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[Genetic alterations in the region of the p53 gene on human chromosome 17 in colorectal cancer].

Most colorectal tumors are characterized, among other genetic alterations, by allele loss of the genes located on the short arm of chromosome 17 (17p13.1), including the p53 suppressor gene. In ovarian and mammary-gland tumors, deletions of another candidate tumor-suppressor gene, located in the 17p13.3 chromosome region, were observed. We analyzed allele losses in the loci of the short arm of chromosome 17 (YNZ22, MCT35.1, and the p53 gene) in colorectal-cancer patients from the former Soviet Union. Tumors with cytogenetic alterations in 17p and/or with a detected loss of heterozygosity at the YNZ22 (D17S30) locus were examined for allele losses in the p53 gene using two polymorphic sites. Different methods revealed alterations on 17p in 24 (48%) out of 50 patients with colorectal carcinomas. In all tumors with an allele loss of the YNZ22 marker (15 out of 44 informative cases), which was detected by means of PCR, allele loss of the p53 gene was found (12 out of 15 informative cases). In 5 out of 13 tumors with cytogenetic alterations in 17p, allele loss of the p53 gene was found, with the YNZ22 marker being unaffected. In one of these tumors, the i(17q) marker was found, and in the remaining four tumors, 17p translocations were detected. In 4 out of 5 tumors with translocations affecting 17p, the t(17;20)(q21;p12) translocation was detected. The informativeness of the screening for 17p translocations, using PCR for the YNZ22 locus, and the reasons for discrepancy between the data of PCR and cytogenetic analyses are discussed.

Alleles↗

Chemotherapy of colorectal cancer.

Advanced colorectal cancer belongs to the most chemotherapy-resistant human malignancies. The cytotoxic agent with the most consistent antitumor activity has been 5-fluorouracil (5-FU). With this drug, response rates vary between 15% (with conventional weekly or 5-day bolus injection) and 30% (with continuous infusions of 24 h to 12 weeks); survival advantages of the latter approach have not been demonstrated. Combinations of 5-FU with other cytotoxic agents with some activity have been found unsuccessful. Because of its complex metabolism the efficacy-toxicity ratio of 5-FU can be positively influenced by biochemical modulation with agents leading to decreased availability of competing substrates, increased availability of co-substrates or more efficient interactions with target substances. Superior response rates (20-40%) have been observed upon the addition of leucovorin, methotrexate and N-(phosphonacetyl)-L-aspartic acid; survival was modestly prolonged (2-3 months) in two leucovorin and one methotrexate study. Interferon-alpha, inactive as a single agent, appears to synergize with 5-FU at the cost of considerable toxicity; results from randomized trials of this combination are awaited. 5-FU has also been the mainstay of adjuvant treatments; in poor-prognosis rectal cancer it appears to improve survival if added to radiotherapy, whereas in combination with levamisole the survival of node-positive colonic carcinoma patients can be prolonged.

Animals↗

Predominance of younger age, advanced stage, poorly-differentiated and mucinous histology in Israeli Arab patients with colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) incidence in the Israeli population is higher in the Jewish population than among Arabs. MATERIALS AND METHODS: To determine the differences in demographic, clinical, histopathological and molecular characteristics of CRC between these two ethnic groups, 125 Arab patients treated at 3 community hospitals over a 20-year period were compared to a group of 208 consecutive Jewish patients. The mutator (replication error-positive [RER]) phenotype was detected by immunohistochemical evaluation of hMLH1 and hMSH2 protein expression in tumor tissue. RESULTS: The Arab patients were younger than the Jewish patients with a higher percentage of poorly-differentiated and mucinous cancers and a higher percentage of advanced stage cancers (Dukes' C+D) at presentation. The mutator phenotype was detected at similar rates in both ethnic groups. CONCLUSION: Our study demonstrated that CRC patients from two major ethnic populations in Israel, Arabs and Jews, differed in terms of the prevalence of the disease, pathological features and age at presentation, but not in frequency of mismatch-repair-positive cancers.

Adaptor Proteins, Signal Transducing↗

Cytoplasmic phospholipase A2 alpha overexpression in stromal cells is correlated with angiogenesis in human colorectal cancer.

In colorectal cancer, cyclooxygenase-2 (COX-2) overexpression in stromal cells induces angiogenesis through EP2 prostaglandin E2 receptor signaling. Cytoplasmic phospholipase A2 (PLA2) alpha preferentially hydrolyses arachidonic acid, which is the limiting substrate for prostaglandin production, from membrane phospholipids. We therefore investigated a possible relationship between cytoplasmic PLA2 and COX-2 overexpression in stromal cells, angiogenesis and microsatellite instability in 48 human colorectal adenocarcinomas. Cytoplasmic PLA2 and COX-2 expression in stromal cells and vascular endothelial growth factor (VEGF) expression in tumor cells were evaluated by immunohistochemistry. Microvessel density was assessed in 10 x 400 fields after CD31 staining. Microsatellite instability was evaluated by PCR and immunohistochemistry. A total of 16 tumors had microsatellite instability. We found an overexpression of cytoplasmic PLA2 in superficial stromal cells. These cells corresponded to fibroblasts and myofibroblasts. There was an association between the number of cytoplasmic PLA2 and COX-2-expressing cells (P=0.006). Cytoplasmic PLA2-positive stromal cells usually also expressed COX-2. A high number of cytoplasmic PLA2-positive stromal cells was correlated with a high microvessel density (P=0.002), a strong VEGF (P=0.01) and the absence of microsatellite instability (P=0.001). The coordinate overexpression of cytoplasmic PLA2 and COX-2 in stromal cells could lead to an important prostaglandin production. These results suggest that cytoplasmic PLA2 overexpression in these cells regulates COX-induced angiogenesis probably by providing arachidonic acid, which is the limiting factor for prostaglandin production. The lower number of cytoplasmic PLA2-positive stromal cells in carcinomas with microsatellite instability could be related to their lower microvessel density and VEGF expression.

Adult↗

In-111 CYT-103 monoclonal antibody imaging in patients with suspected recurrent colorectal cancer.

Recurrent colorectal cancer is seen in as many as 40% of patients after curative resection. In view of the limitations of endoscopic and cross-sectional imaging, external immunoscintigraphy has been added to the follow-up regimen of patients at high-risk of recurrent disease. The authors investigated the utility of immunoscintigraphy with Indium-111 (In-111) CYT-103 (site specifically labeled conjugate of monoclonal antibody B72.3) in 19 patients with suspected recurrences after previous curative resection of colorectal carcinoma. Local or regional recurrences (4 patients) and liver metastasis (6 patients) were indicated by physical examination and computed tomography (CT), whereas nine patients had occult disease with increasing serum carcinoembryonic antigen (CEA) levels and negative conventional workups. Serum CEA levels were elevated (mean, 22 ng/ml) in all patients. Approximately 4.3 mCi In-111 labeled to 1.0 mg CYT-103 was administered intravenously to each patient. Planar and single photon emission computed tomography (SPECT) imaging were performed 2-5 days after infusion. The final diagnosis of recurrence or metastasis was established in 18 patients by second-look surgery or biopsy. One patient died before exploration. Tumor was identified at the following locations: pelvis (12 patients), abdominal wall (2 patients), retroperitoneum (1 patient), liver (5 patients), and omentum (2 patients). Superiority of monoclonal antibody (MoAb) scan is noted in the detection of pelvic and intraabdominal recurrences (100%) versus CT scan (43%). Liver metastases were identified with equal facility by both modalities. In-111 CYT-103 scan findings influenced the management of 10 (55%) of 18 patients. Surgery was avoided in one patient with disseminated metastases detected by the scan. Correct identification of occult local recurrences was made in six patients. An isolated liver metastasis was confirmed in one patient with equivocal CT scan. Finally, additional intraabdominal lesions were detected in two patients. These results suggest an important and beneficial role for In-111 CYT-103 MoAb imaging in patients with suspected recurrent colorectal carcinomas, particularly in patients in whom cross-sectional imaging is negative; such imaging may prevent patients from undergoing unnecessary surgical exploration.

Adenocarcinoma↗

[Immunohistochemical markers in colorectal cancer].

In colorectal cancer, immunohistochemical staining can routinely be used for tumour classification, screening for defective DNA mismatch repair and possibly identification of markers relevant to prediction of outcome of chemotherapy. This article provides a brief description of these applications.

Adenocarcinoma↗

Detecting colorectal cancer.

Although colorectal cancer affects up to 28,000 people in the UK each year, and early detection is associated with a high cure rate, little exists in the way of health promotional literature dealing with the subject. This paper looks at what is needed to make initiatives in this area more useful.

Colorectal Neoplasms↗

Uniquely women's issues in colorectal cancer screening.

Colorectal cancer (CRC) is the third most common cause of cancer in women. Screening has been shown to increase detection and decrease morbidity from this disease, but compliance is poor. This paper reviews special considerations for determining screening intervals in women, factors making screening more difficult in women, and studies reviewing preventative strategies in addition to screening that may reduce CRC.

Colorectal Neoplasms↗

Virtual colonoscopy and colorectal cancer screening.

Colorectal cancer (CRC) is the leading cause of cancer related death in the United States. Virtual colonoscopy is a new method for imaging the colon and has produced promising early results for polyp and cancer detection. The challenge remains to reproduce these favorable results in clinical practice and to evaluate the use of virtual colonoscopy in a purely screening population. Virtual colonoscopy may dramatically improve population participation in screening programs and play a major role in minimizing the impact of CRC.

Colonic Polyps↗

Colonoscopic diagnosis and management of nonpolypoid early colorectal cancer.

Nonpolypoid colorectal neoplasms are grossly classified into three groups: slightly elevated (small flat adenomas), laterally spreading, and depressed. Flat adenomas are not invasive until they are rather large, whereas depressed lesions can invade the submucosa even when they are extremely small. Nonpolypoid lesions are difficult to detect and are often overlooked. Keys to detect them are their slight color change, interruption of the capillary network pattern, slight deformation of the colonic wall, spontaneously bleeding spots, shape change of the lesion with insufflation and deflation of air, and interruption of the innominate grooves. Spraying of indigo carmine dye helps to clarify the lesions. A pit pattern analysis with a zoom colonoscope is useful for the diagnosis and staging of early colorectal cancer. Small flat adenomas are thought to be precursors of protruded polyps and lateral spreading tumors, whereas depressed lesions are thought to grow endophytically and become advanced cancers. Small depressed lesions are treated with an endoscopic mucosal resection (EMR) technique; but when they massively invade the submucosa, surgical resection is indicated. Laterally spreading tumors are not as invasive despite their large size and therefore are good indications for the EMR or piecemeal EMR method. Small flat adenomas need not be treated urgently, as almost none is invasive. Accurate diagnosis with dye-spraying and zoom colonoscopy is vital for deciding the treatment strategy.

Adenoma↗

Race, gender, and colorectal cancer screening.

Colorectal cancer (CRC) screening in asymptomatic, average-risk populations can reduce mortality and incidence of CRC. The United States Preventive Services Task Force, the American Cancer Society, and the Multi-Society Task Force all recommend initiation of screening at the age of 50 yr for men and women of all races, with an identical menu of screening options. However, there are important differences in risk based on gender, race, and ethnicity. These differences could influence the timing of initiation of screening, and the most optimal form of screening test. This commentary discusses the basis for these differences, and proposes that we should consider customization of screening based on gender, race, and ethnicity.

Adult↗

The clinical features of ovarian cancer in hereditary nonpolyposis colorectal cancer.

OBJECTIVE: Hereditary nonpolyposis colorectal cancer (HNPCC) is a hereditary cancer susceptibility disorder associated with a very high risk for carcinoma of the colon and an elevated risk for certain extracolonic cancers including ovarian cancer. Our aim in this study was to describe the clinicopathologic features of ovarian cancer in HNPCC family members. METHODS: . Members of the International Collaborative Group on HNPCC collected retrospective data on 80 ovarian cancer patients who were members of HNPCC families, including 31 known mutation carriers, 35 presumptive carriers (by colorectal/endometrial cancer status), and 14 at-risk family members. RESULTS: Mean age at diagnosis of ovarian cancer was 42.7. Nonepithelial tumors made up only 6.4% of the cancers, and borderline tumors comprised just 4.1% of the epithelial cancers. Among frankly malignant epithelial cases, most cancers were well or moderately differentiated, and 85% were FIGO stage I or II at diagnosis. Synchronous endometrial cancer was reported in 21.5% of cases. CONCLUSIONS: Ovarian cancer in HNPCC differs from ovarian cancer in the general population in several clinically important respects. It occurs at a markedly earlier age. It is more likely to be epithelial. If it is a frankly invasive epithelial cancer, it is more likely to be well or moderately differentiated. HNPCC patients with ovarian cancer are more likely to have a synchronous endometrial cancer than other ovarian cancer patients and are more likely to be diagnosed at an early stage.

Adult↗

Screening and surveillance of colorectal cancer.

Although colorectal cancer (CRC) is the second leading cause of cancer deaths in the United States, it is preventable. Screening modalities include fecal occult blood testing, flexible sigmoidoscopy, double-contrast barium enema, and colonoscopy. Colonoscopy allows effective detection and removal of precursor adenomatous polyps and is the dominant CRC screening modality. Emerging technologies include CT and MR colonography and fecal DNA tests. Effective and cost-effective surveillance after polypectomy and curative CRC resection requires balancing the protective effect of polypectomy while maximizing intervals between examinations; thus, estimation of the risk of recurrence determines the intensity of surveillance for individual patients.

Colonoscopy↗

Metastatic colorectal cancer.

Metastatic colorectal cancer remains a public-health issue on a global scale. With development of a new generation of cytotoxic agents, survival has improved for patients with metastatic disease. How to maximize the benefit of chemotherapy with acceptable toxicity remains incompletely answered. Hepatic resection can provide a significant hope for long term survival, and a subset of patients might benefit from perioperative approaches. More recently, specific molecular processes have been targeted for therapeutic interventions, and encouraging results have been achieved using inhibitors of the Epidermal Growth Factor Receptor and the Vascular Endothelial Growth Factor.

Aged↗

Therapeutic advances in the management of metastatic colorectal cancer.

Metastatic colorectal cancer has long been considered as a short-term, poor prognosis, chemoresistant disease. Until the early 1990s, the impact of systemic chemotherapy on patient outcome was debated. Recently, the emergence of new therapeutic modalities (5-FU modulations and associations with oxaliplatin and irinotecan) has led to a significant improvement in tumor response rates and patient survival. Thus, the indications of curative surgery of visceral metastases, frequently preceded and followed by chemotherapy, systemic or intra-arterial or both, have become more frequent. In this paper we will review and comment on the results of the major clinical trials published in the past 5 years and propose some decision strategies regarding the main clinical situations met in daily practice.

Antimetabolites, Antineoplastic↗

The influence of host response on colorectal cancer prognosis.

Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide. Several tumor characteristics have been shown to be of prognostic significance, although stage at diagnosis continues to be the most important predictor of survival. Emerging new data suggest that the presence of a host response to CRC may also influence survival and other outcomes in CRC. This review summarizes recent evidence regarding the prognostic significance of the host response to CRC. In retrospective analyses, tumor-associated macrophages and tumor-infiltrating lymphocytes appear to be the elements most significantly associated with improved outcomes in CRC. The presence of other cells, including dendritic cells, natural killer cells, eosinophils, and mast cells, also appears to be associated with increased survival. The influence of the host response to CRC needs confirmation in prospective studies, but in the meantime should be part of risk stratification. Novel approaches to further augmenting this response merit study.

Colorectal Neoplasms↗

SMAD4/DPC4 expression and prognosis in human colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is one of the most common malignancies in Western countries. One major event during CRC development is loss of genetic material on chromosome 18, on which the smad4/dpc4 gene is located. SMAD4 is an important mediator of intracellular signaling in the TGF-beta pathway. The functional inactivation of SMAD4 has been reported to occur in CRC. MATERIALS AND METHOD: The protein expression of SMAD4 was evaluated immunohistochemically in 86 formalin-fixed and paraffin-embedded CRC samples. The results were related to clinicopathological variables including survival. RESULTS: The loss of nuclear SMAD4 protein expression was observed in 9.3% of the investigated CRCs and was correlated to poor prognosis in univariate Kaplan-Meier (p=0.034) as well as in multivariate Cox-regression (p=0.028) analyses. CONCLUSION: The loss of nuclear SMAD4 protein expression occurs in a subset of CRC and is associated with poor prognosis.

Aged↗

[Feasibility survey (Phase I-II) of a four drugs combination (5-fluorouracil, folinic acid, carboplatin and irinotecan) delivered using a chronomodulated infusion in the treatment of advanced colorectal cancer].

Seventeen colorectal cancer patients received as first (12 cases) or second line (5 cases) treatment a combined chronotherapy with CPT 11 (infused at day 1 from 2 to 8 am; peak at 5 am), given with 5 FU (700 mg/m2 per day ; days 2-5) and folinic acid (300 mg/m2 per day, days 2-5) both infused from 10 pm to 10 am with a peak at 4 am, and carboplatin (40 mg/m3/day - days 2-5 ; infused from 10 am to 10 pm - peak at 4 pm). The doses of CPT 11 could be easily increased from 120 up to 180 mg/m2 in successive cohorts of four patients through acceptable toxicity. Thus, five patients have already been treated in the phase II part of the trial. An interesting tumoral outcome has been observed: 88% major responses with no progression; median time to progression: nine months and median survival: 19.7 months.

Adult↗