The straight to test endoscopy service for suspected colorectal cancer: meeting national targets but are we meeting our patients' expectations?

AIM: The NHS Cancer Plan describes initiatives to improve patient care in the UK, including the two-week rule cancer referral pathway. To meet this target a straight to test (STT) endoscopy service was devised to expedite diagnosis of suspected colorectal cancer. Our novel study aimed to determine patient satisfaction with this new approach to rapid access investigation. METHOD: An anonymized questionnaire was posted to 300 patients who had undergone STT endoscopy in our unit between January and June 2010. It assessed satisfaction with the service overall, time from referral to investigation, pre-test information, bowel preparation instructions and time to results as well as preference for a traditional pre-test or post-test outpatient appointment and awareness that the referral was for suspected bowel cancer. RESULTS: In all, 174 questionnaires were obtained (58% yield; mean age 68.8; 44.8% men). 82.2% of patients were 'very satisfied' with the service overall, 82.8% with time from referral to test, 75.2% with time from test to results, 73% with endoscopy information and 69.5% with bowel preparation instructions. Eight per cent would rather have seen a specialist prior to endoscopy, 31.6% would have preferred a post-test appointment and 68.4% of patients were aware that referral was for suspected bowel cancer. CONCLUSION: Straight to test is popular with patients. It offers a fast and cost effective service in the diagnosis of colorectal cancer and meets national targets whilst reducing the volume burden on outpatient clinics. However, its success heavily relies on accurate communication between general practitioner, patient and secondary care.

Exocrine pancreatic insufficiency following esophagectomy.

Weight loss following esophagectomy is a management challenge for all patients. It is multifactorial with contributing factors including loss of gastric reservoir, rapid small bowel transit, malabsorption, and adjuvant chemotherapy. The development of a postoperative malabsorption syndrome, as a result of exocrine pancreatic insufficiency (EPI), is recognized in a subgroup of patients following gastrectomy. This has not previously been documented following esophageal resection. EPI can result in symptoms of flatulence, diarrhea, steatorrhea, vitamin deficiencies, and weight loss. It therefore has the potential to pose a significant level of morbidity in postoperative patients. There is some evidence that patients with proven EPI (fecal elastase-1 < 200 µg/g) may benefit from a trial of pancreatic enzyme replacement therapy (PERT). We observed symptoms compatible with EPI in a subgroup of patients following esophagectomy. We hypothesized that this was contributing to malabsorption and malnutrition in these patients. To investigate this, fecal elastase-1 was measured in postoperative patients, and in those with proven EPI, a trial of PERT was commenced in combination with specialist dietary education. At routine postoperative follow-up, which included assessment by a specialist dietitian, those patients with symptoms suggestive of malabsorption were given the opportunity to have their fecal elastase-1 measured. PERT was then offered to patients with fecal elastase-1 less than 200 µg/g (EPI) as well as those in the 200-500 µg/g range (mild EPI) with more severe symptoms. Fecal elastase-1 was measured in 63 patients between June 2009 and January 2011 at a median of 4 months (range 1-42) following surgery. Ten patients had fecal elastase-1 less than 200 µg/g, and all had failed to maintain preoperative weight. All accepted a trial of PERT. Nine (90%) had symptomatic improvement, and seven (70%) increased their weight. Thirty-nine patients had a fecal elastase-1 in the 200-500 µg/g range. Twelve were given a trial of PERT based on level of symptoms, five (42%) reported an improvement in symptoms, but only two (17%) gained weight. Our early results support the observation that EPI is a factor contributing to postoperative morbidity in patients recovering from esophagectomy and that these patients can benefit from a trial of PERT. Our study has limitations, and a formal trial is required to evaluate the impact of EPI and PERT following esophagectomy. Currently, our practice is to measure fecal elastase-1 in any patient with unexplained weight loss or symptoms of malabsorption. In patients with proven EPI or those who are symptomatic with mild EPI, a trial of PERT should be offered and symptoms reassessed.

Necrotising soft tissue infection following mastectomy.

Necrotising fasciitis is a rare but rapidly progressive soft tissue disease which can lead to extensive necrosis, systemic sepsis and death. Including this case, only 7 other cases have been reported in the world literature with only 2 others affecting the patient post mastectomy. This 59 year old Caucasian lady presented with severe soft tissue infection soon after mastectomy, which was successfully treated with a combination of debridement, triangulation, VAC© dressing and skin grafting. Necrotising soft tissue infections following mastectomy are rapidly progressive and potentially extremely serious. It is essential that a high index of clinical suspicion is maintained together with prompt aggressive treatment in a multidisciplinary environment to prevent worsening physical and psychological sequelae.

Defects in the Drosophila myosin rod permit sarcomere assembly but cause flight muscle degeneration.

We have determined the molecular and ultrastructural defects associated with three homozygous-viable myosin heavy chain mutations of Drosophila melanogaster. These mutations cause a dominant flightless phenotype but allow relatively normal assembly of indirect flight muscle myofibrils. As adults age, the contents of the indirect flight muscle myofibers are pulled to one end of the thorax. This apparently results from myofibril "hyper-contraction", and leads to sarcomere rupture and random myofilament orientation. All three mutations cause single amino acid changes in the light meromyosin region of the myosin rod. Two change the same glutamic acid to a lysine residue and the third affects an amino acid five residues away, substituting histidine for arginine. Both affected residues are conserved in muscle myosins, cytoplasmic myosins and paramyosins. The mutations are associated with age-dependent, site-specific degradation of myosin heavy chain and failure to accumulate phosphorylated forms of flightin, an indirect flight muscle-specific protein previously localized to the thick filament. Given the repeating nature of the hydrophobic and charged amino acid residues of the myosin rod and the near-normal assembly of myofibrils in the indirect flight muscle of these mutants, it is remarkable that single amino acid changes in the rod cause such severe defects. It is also interesting that these severe defects are not apparent in other muscles. These phenomena likely arise from the highly organized nature and rigorous performance requirements of indirect flight muscle, and perhaps from the interaction of myosin with flightin, a protein specific to this muscle type.

Recovery of dominant, autosomal flightless mutants of Drosophila melanogaster and identification of a new gene required for normal muscle structure and function.

To identify further mutations affecting muscle function and development in Drosophila melanogaster we recovered 22 autosomal dominant flightless mutations. From these we have isolated eight viable and lethal alleles of the muscle myosin heavy chain gene, and seven viable alleles of the indirect flight muscle (IFM)-specific Act88F actin gene. The Mhc mutations display a variety of phenotypic effects, ranging from reductions in myosin heavy chain content in the indirect flight muscles only, to reductions in the levels of this protein in other muscles. The Act88F mutations range from those which produce no stable actin and have severely abnormal myofibrillar structure, to those which accumulate apparently normal levels of actin in the flight muscles but which still have abnormal myofibrils and fly very poorly. We also recovered two recessive flightless mutants on the third chromosome. The remaining five dominant flightless mutations are all lethal alleles of a gene named lethal(3)Laker. The Laker alleles have been characterized and the gene located in polytene bands 62A10,B1-62B2,4. Laker is a previously unidentified locus which is haplo-insufficient for flight. In addition, adult wild-type heterozygotes and the lethal larval trans-heterozygotes show abnormalities of muscle structure indicating that the Laker gene product is an important component of muscle.

Lymphocytes of the intestinal mucosa of chickens.

Examination, by light and electron microscopy, of the morphology and the staining properties of intraepithelial lymphocytes from the intestine of the chicken revealed a population of lymphoid cells, of which a proportion (up to 20%) is granulated. The majority of cells were immunoreactive with anti-T cell serum and can therefore be considered to be related to T-lymphocytes, but they did not proliferate when cultured with phytohaemagglutinin. The granulated cells were identical to those previously designated globule-containing leukocytes, but were distinct from mast cells in their morphology, staining reactions and the stability of the granules in different fixatives and buffers.

The effect of immunity on the early events in the life-cycle of Eimeria tenella in the caecal mucosa of the chicken.

A comparison was made between the early events (asexual stages) in the life-cycle of Eimeria tenella in specifically immunized and control chickens. Particular attention was paid to the quantitative aspects and to the transport of sporozoites within intra-epithelial lymphocytes (IEL) from the enterocytes of the surface epithelium to the enterocytes of the crypts. There was a moderate decrease in the number of parasites initially seen in the mucosa of the immune birds, suggesting that some of the effects of immunity are exerted before penetration of the surface enterocytes, but the reduction in the numbers of developing parasites was more marked. This latter effect was due, at least partly, to failure of transfer of sporozoites from IELs to crypt enterocytes. These findings are discussed in relation to the efficacy of the immunity induced.

Marek's disease in turkeys: the induction of lesions and the establishment of lymphoid cell lines.

The inoculation of turkeys with large doses of a virulent strain of Marek's disease virus (GA strain), but not of two other virulent strains (HPRS-16 and JM), was found to induce a disease resembling Marek's disease of the chicken. The most prominent lesions were lymphocytic leukaemia and lymphoid and reticular hyperplasia in the spleen and the liver. These developed after a prolonged latent period and the early histological changes (lymphoid cell destruction and reticuloendothelial cell hyperplasia) reported in chickens were not observed. Twelve cell lines were established from suspensions of spleen cells or of buffy coat cells from infected turkeys. These cells expressed both Marek's disease tumour-associated surface antigen and T-cell antigens. The cells carried the Marek's disease virus genome and when inoculated into chickens induced typical Marek's disease lymphomas. Nine of the cell lines were infected with an avian leukosis virus, but three lines were free of such infection. All cell lines had normal turkey karyotypes.

Invasion of chicken caecal and intestinal lamina propria by crypt epithelial cells infected with coccidia.

The development of second generation schizonts of Eimeria necatrix and E. tenella was studied with the electron microscope. Invasion of the crypt epithelial cells by merozoites of the first generation schizonts caused changes in the morphology of the infected cells and stimulated their migration into the lamina propria through breaks which appeared in the basement membrane of the crypts. Second generation schizonts developed in the lamina propria within these crypt cells whose epithelial origin was confirmed by their interconnection by desmosomes and tight junctions and by their possession of characteristic microvilli. A comparison is made between this invasion of the lamina propria by parasitized cells and invasion of connective tissue by malignant epithelial cells; the possible mechanisms involved are discussed.

Mucosal transport of Eimeria tenella in the cecum of the chicken.

A study of the early life history of Eimeria tenella with the electron microscope confirmed that sporozoites do not directly enter the enterocytes of the crypts, in which they develop, but are carried there by host cells. However, these cells are not macrophages, as previously thought, but intraepithelial lymphocytes. The evidence presented demonstrates that sporozoites first penetrate surface enterocytes and then enter intraepithelial lymphocytes that leave the epithelium, pass through the lamina propria and enter the crypts.

Parasite-host relationships during the development of Eimeria dispersa Tyzzer 1929, in the turkey (Meleagris gallopavo gallopavo) with a description of intestinal intra-epithelial leucocytes.

An electron microscopical study was made on the development of Eimeria dispersa in the small intestine of the domestic turkey. Turkey poults, 10-14 days of age, were inoculated with oocysts and pieces of intestinal tissue were fixed at intervals between 3.5 and 114 h after inoculation. Sporozoites were occasionally seen in enterocytes but more often in 'pale' cells closely resembling lymphocytes. These cells were insinuated between enterocytes and in this study are referred to as intestinal intra-epithelial leucocytes (IEL). Maturation of the first-generation of schizogony occurred in this type of cell. Other generations of schizonts and gametogony occurred in epithelial cells and were characterized by the presence of 'spines' arranged around the parasitophorous vacuole extending into the cytoplasm of the host cell. A limited study of the parasite in the Bobwhite quail, Colinis virginianus, showed that development occurred in similar cells to those of the turkey. The 'spines', which were characteristic of later stages of E. dispersa in the turkey, were also present in this host and seemed to be a characteristic of E. dispersa, not of the host species.

Idiopathic polyneuritis in SPF chickens.

Paralysis due to peripheral neuritis occurred sporadically in a flock of Rhode Island Red chickens over a period of 8 years and is named idiopathic neuritis (IP). The flock was housed in isolators and free from many common pathogens including all known neurotropic viruses of chickens. The pathology of the nerve lesions, including their ultrastructure, is described and comparisons made with the lesions of Marek's disease and experimental allergic neuritis in chickens. Demyelination with invasion of nerve fibres with lymphocytes and macrophages occurs in all three diseases but there are differences in lesion distribution and intensity of cellular infiltration. The closest similarity is between the lesions of IP and the B-type lesions of Marek's disease. Attempts to isolate a cytopathic virus and to transmit the disease by inoculation failed to demonstrate an infectious causal agent. An autoimmune response to normal nerve is suggested as the most likely aetiology amongst several alternatives. The heritability of IP is not established, but the disease has not been detected in a light Sussex flock maintained under similar conditions.

Ultrastructure of the central nervous system in Marek's disease and the effect of route of infection on lesion incidence in the central nervous system.

The ultrastructure of the lesions of the central nervous system (CNS) of chickens was examined at intervals after intra-abdominal inoculation of Marek's disease virus (MDV). No transient paralysis occurred. Peri-vascular accumulations of lymphocytes and macrophages (cuffing) were accompanied by invasion of the CNS by these blood-borne leukocytes in the most severe lesions. Only minor damage to axons, myelin or glial cells was detected and no structural evidence for viral replication was observed. Intracerebral inoculation of cell-free MDV induced similar lesions in the CNS and there was no evidence for local exacerbation of their severity, although a few chickens developed transient paralysis. It is concluded that replication of MDV in the CNS is unlikely to be the direct cause of the CNS lesions.

Presence of a complete endothelial barrier between lymph and lymphoid tissue in the lumbar lymph nodes of the duck (Anas platyrhynchos).

The ultrastructure of the lumbar lymph nodes of the domestic duck is described and compared with published accounts of mammalian lymph nodes. The barrier to cell migration between lymphoid tissue and lymph is more formidable in the duck than in the mammal. In the duck the lymphatic endothelium lining the lymph spaces is continuous and bonded with desmosomes whereas in the mammal it is unbonded and fenestrated. In both types of node there are filtering zones and areas of dense lymphatic tissue but their topographical organisation differs. There is no cortex or medulla in the duck lymph node and filtration occurs in extensive lymphatic spaces traversed by numerous trabeculae to which are attached rounded phagocytic macrophages. Dense lymphoid tissue is scattered throughout the node, suspended by trabeculae or attached to the capsule and there are blood vessels analogous to the post capillary venules of mammalian nodes where lymphocytes migrate between blood and lymphoid tissue.

The effect of virus dose on the development of Marek's disease in two strains of chickens.

The effect of inoculating different doses of Marek's disease virus on the consequent lymphocyte-associated viraemia titres, survival time and mortality was studied in two strains of chickens, one highly susceptible (a strain of Rhode Island Red) and one moderately resistant (a strain of Light Sussex) to Marek's disease. In both strains an increase in the infecting dose of virus increased the ensuing viraemia, and there was an inverse relationship between virus dose and survival time. There was a negative correlation between viraemia titres and survival time. The modulation of infecting dose had no effect on overall mortality among the susceptible, Rhode Island Red strain, chickens, but did influence the mortality of the Light Sussex strain chickens. It was suggested that the outcome of infection within an individual may be determined by a rather subtle interaction between the infection and transformation of a limiting number of target cells and an immune response directed against such infected or transformed cells, and that in different breeds of chickens these two factors may differ in importance.

Chronological study of ultrastructural changes in the peripheral nerves in Marek's disease.

A chronological study was made of the ultrastructural changes in peripheral nerves following inoculation of 1-day-old chicks with a neurogenic strain of Marek Disease virus. No virus particles were found in nerves. Cellular infiltration of nerves was detected as early as 5 days after inoculation and by 3 weeks some nerves contained proliferative lesions which possessed many of the ultrastructural features characteristic of normal, reactive lymphoid tissue. About 4 weeks after inoculation, coinciding with the onset of neurological signs, areas of widespread demyelination appeared within these lesions; lymphocytes and macrophages penetrated and destroyed the myelin sheath, but spared Schwann cells and most axons. Later oedematous, sparsely infiltrated B type lesions were observed, some of which contained demyelinated nerve fibres undergoing repair; these were therefore a stage in the regression of the proliferative lesions. Our observations do not favour the hypothesis that cellular infiltration of nerves in Marek's disease is the direct result of auto-sensitization to normal myelin. They are consistent with the hypothesis that demyelination is a secondary feature and that the primary lesions are preferential sites for immune demyelination.

Haemopoietic cells in peripheral nerves of SPF chickens.

Foci of haemopoiesis were found in the peripheral nerves of SPF Rhode Island Red chickens and conventionally reared Brown Leghorn chickens. They contained cells which closely resembled the development stages in the bone marrow of erythrocytes, heterophil leukocytes or thrombocytes, but did not include lymphocytes. When birds from these flocks are used to study neuropathological disease, ectopic haemopoiesis in nerves must be distinguished from pathological lesions.