[Gastrointestinal polyposis syndromes]. / Gastrointestinale Polyposissyndrome.

BACKGROUND: Gastrointestinal polyposis syndromes are the second most common cause of hereditary colorectal carcinomas after Lynch syndrome (hereditary non-polyposis colon cancer, HNPCC). The detection of a causal germline mutation in an affected family member serves for differential diagnosis, assessment of the recurrence risk and predictive testing of healthy individuals at risk. OBJECTIVES: The present article aims to provide an overview of the differential diagnosis of different gastrointestinal polyposis syndromes based on the endoscopic findings, polyp histology, extraintestinal phenotype and molecular genetic diagnostics. MATERIALS AND METHODS: The present article is based on a literature search on gastrointestinal polyposis syndromes. RESULTS: In addition to familial adenomatous polyposis (FAP), there are further subtypes of adenomatous polyposis that can often only be distinguished by the detection of a causative germline mutation and are sometimes associated with different extracolonic manifestations. In hamartomatous polyposis syndromes, the clinical overlaps often cause differential diagnostic problems. Serratated polyposis syndrome is possibly the most frequent polyposis syndrome, although its cause is currently largely unexplained. CONCLUSIONS: Early detection and correct classification of polyposis is crucial for adequate prevention and therapy. Access to multidisciplinary expert centres is useful for the care of families.

[Gastrointestinal polyposis syndromes]. / Polyposissyndrome des Gastrointestinaltrakts.

Hereditary gastrointestinal polyposis syndromes account for around 1% of all colorectal cancers; most of them are associated with a broad spectrum of extracolonic tumors. The initial diagnosis is based on endoscopic findings and polyp histology. Molecular genetic screening is important for the delineation of conditions with a similar phenotype such as autosomal dominant familial adenomatous polyposis (FAP) and autosomal recessive MUTYH-associated polyposis (MAP). Identification of the germline mutation in an affected person is a prerequisite for the exact evaluation of the recurrence risk in relatives and the predictive testing of asymptomatic persons at risk. Beside cases with attenuated adenomatosis or few colorectal adenomas, diagnostic difficulties are common among the hamartomatous polyposes such as the juvenile polyposis syndrome due to their broad clinical overlap and uncertainties in histological assessment. Several poorly defined nonhereditary polyposis syndromes and those with an as yet unknown etiology exist including hyperplastic polyposis syndrome. Early detection and accurate classification are essential since effective methods for surveillance and treatment are available.

Chemoprotection of human hematopoietic stem cells by simultaneous lentiviral overexpression of multidrug resistance 1 and O(6)-methylguanine-DNA methyltransferase(P140K).

Myelotoxicity is a dose-limiting effect of many chemotherapeutic regimens. Thus, there is great interest in protecting human hematopoietic stem cells by the transfer of drug resistance genes. The main focus of this study was the simultaneous overexpression of multidrug resistance 1 (MDR1) and the O(6)-benzylguanine (O(6)-BG)-resistant mutant MGMT(P140K) (O(6)-methylguanine-DNA methyltransferase) with a bicistronic lentiviral vector (HR'SIN-MDR1-IRES-MGMT(P140K)), with regard to the capability to convey chemoprotection in the leukemia cell line, HL60, and human hematopoietic stem cells (CD34(+)). Combination therapy with O(6)-BG/1-(2-chloroethyl)-3-(4-amino-2-methylpyrimidine-5-yl)methyl-1-nitrosourea) (ACNU) plus paclitaxel showed a significant survival advantage of HL60 cells transduced with this combination vector. In CD34(+) cells, monotherapy with O(6)-BG/temozolomide (TMZ) resulted in an increased percentage of MGMT-positive cells (vs untreated cells) after transduction with HR'SIN-MDR1-IRES-MGMT(P140K) (28.3%). For combination therapy with O(6)-BG/temozolomide plus paclitaxel the increase was higher with the combination vector (52.8%) than with a vector expressing MGMT(P140K) solely (29.1%). With regard to MDR1-positive cells the protective effect of the combination vector (88.5%) was comparable to the single vector HR'SIN-MDR1 (90.0%) for monotherapy with paclitaxel and superior for combination therapy with O(6)-BG/temozolomide plus paclitaxel (84.6 vs 69.7%). In conclusion, the combination vector presents simultaneous protective effects of two drug-resistance genes, offering an opportunity to increase the cancer therapeutic index.

Dye chromoendoscopy leads to a higher adenoma detection in the duodenum and stomach in patients with familial adenomatous polyposis.

Backround and study aims Duodenal cancer is the cancer most often seen in patients with familial adenomatous polyposis (FAP) who have undergone risk-reducing colonic surgery. Almost all patients with FAP eventually develop duodenal adenomas and risk for duodenal cancer is up to 12 % with poor prognosis. In addition, there is a rising concern regarding increased gastric cancer risk in patients with FAP. Our aim was to enhance polyp detection by using CE (CE) with the application of indigo carmine dye. Patient and methods We conducted a prospective, blinded study of patients with FAP undergoing endoscopic examination of the upper gastrointestinal tract. First, a standard white-light examination (WLE) was done followed by an examination performed by an endoscopist who was blinded to the previous examination, using chromoendoscopy (CE) (0.4 % indigo carmine dye). Results Fifty patients were included in the study. Using WLE, a median number of 13 adenomas (range 0-90) was detected compared to 23 adenomas/patient (range 0-150; P  < 0.0001) detected after staining, leading to a higher Spigelman stage in 16 patients (32 %; P  = 0.0003). CE detected significantly more larger adenomas (> 10 mm) than WLE (12 vs. 19; P  = 0.0391). In the gastric antral region, a median number of 0 adenomas (range 0-6) before and 0.5 adenomas (range 0-7) after staining ( P  = 0.0025) were detected. Conclusion This prospective endoscopic trial, to our knowledge the largest in patients with FAP, showed a significant impact of CE on adenoma detection and therapeutic management in the upper gastrointestinal tract. This leads to more intensive surveillance intervals.

F2A sequence linking MGMT(P140K) and MDR1 in a bicistronic lentiviral vector enables efficient chemoprotection of haematopoietic stem cells.

Chemoprotection of haematopoietic stem cells (HSCs) by gene therapeutic transfer of drug-resistance genes represents the encouraging approach to prevent myelosuppression, which is one of the most severe side effects in tumor therapy. Thus, we cloned and evaluated six different bicistronic lentiviral SIN vectors encoding two transgenes, MGMT(P140K) (an O(6)-benzylguanine-resistant mutant of methylguanine-DNA methyltransferase) and MDR1 (multidrug resistance 1), using various linker sequences (IRESEMCV, IRESFMDV and 2A-element of FMDV (F2A)). Expression of both transgenes in HL-60 and in K562 cells was assayed by quantitative real-time PCR. Combination therapy with ACNU plus paclitaxel in HL-60 cells and with carmustin (BCNU) plus doxorubicin in K562 cells resulted in the most significant survival advantage of cells transduced with the lentiviral vector HR'SIN-MGMT(P140K)-F2A-MDR1 compared with untransduced cells. In human HSCs, overexpression of both transgenes by this vector also caused significantly increased survival and enrichment of transduced cells after treatment with BCNU plus doxorubicin or temozolomide plus paclitaxel. In summary, we could show significant chemoprotection by overexpression of MDR1 and MGMT(P140K) with a lentiviral vector using the F2A linker element in two different haematopoietic cell lines and in human primary HSCs with various combination regimens. Consequently, we are convinced that these in vitro investigations will help to improve combination chemotherapy regimens by reducing myelotoxic side effects and increasing the therapeutic efficiency.