OATP1B1 and tumour OATP1B3 modulate exposure, toxicity, and survival after irinotecan-based chemotherapy.

BACKGROUND: Treatment of advanced and metastatic colorectal cancer with irinotecan is hampered by severe toxicities. The active metabolite of irinotecan, SN-38, is a known substrate of drug-metabolising enzymes, including UGT1A1, as well as OATP and ABC drug transporters. METHODS: Blood samples (n=127) and tumour tissue (n=30) were obtained from advanced cancer patients treated with irinotecan-based regimens for pharmacogenetic and drug level analysis and transporter expression. Clinical variables, toxicity, and outcomes data were collected. RESULTS: SLCO1B1 521C was significantly associated with increased SN-38 exposure (P<0.001), which was additive with UGT1A1*28. ABCC5 (rs562) carriers had significantly reduced SN-38 glucuronide and APC metabolite levels. Reduced risk of neutropenia and diarrhoea was associated with ABCC2-24C/T (odds ratio (OR)=0.22, 0.06-0.85) and CES1 (rs2244613; OR=0.29, 0.09-0.89), respectively. Progression-free survival (PFS) was significantly longer in SLCO1B1 388G/G patients and reduced in ABCC2-24T/T and UGT1A1*28 carriers. Notably, higher OATP1B3 tumour expression was associated with reduced PFS. CONCLUSIONS: Clarifying the association of host genetic variation in OATP and ABC transporters to SN-38 exposure, toxicity and PFS provides rationale for personalising irinotecan-based chemotherapy. Our findings suggest that OATP polymorphisms and expression in tumour tissue may serve as important new biomarkers.

Polypoid mucosal prolapse complicating low rectal adenomas: beware the inflammatory cloacogenic polyp!

AIMS: Polypoid mucosal prolapse near the anorectal junction mimics adenomas endoscopically and histopathologically. The aim was to describe the phenomenon of polypoid mucosal prolapse arising secondary to adenomas at the anorectal junction. METHODS AND RESULTS: Four cases of low rectal adenoma with polypoid mucosal prolapse were assessed histopathologically, as well as with p53 and Ki67 antibodies. Two were male and two female; the mean age was 45 years. Available follow-up has revealed no recurrence in any patient. All cases showed mucosal expansion with ulceration or erosion, crypt architectural irregularity, fibromuscular proliferation between crypts and variable epithelial serration and inflammation. Each case also showed unequivocal dysplasia, often co-mingled with features of prolapse, highlighted by p53 and Ki67 immunohistochemistry, which demonstrated positivity within dysplastic areas. CONCLUSIONS: Histopathologists must recognize the potential for adenomatous/dysplastic foci in anorectal lesions to superficially resemble inflammatory cloacogenic polyps. We recommend use of immunomarkers p53 and Ki67 to aid the interpretation of challenging cases. We believe that polypoid mucosal prolapse changes can be a secondary phenomenon, due to adenomas close to or at the anorectal junction.

Gastrointestinal Kaposi's sarcoma: CD117 expression and the potential for misdiagnosis as gastrointestinal stromal tumour.

AIMS: Gastrointestinal Kaposi's sarcoma (KS) may mimic gastrointestinal stromal tumours (GISTs) histologically. Studies have shown that KS outside the gastrointestinal (GI) tract may express CD117, an antibody usually used to support a diagnosis of GIST. The aim was to evaluate the clinicopathological features of GI KS, including the expression of CD117 with and without antigen retrieval. METHODS AND RESULTS: Fourteen GI KS were assessed histologically, 12 of which were also subjected to immunohistochemistry for CD34, human herpesvirus (HHV) 8, DOG1 and CD117. CD117 immunohistochemistry was performed with and without antigen retrieval. All cases showed an infiltrative spindle cell tumour. Lamina propria infiltration, lymphoplasmacytic inflammation, extravasated red blood cells and haemosiderin were typical histological features. In all cases tumour cells were positive for CD34 and HHV8, but negative for DOG1. CD117 was positive in four of 12 cases without antigen retrieval and 10 of 12 cases with antigen retrieval. CONCLUSIONS: The microscopic distinction of GI KS from GIST can be difficult. Clues that raise the possibility of GI KS include young patient age, a history of immunosuppression, lamina propria infiltration, lymphoplasmacytic inflammation, extravasated red blood cells and haemosiderin deposition. Use of the immunomarkers CD117 (without antigen retrieval), HHV8 and DOG1 may aid in the distinction between GI KS and GIST.

Clinical significance of the RT-PCR positive sentinel node in melanoma.

BACKGROUND: The clinical relevance of RT-PCR positivity for melanoma markers in the sentinel node remains controversial. Our purpose was to determine whether patients with a histologically negative but RT-PCR positive node were at an increased risk for recurrence than their RT-PCR negative counterparts. METHODS: Thirty-nine adult patients underwent sentinel node biopsies for melanoma between 1998 and 2000. Each sentinel node was bivalved. Half was serially sectioned and examined by routine hematoxylin and eosin (H&E) and immunohistochemistry (IHC; S100, HMB-45, melanA, and tyrosinase). The other half was analyzed by a nested RT-PCR assay for tyrosinase. RESULTS: Patients were followed for recurrence with a mean follow-up of 71.1 months. The odds ratio of recurrence for RT-PCR positive versus RT-PCR negative patients was 1.39 (0.34, 5.62; p = 0.73). Within the histology negative subgroups, the risk of recurrence in the RT-PCR positive group (26.7%) was not significantly different from the risk of recurrence in the RT-PCR negative group (22.2%) (p = 0.33 chi-squared). RT-PCR of the sentinel node was not a predictor for recurrence on multivariate analysis (p = 0.65). CONCLUSION: Sentinel node RT-PCR positivity did not risk stratify histologically negative melanoma patients beyond routine pathologic examination in this series.

Granular cell tumours of the gastrointestinal tract: expression of nestin and clinicopathological evaluation of 11 patients.

AIMS: Granular cell tumours (GCTs) in the gastrointestinal (GI) tract are rare, with few series reported in the literature. Nestin is a recently identified intermediate filament protein that is expressed in neuroectodermal stem cells and skeletal muscle progenitor cells and has been shown to be expressed in gastrointestinal stromal tumours (GISTs) and GI schwannomas. Herein, we describe the clinicopathological and immunohistochemical features of 11 GI GCTs, introducing nestin as an additional marker that identifies these tumours. METHODS AND RESULTS: The archives of the departments of pathology at London Health Sciences Centre (London, Ontario) and St Michael's Hospital (Toronto, Ontario) were searched for GCTs occurring in the GI tract, yielding 11 cases. Histological features were assessed and immunohistochemistry was performed with S100 protein, nestin, glial fibrillary acidic protein (GFAP), CD34, desmin, CD117, and inhibin-alpha. Charts were reviewed for clinical information. Ages at diagnosis ranged from 31 to 73 years; there were six males and four females. All GCTs were solitary, six in the oesophagus, three in the caecum, one in the rectum and one perianal. Most lesions were discovered incidentally. The size of the GCTs ranged from 4 mm to 30 mm. All were submucosal, typically firm, with a white-yellow appearance. Histologically, the GCTs showed moderate cellularity, predominantly solid growth with areas of nesting. While lesional cells were mainly plump and polygonal, areas of spindling were present in several tumours, more frequently in the colorectum. Margins were circumscribed. Nuclei were round to oval, with even chromatin and small nucleoli. Mitoses were rare to absent and necrosis was absent in all cases. Staining with periodic acid-Schiff, with diastase predigestion, showed globular and diffuse positivity within the cytoplasm. Moderate to strong expression of S100 protein and nestin was observed in 11 of 11 and seven of seven tumours, respectively. GFAP, CD34, desmin, CD117 and inhibin-alpha were negative. While patients were variably managed with resection or observation, all remain clinically well, without disease progression. CONCLUSIONS: Although rare, GI GCTs have characteristic clinicopathological features. Nestin may be a useful immunohistochemical marker for identifying these tumours; the presence of this persistent stem cell cytoskeletal filament within GI GCTs suggests that these lesions may arise from a multipotential stem cell in the GI tract.

Visceral aneurysms in Ehlers-Danlos syndrome: case report and review of the literature.

A patient with Ehlers-Danlos syndrome type IV had a celiac artery aneurysm. There are only nine previously published cases of visceral artery aneurysms in this condition, and surgical management was used in only four of them. This is, we believe, the first published report of a successfully treated celiac artery aneurysm in this condition in which the hazards of treatment and our rationale are explained. The literature of this rare problem is also reviewed.

Periprosthetic acetabular fracture associated with extensive osteolysis.

Periprosthetic fracture of the acetabulum is an uncommon complication of total hip arthroplasty. The management is reported to be difficult, and complications such as nonunion and implant loosening are common. We described herein a case of nontraumatic periprosthetic acetabular fracture associated with significant osteolysis, which was successfully managed by addressing the fracture and osteolysis independently.

Using GIS in risk analysis: a case study of hazardous waste transport.

This paper provides an illustration of how a geographic information system (GIS) can be used in risk analysis. It focuses on liquid hazardous waste transport and utilizes records archived by the London Waste Regulatory Authority. This data source provides information on the origin and destination of each waste stream, but not the route followed during transport. A GIS was therefore employed to predict the paths used, taking into account different routing criteria and characteristics of the available road network. Details were also assembled on population distribution and ground-water vulnerability, thus providing a basis for evaluating the potential consequences of a waste spillage during transport. Four routing scenarios were implemented to identify sections of road which consistently saw heavy traffic. These simulations also highlighted that some interventions could lead to risk tradeoffs rather than hazard mitigation. Many parts of the research would not have been possible without a GIS, and the study demonstrates the considerable potential of such software in environmental risk assessment and management.

Triple treat. One chapter's Project Alpha activities.

The concept of Project Alpha, a chapter-level program to promote the implementation of perioperative nursing content in nursing education programs, was introduced at the 27th annual AORN Congress in 1980. Project Alpha activities were designated as basic (ie, Project Alpha awareness, education), intermediate (ie, Project Alpha promotion, clinical preceptoring), and advanced (ie, extern program, integrated perioperative module). This article reports one chapter's success in implementing Project Alpha.

Biochemical indicators of liver injury in calves with experimental fascioliasis.

Twenty calves were infected with 1000 metacercariae of Fasciola hepatica, the activities of 10 enzymes in plasma or serum were assayed and concentrations in serum of proteins, urea and bilirubin were determined. These values were compared with control data obtained from 14 uninfected calves. Aspartate aminotransferase, lactate dehydrogenase, sorbitol dehydrogenase, glutamate dehydrogenase, ornithine carbamoyl transferase and gamma-glutamyl transpeptidase activities increased in infected calves. Total serum protein increased, albumin decreased, globulin increased and the albumin/globulin ratio was decreased in infected calves. Plasma alanine aminotransferase, leucine aminopeptidase, alkaline phosphatase and cholinesterase activities and serum concentration of urea and bilirubin were unaffected. It was concluded that glutamate dehydrogenase and gamma-glutamyl transpeptidase were the most sensitive indicators of liver cell damage in fascioliasis.

Chemotherapy of infection with Fasciola hepatica in cattle.

Diamphenethide and a mixture of nitroxynil and hexachlorophane, which are effective against Fasciola hepatica in sheep, are effective in cattle if allowance is made for the slower rate of development and the more intense liver reaction which is associated with resistance. Adult parasites are mostly rejected around the time of maturity so that therapy in cattle must be directed against the early developmental stage using an appropriate drug.