 85% of farms for one or more anthelmintics and on 10% of farms for six anthelmintics. No resistance was identified on three farms. The 4-way combination product was efficacious (n = 4 farms). Napthalophos resistance was detected on one farm only. Resistance to levamisole (42% of farms), moxidectin injection (50% of farms) and the closantel/abamectin combination (67% of farms) was identified. Moxidectin oral was efficacious against Trichostrongylus colubriformis, which was predominant on only one farm. Of the farms tested, 55% ran meat breeds, 60% dosed more than the recommended dose rate and 70% always, mostly or when possible practised a ‘drench and move’ strategy. Conclusion This level of anthelmintic resistance in southern Queensland will severely compromise worm control and force increased use of monepantel.

GATA Transcription Factors in Tissue Homeostasis and Pathology of the Gastrointestinal Tract and Liver

Mammalian gastrointestinal tract and liver are self-renewing organs that are able to sustain themselves due to stem cells present in their tissues. In constant, inflammation-related epithelial damage, vigorous activation of stem cells may lead to their uncontrolled proliferation, and further, to cancer. GATA-4, GATA-5, and GATA-6 regulate cell proliferation and differentiation in many mammalian organs. Lack of GATA-4 or GATA-6 leads to defective endodermal development and cell differentiation. GATA-4 and GATA-5 are considered the ones with tumor suppressive functions, whereas GATA-6 is more related to tumor promotion. In the digestive system their roles in inflammation and tumor-related molecular pathways remain unclear. In this study, we examined the GATA-related molecular pathways involved in normal tissue organization and renewal and in inflammation-related epithelial repair in the gastrointestinal tract and liver. The overall purpose of this study was to elucidate the relation of GATA factors to gastrointestinal and hepatic disease pathology and to evaluate their possible clinical significance in tumor biology. The results indicated distinct expression patterns for GATA-4, GATA-5, and GATA-6 in the human and murine gastrointestinal tract and liver, and their involvement in the regulation of intestine-specific genes. GATA-5 was confined to the intestines of suckling mice, suggesting an association with postnatal enzymatic changes. GATA-4 was upregulated in bowel inflammation concomitantly with TGF-β signaling. In gastrointestinal tumors, GATA-4 was restricted to benign neoplasias of the stomach, while GATA-6 was detected especially at the invasive edges of malignant tumors throughout the gut. In the liver, GATA-4 was upregulated in pediatric tumors along with erythropoietin (Epo), which was detected also in the sera of tumor patients. Furthermore, GATA-4 was enhanced in areas of vigorous hepatic regeneration in patients with tyrosinemia type I. These results suggest a central role for GATA-4 in pediatric tumor biology of the liver. To conclude, GATA-4, GATA-5, and GATA-6 are associated with normal gastrointestinal and hepatic development and regeneration. The appearance of GATA-4 along with TGF-β-signaling in the inflammatory bowel suggests a protective role in the response to inflammation-related epithelial destruction. However, in extremely malignant pediatric liver tumors, GATA-4 function is unlikely to be tumor-suppressing, probably due to the nature of the very primitive multipotent tumor cells. GATA-4, along with its possible downstream factor Epo, could be utilized as novel hepatic tumor markers to supplement the present diagnostics. They could also serve a function in future biological therapies for aggressive pediatric tumors.

Novel matrix metalloproteinases in intestinal inflammation and in cancer of the gastrointestinal tract

Matrix metalloproteinases (MMPs) comprise a family of 23 zinc-dependent human endopeptidases that can degrade virtually all components of the extracellular matrix (ECM). They are classified into eight subgroups according to their structure and into six subgroups based on their substrate-specificity. MMPs have been implicated in inflammation, tissue destruction, cell migration, arthritis, vascular remodeling, angiogenesis, and tumor growth and invasion. MMPs are inhibited by their natural inhibitors, tissue inhibitors of metalloproteinases (TIMPs). Different MMPs function in the same tasks depending on the tissue or cancer subtype. I investigated the role of recently discovered MMPs, especially MMPs-19 and -26, in intestinal inflammation, in intestinal and cutaneous wound healing, and in intestinal cancer. Several MMPs and TIMPs were studied to determine their exact location at tissue level and to obtain information on possible functions of MMPs in such tissues and diseases as the healthy intestine, inflammatory bowel disease (IBD), neonatal necrotizing enterocolitis (NEC), pyoderma gangrenosum (PG), and colorectal as well as pancreatic cancers. In latent celiac disease (CD), I attempted to identify markers to predict later onset of CD in children and adolescents. The main methods used were immunohistochemistry, in situ hybridization, and Taqman RT-PCR. My results show that MMP-26 is important for re-epithelialization in intestinal and cutaneous wound healing. In colon and pancreatic cancers, MMP-26 seems to be a marker of invasive potential, although it is not itself expressed at the invasive front. MMP-21 is upregulated in pancreatic cancer and may be associated with tumor differentiation. MMPs-19 and -28 are associated with normal tissue turnover in the intestine, but they disappear in tumor progression as if they were protective markers . MMP-12 is an essential protease in intestinal inflammation and tissue destruction, as seen here in NEC and in previous CD studies. In patients with type 1 diabetes (T1D), MMPs-1, -3, and -12 were upregulated in the intestinal mucosa. Furthermore, MMP-7 was strongly elevated in NEC. In a model of aberrant wound repair, PG, MMPs-8, -9, and 10 and TNFα may promote ECM destruction, while absence of MMP-1 and MMP-26 from keratinocytes retards re-epithelialization. Based on my results, I suggest MMP-26 to be considered a putative marker for poor prognosis in pancreatic and colon cancer. However, since it functions differently in various tissues and tumor subtypes, this use cannot be generalized. Furthermore, MMP-26 is a beneficial marker for wound healing if expressed by migrating epithelial cells. MMP-12 expression in latent CD patients warrants research in a larger patient population to confirm its role as a specific marker for CD in pathologically indistinct cases. MMP-7 should be considered one of the most crucial proteases in NEC-associated tissue destruction; hence, specific inhibitors of this MMP are worth investigating. In PG, TNFα inhibitors are potential therapeutic agents, as shown already in clinical trials. In conclusion, studies of several MMPs in specific diseases and in healthy tissues are needed to elucidate their roles at the tissue level. MMPs and TIMPs are not exclusively destructive or reparative in tissues. They seem to function differently in different tissues. To identify selective MMP inhibitors, we must thoroughly understand the MMP profile (degradome) and their functions in various organs not to interfere with normal reparative functions during wound repair or beneficial host-response effects during cancer initiation and growth.

Gastrointestinal complications after kidney transplantation

The aim of the study was to evaluate gastrointestinal (GI) complications after kidney transplantation in the Finnish population. The adult patients included underwent kidney transplantation at Helsinki University Central Hospital in 1990-2000. Data on GI complications were collected from the Finnish Kidney Transplantation Registry, patient records and from questionnaires sent to patients. Helicobacter pylori IgG and IgA antibodies were measured from 500 patients before kidney transplantation and after a median 6.8-year follow up. Oesophagogastroduodenoscopy with biopsies was performed on 46 kidney transplantation patients suffering from gastroduodenal symptoms and 43 dyspeptic controls for studies of gastroduodenal cytomegalovirus (CMV) infection. Gallbladder ultrasound was performed on 304 patients after a median of 7.4 years post transplantation. Data from these 304 patients were also collected on serum lipids, body mass index and the use of statin medication. Severe GI complications occurred in 147 (10%) of 1515 kidney transplantations, 6% of them fatal after a median of 0.93 years. 51% of the complications occurred during the first post transplantation year, with highest incidence in gastroduodenal ulcers and complications of the colon. Patients with GI complications were older and had more delayed graft function and patients with polycystic kidney disease had more GI complications than the other patients. H.pylori seropositivity rate was 31% and this had no influence on graft or patient survival. 29% of the H.pylori seropositive patients seroreverted without eradication therapy. 74% of kidney transplantation patients had CMV specific matrix protein pp65 or delayed early protein p52 positive findings in the gastroduodenal mucosa, and 53% of the pp65 or p52 positive patients had gastroduodenal erosions without H.pylori findings. After the transplantation 165 (11%) patients developed gallstones. A biliary complication including 1 fatal cholecystitis developed in 15% of the patients with gallstones. 13 (0.9%) patients had pancreatitis. Colon perforations, 31% of them fatal, occurred in 16 (1%) patients. 13 (0.9%) developed a GI malignancy during the follow up. 2 H.pylori seropositive patients developed gastroduodenal malignancies during the follow up. In conclusion, severe GI complications usually occur early after kidney transplantation. Colon perforations are especially serious in kidney transplantation patients and colon diverticulosis and gallstones should be screened and treated before transplantation. When found, H.pylori infection should also be treated in these patients.

Cow’s milk related gastrointestinal symptoms in adults

The purpose of this study was to evaluate subjective food-related gastrointestinal symptoms and their relation to cow’s milk by determining the genotype of adult-type hypolactasia, measuring antibodies against milk protein, and screening the most common cause for secondary hypolactasia, namely coeliac disease. The whole study group comprised 1900 adults who gave a blood sample for the study when they attended a health care centre laboratory for various reasons. Of these 1885 (99%) completed a questionnaire on food-related gastrointestinal symptoms. Study No. I evaluated the prevalence of adult-type hypolactasia and its correlation to self-reported milk induced gastrointestinal symptoms. The testing for hypolactasia was done by determination of the C/T-13910 genotypes of the study subjects. The results show that patients with the C/C-13910 genotype associated with adult type hypolactasia consume less milk than those with C/T-13910 and T/T-13910 genotypes. Study No. II evaluated the prevalence and clinical characteristics of undiagnosed coeliac disease in the whole study population with transglutaminase and endomysium antibodies and their correlation with gastrointestinal symptoms. The prevalence of coeliac disease was 2 %, which is surprisingly high. Serum transglutaminase and endomysium antibodies are valuable tools for recognising an undiagnosed coeliac disease in outpatient clinics. In the study No. III the evaluation of milk protein IgE related hypersensitivity was carried out by stratifying all 756 study subjects with milk related problems and randomly choosing 100 age and sex matched controls with no such symptoms from the rest of the original study group. In the study No. IV 400 serum samples were randomly selected for analyzing milk protein related IgA and IgG antibodies and their correlation to milk related GI-symptoms. The measurement of milk protein IgA, IgE or IgG (studies No. III and IV) did not correlate clearly to milk induced symptoms and gave no clinically significant information; hence their measurement is not encouraged in outpatient clinics. In conclusion, adult type hypolactasia is often considered the reason for gastrointestinal symptoms in adults and determination of the C/T-13910 genotypes is a practical way of diagnosing adult type hypolactasia in an outpatient setting. Undiagnosed coeliac disease, should be actively screened and diagnosed in order to apply a gluten free diet and avoid the GI-symptoms and nutritional deficiencies. Cow’s milk hypersensitivity in the adult population is difficult to diagnose since the mechanism in which it is mediated is still unclear. Measuring of cow’s milk protein specific antibodies IgE, IgA or IgG do not correlate with subjective milk-related GI-symptoms.