Inflammatory pseudotumor of the alimentary tract: clinical and surgical experience.

BACKGROUND/PURPOSE: Initially described in 1937, inflammatory pseudotumor (IPT) inflammatory myofibroblastic tumor (IMT) or plasma cell granulomas are synonymous for an inflammatory solid tumor that contains spindle cells, myofibroblasts, plasma cells, and histocytes. Common sites of presentation include lung, mesentary, liver, and spleen; intestinal presentations are rare, and the etiology remains obscure. This report details the clinical and surgical experiences in 4 children with alimentary tract IPT at a single institution. METHODS: A retrospective chart review was conducted of pediatric patients with the pathologic diagnosis of IPT. RESULTS: Between 1990 and 1999, 4 patients (4 girls, ages 5 to 15 years) were identified with gastrointestinal tract origins of IPT. Symptoms at presentation included anemia (n = 4), intermittent abdominal pain (n = 3), fever (n = 3), weight loss (n = 2), diarrhea (n = 2), dysphagia (n = 1). Two patients had comorbid conditions of juvenile rheumatoid arthritis and mature B cell lymphoma. Three of 4 patients had elevated sedimentation rates. The sites of origin were the gastroesophageal junction, the colon, the rectum, and the appendix, with the referral diagnosis achalasia, perforated appendix, inflammatory bowel disease, and recurrent lymphoma, respectively. All were treated with aggressive surgical resection, and 3 girls have had no recurrences since the initial surgery. One patient had 3 recurrences within 8 months of presentation; she remains disease free 8 years later. CONCLUSIONS: IPT, although rare in the gastrointestinal tract, mimics more common problems. Successful surgical management is possible even in cases of multiple recurrences.

Patterns of childhood cancer among siblings.

The National Registry of Childhood Tumours contains over 51000 records of children born in Great Britain who developed cancer under the age of 15 years. Patterns of childhood cancer among families containing more than one child with cancer have been studied. A total of 225 "sib pair' families have been ascertained from interviews with parents of affected children, from hospital and general practitioner records and from manual and computer searches of names and addresses of patients. A number of special groups have been identified, including those with a known genetic aetiology such as retinoblastoma, twins and families with three or more affected children. A further 148 families not in any of the above groups contain two children with cancer: in 46 families the children had tumours of the same type, most commonly leukaemia. Some of the families are examples of the Li-Fraumeni syndrome; some are associated with other conditions, including Down's syndrome. There is clearly a genetic element in the aetiology of cancer in some families discussed here; shared exposure to environmental causes may account for others and some will be simply due to chance.

Induction and subcellular localization of two major stress proteins in response to copper in the fathead minnow Pimephales promelas.

In the present study we characterize the stress response induced by copper in the fathead minnow, Pimephales promelas. The fathead minnow epithelial cell line ATCC CCL 42 was used to examine the induced synthesis and subcellular localization of the two major stress proteins, stress 70 and cpn60. Western blot analysis demonstrated increased stress70 in cells exposed to 400 and 500 microM Cu. Two-dimensional analysis revealed three isoforms of stress70, one of 70 kDa and two of 72 kDa, at the highest Cu concentration. Chaperonin60 abundance did not change over the same range of Cu concentrations. Indirect immunofluorescence microscopy revealed that stress70 localized in the cytoplasm, particularly in the paranuclear region. Chaperonin60 was localized in mitochondria. Further, when we examined the stress response elicited by Cu in fathead minnow larvae in vivo, we found that Cu induced the stress response at nominal Cu concentrations that were more than an order of magnitude lower that in the cell culture. This disparity between the concentration of Cu, which induced the stress response in cells in culture and in vivo, may be the result of differences in Cu complexation that alter its availability, uptake and toxicity.

Copper inhibits the induction of stress protein synthesis by elevated temperatures in embryos of the sea urchin Strongylocentrus purpuratus.

A major component of the cellular stress response entails the induced synthesis of a suite of stress proteins under environmentally adverse conditions that functions to protect organisms from environmentally induced damage. Here, we examined induction of the stress response in the embryos of the sea urchin Strongylocentrus purpuratus under a combination of environmentally realistic conditions. First, we examined the response elicited over a range of free cupric ion activities, (Cu2+), using a metal buffer system to control trace metal speciation. We observed no pronounced differences in translational patterns in embryos exposed to free cupric ion activities, (Cu2+), of 10(-13)-10(-9) M by metabolic labeling, 1-dimensional electrophoresis and autoradiography. Further separation by 2-dimensional electrophoresis, however, revealed electrophoretically discernable variants of several groups of proteins at the higher Cu concentrations and the synthesis of a 60 kDa protein at (Cu2+) of 10(-9) M. In addition, there were differences in the stress response induced by heat-shock treatment in embryos cultured in seawater with different Cu concentrations; radiolabel was incorporated into a greater number of cellular proteins in embryos at lower (Cu2+) and the induced synthesis of stress proteins was greater. These data suggest that elevations in (Cu2+) impair the ability of the embryos to mount the stress response upon exposure to elevated temperatures and that Cu may alter critical developmental pathways by inhibiting the synthesis of regulatory proteins. Such effects on gene expression can result in manifestations that have been widely attributed to Cu toxicity, including developmental abnormalities and increased sensitivity to environmental extremes. We suggest that the particular sensitivity of embryonic systems upon exposure to multiple stressors may be a consequence of these mechanisms.

Tissue-specific differences in accumulation of stress proteins in Mytilus edulis exposed to a range of copper concentrations.

This study examines the expression and accumulation of two major stress proteins, stress70 and chaperonin60 (cpn60), in the gill and mantle of blue mussels, Mytilus edulis, which were exposed to a range of Cu concentrations for 7 days. Scope-for-growth (SFG), mortality, and Cu accumulation in gill and mantle tissue were also measured to monitor the physiological effects of Cu exposure in the organisms. In general Cu accumulated to a greater extent in gill relative to mantle tissue. A reduction of SFG index and increased mortality was also observed at the two highest Cu concentrations. We found no significant differences between the two tissues in the expression of cpn60 and stress70 for mussels exposed to Cu ranging from 0 to 10 micrograms/liter Cu (cpn60) and 0 to 32 micrograms/liter Cu (stress70) in sea-water. However, differences in the stress response were observed between the gill and the mantle tissue of mussels exposed to higher Cu concentrations. Chaperonin concentrations were greater than an order of magnitude higher in the gill than in the mantle for these mussels. Further, although the accumulation of stress70 was similar between the two tissues, two additional proteins reacted with antibody to stress70 in gill, but not mantle tissue, of mussels exposed to 100 micrograms/litter Cu. This study suggests that the physiological processes involved in contaminant uptake, distribution, and detoxification may affect the tissue-level expression of the stress response in multicellular organisms. Further, the intensity of the stress response and relative concentrations of chaperonin and stress70 among tissues may help identify tissues which are the most vulnerable to damage caused by a particular environmental stressor.

Heat-inducible proteins that react with antibodies to chaperonin60 are localized in the nucleus of a fish cell line.

We report in the present paper that proteins which react with a polyclonal antibody (pAb) raised against the heat-shock protein chaperonin60 (cpn60) were revealed by indirect immunofluorescence in the nucleus of a fish (fathead minnow, Pimephales promelas) cell line after heat-shock. This immunoreactive cpn60 associated with the nucleolus and with discrete foci. An increased abundance of two nuclear proteins of approx. 57 and 42 kDa, present in approximately equal amounts, was detected by Western blotting using an anti-cpn60 pAb as a probe during the same time period that cpn60 was revealed in the nucleus. These proteins also reacted with a monoclonal antibody (mAb) against human cpn60 but did not react with an mAb against the cytoplasmic chaperonin, TCP1. The kinetics of translocation and pattern of nuclear localization of this immunoreactive cpn60 differed from that of stress70, another major family of heatshock proteins. We suggest that these nuclear immunoreactive cpn60 proteins are members of the cpn60 family and that they play a chaperone role in folding and assembly of proteins in the nucleus which is distinct from that of stress70.

Stress proteins as biomarkers of contaminant exposure in archived environmental samples.

Stress proteins have been shown to provide information on the biological impact of toxic chemicals to organisms and to predict adverse consequences of that exposure. In this study we have examined the accumulation to two major stress proteins, hsp60 and hsp70, in banked samples to determine if they accumulate at high levels in organisms exposed to contaminants in their environment. We found that relative to laboratory controls, stress proteins concentrations were elevated in mussels and fish tissue collected as part of the NOAA National Status and Trends Program. Sediment and water chemistry from the stations where these organisms were collected and data on contaminant body burdens of these same organisms indicated that they had been exposed to contaminants for long durations in their environment. This study suggests that stress protein accumulation may provide a method for quantifying adverse biological impacts of exposure to chemicals in the environment when examined in wild populations from contaminated sites. This approach may also prove valuable in retrospective studies when used in banked specimens which have been collected as part of a large scale surveillance monitoring programs.

Stress proteins in aquatic organisms: an environmental perspective.

The cellular stress response protects organisms from damage resulting from exposure to a wide variety of stressors, including elevated temperatures, ultraviolet (UV) light, trace metals, and xenobiotics. The stress response entails the rapid synthesis of a suite of proteins referred to as stress proteins, or heat-shock proteins, upon exposure to adverse environmental conditions. These proteins are highly conserved and have been found in organisms as diverse as bacteria, molluscs, and humans. In this review, we discuss the stress response in aquatic organisms from an environmental perspective. Our current understanding of the cellular functions of stress proteins is examined within the context of their role in repair and protection from environmentally induced damage, acquired tolerance, and environmental adaptation. The tissue specificity of the response and its significance relative to target organ toxicity also are addressed. In addition, the usefulness of using the stress response as a diagnostic in environmental toxicology is evaluated. From the studies discussed in this review, it is apparent that stress proteins are involved in organismal adaptation to both natural and anthropogenic environmental stress, and that further research using this focus will make important contributions to both environmental physiology and ecotoxicology.

Patterns of risk of hereditary retinoblastoma and applications to genetic counselling.

A registry including information about nearly 1,600 cases of retinoblastoma diagnosed in Britain has been created at the Childhood Cancer Research Group. Cases have been classified as 'old germ cell mutation', 'new germ cell mutation' or 'sporadic non-hereditary'. For a population-based group of 918 cases diagnosed between 1962 and 1985 we have calculated the proportions of unilateral/bilateral and hereditary/non-hereditary cases. Bilateral cases represent 40% of the total number over this period; the proportion known to be hereditary is 44%, a higher proportion than has been reported elsewhere. By following up selected groups of cases, an estimate has been made of the proportions of siblings of retinoblastoma patients and offspring of survivors from retinoblastoma who are themselves affected with the disease. Where there is no previous family history, the risk for siblings of retinoblastoma patients of developing the disease is approximately 2% if the disease in the affected child is bilateral and 1% if it is unilateral, assuming that there are no other siblings; if there are unaffected siblings the risks for subsequent children are lower. Children of patients with hereditary retinoblastoma have a one in two chance of carrying the germ cell mutation and for those who are carriers the probability of developing retinoblastoma is very close to the accepted figure of 90% if the parents have bilateral retinoblastoma but probably less if they have the unilateral form. For children of patients not known to be carriers, the probability of developing retinoblastoma is estimated to be about 1%, considerably lower than the previously accepted figure of about 5%. Retinoblastoma kindreds consist mainly of bilateral cases but there is evidence that some kindreds have a high proportion of unilateral cases. The ways in which these findings may be used in conjunction with modern techniques of molecular biology for prenatal and postnatal genetic counselling are discussed.

Non-ocular cancer in relatives of retinoblastoma patients.

A series of 1,438 parents and 2,663 other relatives of retinoblastoma patients have been followed up to ascertain the incidence among them of non-ocular cancer. Among 117 of these relatives who were known carriers of the mutation of the retinoblastoma gene 23 cases of non-ocular cancer developed during the follow-up period of the study. This compares with an expected number of 2.3, a relative risk of 9.9. A total of 25 deaths among these carriers included 21 from non-ocular cancer; the expected number was 1.8, a relative risk of 11.6. Relatives who are carriers are about 15 times more likely to die from lung cancer than the general population. Previous findings of an association of melanoma and bladder cancer with retinoblastoma are borne out in this study. The incidence of non-ocular cancer among relatives of hereditary cases who are not definitely known to be carriers shows an excess risk of 1.6: it is concluded that a proportion of these relatives are in fact carriers of the mutated retinoblastoma gene. For relatives who are not gene carriers there appears to be no excess risk of developing cancer. Carriers relatives who are not themselves affected with retinoblastoma may be inherently less liable than affected carriers to the further genetic changes which lead to the development of both retinoblastoma and subsequent non-ocular cancer.

Retinoblastoma in Great Britain 1969-80: incidence, treatment, and survival.

Patients with retinoblastoma diagnosed from 1969 to 1980 have been followed up for periods of up to 17 years. Data from a previous study of patients diagnosed from 1962 to 1968 have been included for analysis of incidence and second primary tumours, and for study of trends in treatment. The registration rate in Britain (which may be about 10% less than the true incidence) is about one in 23,000 live births, approximately 40% of cases being known to be genetic. There is no apparent trend in incidence during the period covered by these two studies. The three-year survival rate in 88%. Patients with bilateral tumours have a better survival rate than those with unilateral tumours for the first few years, but their long-term survival rate is worse because of later deaths from ectopic intracranial retinoblastoma or second primary neoplasms. Older children tend to have a worse prognosis, which is related to the fact that their tumours are diagnosed at a more advanced stage. There is a significantly higher survival rate for boys than for girls; this is partly accounted for by difference in age and stage at diagnosis between the sexes. Children referred to units specialising in the treatment of retinoblastoma have a higher three-year survival rate than those treated at other hospitals. Comparing methods of treatment between the periods 1962-8 and 1969-80, we find there has been a trend towards more conservative treatment. The use of chemotherapy is now usually reserved for recurrences and metastases and for palliative treatment in terminal retinoblastoma.

Second primary neoplasms in patients with retinoblastoma.

In a series of 882 retinoblastoma patients, 384 known to have the genetic form of the disease and 498 others, 30 patients developed second primary neoplasms. The spectrum of these second neoplasms is discussed in relation to the forms of treatment used for the retinoblastoma. Cumulative incidence rates of second tumours in the whole series are 2.0% at 12 years after diagnosis and 4.2% after 18 years. For patients with the genetic form of retinoblastoma the cumulative incidence rate after 18 years is 8.4% for all second neoplasms and 6.0% for osteosarcomas alone. The inherent risk among survivors from genetic retinoblastoma of developing an osteosarcoma, excluding all possible effects of treatment, is estimated to be 2.2% after 18 years. Within the field of radiation treatment the cumulative incidence rate for all second neoplasms after 18 years is 6.6% and for osteosarcomas alone 3.7%. There is some evidence that patients with genetic retinoblastoma are particularly sensitive to the carcinogenic effects of radiation. The results also suggest that the use of cyclophosphamide may increase the risk of second primary neoplasms in patients with genetic retinoblastoma. The incidence rates of second primary neoplasms in retinoblastoma survivors reported here are lower than those quoted for previously published series. Evidence from this and other papers strongly suggests an association between retinoblastoma and malignant melanoma.

Relationships between free cadmium ion activity in seawater, cadmium accumulation and subcellular distribution, and growth in polychaetes.

We have examined the relationships between Cd ion activity [Cd2+], in seawater, Cd accumulation and subcellular distribution and growth in the polychaete Neanthes arenaceodentata. Organisms were exposed for 3 weeks to a range of [Cd2+] in a Cd-chelate buffer system. Cadmium accumulation and growth were monitored weekly for each exposure group and subcellular Cd distributions were determined at the end of the 3-week period. We found Cd associated with all of the subcellular fractions except the very low molecular weight ligands. Total Cd accumulation was greatest at day 7 and decreased over time in all but the highest [Cd2+] where it remained constant. For each point in time, however, there was a linear relationship between total Cd and [Cd2+] in seawater. Linear relationships were also observed between [Cd2+] and Cd loading in each subcellular ligand pool. Specific growth rates varied with both [Cd2+] and time in a nonlinear manner.

Free cupric ion activity in seawater: effects on metallothionein and growth in crab larvae.

Crab zoeae (Rhithropanopeus harrisii) were exposed during their development opment to a range of free cupric ion activities regulated in seawater by use of a copper chelate buffer system. Most cytosolic copper was found to be associated with metallothionein. Copper-thionein could be related to free cupric ion activity, and a shift in copper-thionein accumulation was correlated with inhibition of larval growth. These data reveal predictable relations between cupric ion activity in seawater and processes at the cellular and organismic levels.

Occupations of fathers of children dying from neoplasms.

It has been suggested in a number of recent reports that there is a possible relationship between parental occupation and malignant disease in children. A proportional mortality analysis relating deaths among children in England and Wales in 1959-63 and 1970-72 to occupation of father as stated on the child's death certificate has not shown any convincing evidence for such associations. Earlier papers published on the subject are reviewed. Although there is some slight evidence for associations between childhood tumours and certain parental occupations there is little consistency between the results reported by different authors. A previously reported association between higher social class and deaths from neoplasms was found also in this study. The explanation for this finding is unknown, and it remains possible that it is an artefact.

Childhood cancer and drugs in pregnancy.

A study was carried out on 11 169 matched case-control pairs of children aged up to 15 years included in the Oxford Survey of Childhood Cancers to see whether an association exists between cancer in children and drugs given to their mothers during pregnancy. The mothers of children who developed cancer reported about 25% more illnesses during pregnancy than mothers of healthy control children. Two specific illnesses, pulmonary tuberculosis and epilepsy, were investigated. For these there was a higher than average case-control excess of reports and there had been a suggestion that the drugs used in treatment, isoniazid and phenytoin, might be carcinogenic. The results of this investigation provide no real evidence for any association between the drugs taken by the mothers during pregnancy and subsequent cancer in the child.

Retinoblastoma: a study of natural history and prognosis of 268 cases.

The natural history and prognosis of retinoblastoma were analysed using data relating to the 268 cases registered during 1962-8 in England, Scotland, and Wales. The children were followed up for a minimum of four years; the proportion surviving for four years was 86%. The most important factors affecting survival rate were the stage of the tumour at diagnosis and the hospital of treatment. Of children surviving for three years after treatment only three died during the subsequent period of follow-up, which varied from one to seven years. Among children with retinoblastoma treated between 1949 and 1968 nine died between seven and 13 years later of other cancers: seven from osteosarcomas, one from angiosarcoma, and one from fibrosarcoma.

Group characteristics of children with cerebral and spinal cord tumours.

A study of 2072 children who developed cerebral or spinal cord tumours of varying degrees of malignancy before 15 years of age has shown that there is equally good representation of fatal and non-fatal cases in official registrations. Attack rates are higher for boys than girls and the prognosis is better for girls than boys. The risk of an early death is negatively correlated with age at diagnosis, and the risk of a late death shows the opposite relationship. These observations and a relatively high incidence of hindbrain tumours are suggestive of an embryonic origin for most of the cases.