Genetic mapping of novel modifiers for ApcMin induced intestinal polyps’ development using the genetic architecture power of the collaborative cross mice

Background Familial adenomatous polyposis is an inherited genetic disease, characterized by colorectal polyps. It is caused by inactivating mutations in the Adenomatous polyposis coli (Apc) gene. Mice carrying a nonsense mutation in the Apc gene at R850, which is designated ApcMin/+ (Multiple intestinal neoplasia), develop intestinal adenomas. Several genetic modifier loci of Min (Mom) were previously mapped, but so far, most of the underlying genes have not been identified. To identify novel modifier loci associated with ApcMin/+, we performed quantitative trait loci (QTL) analysis for polyp development using 49 F1 crosses between different Collaborative Cross (CC) lines and C57BL/6 J-ApcMin/+mice. The CC population is a genetic reference panel of recombinant inbred lines, each line independently descended from eight genetically diverse founder strains. C57BL/6 J-ApcMin/+ males were mated with females from 49 CC lines. F1 offspring were terminated at 23 weeks and polyp counts from three sub-regions (SB1–3) of small intestinal and colon were recorded. Results The number of polyps in all these sub-regions and colon varied significantly between the different CC lines. At 95% genome-wide significance, we mapped nine novel QTL for variation in polyp number, with distinct QTL associated with each intestinal sub-region. QTL confidence intervals varied in width between 2.63–17.79 Mb. We extracted all genes in the mapped QTL at 90 and 95% CI levels using the BioInfoMiner online platform to extract, significantly enriched pathways and key linker genes, that act as regulatory and orchestrators of the phenotypic landscape associated with the ApcMin/+ mutation. Conclusions Genomic structure of the CC lines has allowed us to identify novel modifiers and confirmed some of the previously mapped modifiers. Key genes involved mainly in metabolic and immunological processes were identified. Future steps in this analysis will be to identify regulatory elements – and possible epistatic effects – located in the mapped QTL.

Oncology

Childhood cancer is different to adult cancers in a number of ways including site, type, and behaviour. The commonest childhood malignancies are leukaemia, tumours of the brain and spinal cord, and lymphoma (>75% of all childhood cancers). This chapter outlines the general principles, provides survival statistics and a glossary, before discussing Wilms tumour, liver tumours, intestinal neoplasia, neuroblastoma, testicular tumours, lymphomas, rhabdomyosarcoma, soft tissue neoplasia, endocrine tumours, and ovarian tumours.

DIAGNOSTIC ACCURACY OF ONE SAMPLE OR TWO SAMPLES QUANTITATIVE FECAL IMMUNOCHEMICAL TESTS FOR INTESTINAL NEOPLASIA DETECTION

ABSTRACT BACKGROUND: Rectal bleeding is the most important symptom of intestinal neoplasia; thus, tests of occult blood detection in stools are widely used for pre neoplastic lesions and colorectal cancer (CRC) screening. OBJECTIVE: Evaluate the accuracy of OC-Sensor quantitative test (Eiken Chemical, Tokyo, Japan) at cut-off 10 µg Hb/g feces (50 ng/mL) in a cohort of subjects that had to undergo diagnostic colonoscopy, and if more than one sample collected in consecutive days would improve the diagnostic accuracy of the test. METHODS: Patients (mean age 56.3±9.7 years) that underwent colonoscopy prospectively randomly received one (1-sample FIT, FIT 1) or two (2-sample FIT, FIT 2) collection tubes. They collected the stool sample before starting colonoscopy preparation. Samples were analyzed by the OC-Auto Micro 80 (Eiken Chemical, Tokyo, Japan). The performance of FIT 1 and FIT 2 were compared to the colonoscopy findings. RESULTS: Among 289 patients, CRC was diagnosed in 14 (4.8%), advanced adenoma in 37 (12.8%), early adenoma in 71 (24.6%) and no abnormalities in 141 (48.8%). For FIT 1, the sensitivity for CRC was 83.3% (95%CI 36.5-99.1%), for advanced adenoma was 24% (95%CI 10.1-45.5%), with specificity of 86.9% (95%CI 77.3-92.9%). For FIT 2, the sensitivity for CRC was 75% (95%CI 35.6-95.5%), for advanced adenoma was 50% (95%CI 22.3-77.7%), with specificity of 92.9% (95%CI 82.2-97.7%). The positive likelihood ratios were 1.8 (95%CI 0.7-4.4 for FIT 1) and 7.1 (95%CI 2.4-21.4 for FIT 2) for advanced adenoma, and 6.4 (95%CI 3.3-12.3, for FIT 1) and 10.7 (95%CI 3.8-29.8, for FIT 2) for CRC. The negative likelihood ratio were 0.9 (95%CI 0.7-1, for FIT 1) and 0.5 (95%CI 0.3-0.9, for FIT 2) for advanced adenoma, and 0.2 (0.03-1.1, for FIT 1) and 0.3 (0.08-0.9, for FIT 2) for CRC. The differences between FIT 1 and FIT 2 performances were not significant. However, the comparison of the levels of hemoglobin in feces of patients of FIT 1 and FIT 2 showed that the differences between no polyp group and advanced adenoma and CRC were significant. CONCLUSION: The accuracy of OCR Sensor with 10 µg Hb/g feces cut-off was comparable to other reports and two-sample collection improved the detection rate of advanced adenoma, a pre neoplastic condition to prevent CRC incidence.

Diagnosis and management of inflammatory bowel disease-associated neoplasia: considerations in the modern era

Patients with inflammatory bowel disease (IBD) are at an increased risk of developing intestinal neoplasia—particularly colorectal neoplasia, including dysplasia and colorectal cancer (CRC)—as a primary consequence of chronic inflammation. While the current incidence of CRC in IBD is lower compared with prior decades, due, in large part, to more effective therapies and improved colonoscopic technologies, CRC still accounts for a significant proportion of IBD-related deaths. The focus of this review is on the pathogenesis; epidemiology, including disease- and patient-related risk factors; diagnosis; surveillance; and management of IBD-associated neoplasia.

Gastrointestinal Stromal Tumor Associated with Hypertrophic Osteopathy in a Dog

Background: Gastrointestinal stromal tumor (GIST) is a malignant mesenchymal neoplasm rarely described in the veterinary routine. The aim of this study was to report a case of GIST accompanied by a periosteal reaction, suggestive of hypertrophic osteopathy, in a dog.Case: An 11-year-old male dog had a history of progressive weight loss, difficulty in locomotion, and dyspnea. During clinical care, increased bone volume was observed. Blood samples were collected for a complete blood count and biochemical analysis. The dog also underwent thoracic radiography and abdominal ultrasonography. The test results revealed anemia, leukocytosis, hypocalcemia, hypoalbuminemia, and hypocholesterolemia. The radiographic images of the limbs showed a generalized periosteal reaction, and thoracic radiography indicated changes compatible with mild chronic lung disease. Ultrasonographic findings indicated a neoformation in the intestinal loop of the right mesogastric region and increased volume in the left testicle, both of which were indicative of neoplasia. Therefore, the dog was referred for surgery, wherein the intestinal mass and both testes were removed; the intestinal mass and left testicle were subjected to histopathological diagnosis. The results of the biopsies confirmed that the testicular neoplasm was a seminoma, whereas the intestinal nodule was compatible with GIST, and immunohistochemical analysis was necessary to confirm the diagnosis. On the basis of positive labeling for the antibodies vimentin, desmin, S100, and c-kit, the diagnosis of GIST was confirmed. Therefore, the animal underwent metronomic chemotherapy with 12 mg/m2 cyclophosphamide every 24 h for 3 months, and thereafter every 48 h for 6 months. Moreover, the dog was periodically monitored via imaging (radiography of the anterior and posterior limbs, abdominal ultrasonography, and computed tomography). A few months after the surgical resection of the intestinal nodule, radiography revealed that the periosteal reactions had disappeared, but ultrasonography revealed nonspecific alterations of mild thickening and enlargement of the intestinal loops. Computed tomography revealed two nodular areas of soft-tissue attenuation in the right mesogastric region. Although the possibility of tumor recurrence was raised, the animal’s owner chose only to perform palliative treatment. After 4 months, ultrasonography revealed a neoformation in the right mesogastric region. On July 29, 2018 the animal had a worsening of its clinical condiction, with tumor recurrence by ultrasound exam. The owners didn´t accept returning to the oncologist and made an option for a conservative treatment with tramadol (3 mg/kg/TID), dipirone(25 mg/kg/TID), and vitaminic supplement based on docosahexaenoic acid plus eicosapentaenoic acid (30 mg/kg, once daily) On August, 28, 2018 he was euthanized. The dog’s postsurgical survival time was 15 months.Discussion: The dog described in the present report was large and elderly, both of which are predisposing factors for GIST development. Although non-specific, progressive weight loss may be associated with intestinal neoplasia, owing to the impairment of digestion and nutrient absorption, because a part of the duodenal mucosa was compromised by neoplasia. The difficulty in locomotion, which did not respond to treatment, was attributed to the periosteal reaction confirmed by radiographic exam. This, in turn, was associated with hypertrophic osteopathy secondary to neoplasia, because the condition regressed after the removal of the intestinal nodule. The histopathological findings related to intestinal neoplasia were suggestive of GIST; positive immunoblotting for c-kit, vimentin, S100, and desmin confirmed the diagnosis. Although the veterinarian alerted the owner to the suspicion of recurrence and suggested continuing treatment, the owner chose not to.