Electrical stimulation induces propagated colonic contractions in an experimental model.

BACKGROUND: Direct colonic electrical stimulation may prove to be a treatment option for specific motility disorders such as chronic constipation. The aim of this study was to provoke colonic contractions using electrical stimulation delivered from a battery-operated device. METHODS: Electrodes were inserted into the caecal seromuscular layer of eight anaesthetized pigs. Contractions were induced by a neurostimulator (Medtronic 3625). Caecal motility was measured simultaneously by video image analysis, manometry and a technique assessing colonic transit. RESULTS: Caecal contractions were generated using 8-10 V amplitude, 1000 micros pulse width, 120 Hz frequency for 10-30 s, with an intensity of 7-15 mA. The maximal contraction strength was observed after 20-25 s. Electrical stimulation was followed by a relaxation phase of 1.5-2 min during which contractions propagated orally and aborally over at least 10 cm. Spontaneous and stimulated caecal motility values were significantly different for both intraluminal pressure (mean(s.d.) 332(124) and 463(187) mmHg respectively; P < 0.001, 42 experiments) and movement of contents (1.6(0.9) and 3.9(2.8) mm; P < 0.001, 40 experiments). CONCLUSION: Electrical stimulation modulated caecal motility, and provoked localized and propagated colonic contractions.

[Current management of anal incontinence]. / Prise en charge actuelle de l'incontinence anale.

Even though anal incontinence affects a significant proportion of the population, causing a major burden to both patient and society, it still remains "the last closet issue". Less than a third of patients will share this problem with their physician. Consequently, the incidence of anal incontinence is difficult to determine, varying from 2-50%. Since this disabling condition is often associated with urinary incontinence and/or pelvic organ prolapse, a multidisciplinary team approach is required. A wide range of therapeutic options are available. When dietary, medical and rehabilitative treatments have failed, sacral neuromodulation should be considered in selected cases. More invasive surgery is usually undertaken in the presence of major structural defects. The aim of this article is to suggest a comprehensive way of identifying and treating anal incontinence.

[The management of an incidental liver lesion]. / Prise en charge d'une lésion hépatique découverte fortuitement.

The widespread use of abdominal imaging technologies has led to an increase in the incidental finding of liver tumors. Most of these lesions are asymptomatic and will not require any treatment. With the use of contrast-enhanced radiological studies, most of the tumors can be reliably diagnosed by non-invasive means. In case of diagnostic uncertainty, patients should not undergo percutaneous biopsy but rather complete resection of the lesion for an unequivocal diagnosis. Such pathologies must be taken charge of in centers with expertise by interdisciplinary teams.

[Trends in surgery]. / Chirurgie.

More than the number of real novelties, trends and preliminary results characterise the annual development in surgery. The wealth and diversity of topics to be covered require arbitrary choices, therefore not necessarily complete. The constant development of choledocolithiasis management, dominated by minimal invasive technology, treatments of unusual nature of two frequent proctological conditions, fistulae and haemorrhoids, the increasing importance of metabolic bariatric surgery, as well as the strict rules of effective melanoma treatment, represent as many directions in which the operating procedure, although unseen, continue to gain quality and security.

[Fast track surgery]. / Chirurgie fast track.

Fast track (FT) surgery is a multimodal concept aiming to reduce postoperative pain and stress-induced organ dysfunction. Key elements are perioperative fluid restriction, epidural analgesia, early oral nutrition and early mobilization. Therefore, multidisciplinary teamwork is required in order to obtain the optimal outcome of reduced postoperative complications and a hospital stay of only three or four days after open colectomy. Most of the patients undergoing colorectal surgery qualify for FT surgery. Meanwhile, FT principles are applied in a variety of open and laparoscopic procedures. The aim of this review is to highlight the principles of FT and to answer the question why FT surgery should nowadays be considered as standard care.

Secretion of bioactive granulocyte-macrophage colony-stimulating factor by human colorectal carcinoma cells.

Secretion of several cytokines by colorectal carcinoma cells has been substantiated. These do not include granulocyte-macrophage colony-stimulating factor (GM-CSF) thus far. We show that the supernatant of two human colorectal carcinoma cell lines, LS1034 and SW480, stimulates proliferation of GM-CSF-dependent M07e cells. The activity was constitutively secreted by LS1034 cells and could be induced by serum-free culture conditions in SW480 cells. Addition of a neutralizing anti-GM-CSF antibody completely inhibited this activity. Preabsorption with anti-GM-CSF antibody removed all M07e growth-stimulating activity from LS1034 and SW480 supernatant. Western blot analysis revealed the presence of GM-CSF in LS1034 supernatant. Our results indicate that human colorectal carcinoma cells secrete indeed biologically active GM-CSF.

Responsiveness of three newly established human colorectal cancer cell lines to transforming growth factors beta 1 and beta 2.

We have established 3 new human colorectal cancer cell lines (LS411N, LS513, and LS1034) from clinical biopsy samples. These lines are tumorigenic and grow s.c. as adenocarcinomas in nude mouse xenografts. Specific marker chromosomes are observed in each line. Carcinoembryonic antigen is expressed at the surface of all 3 lines, but with marked quantitative differences. Indeed, less than 10% of the cells from the HT-29 line used as a reference express carcinoembryonic antigen while more than 90% of the LS1034 cells do so. LS513 and LS1034 consistently express HLA class I antigens and intercellular adhesion molecule 1 which are not detected at the surface of the LS411N cells. No expression of HLA class II antigens DR, DQ, and DP has been measured on any of the lines. All three lines grow well in 5% fetal calf serum medium without addition of exogenous growth factors. The LS1034 line has been adapted to growth in serum-free conditions and exhibits increased clonogenicity when cells are seeded in serum-free methylcellulose medium, as compared with medium containing 5% fetal calf serum. The LS513 and LS1034 lines have proved to be of particular interest since they respond to the growth-inhibitory action of TGF-beta 1 and TGF-beta 2 in both liquid and semisolid medium. Both factors were, at pM concentrations, equipotent inhibitors of LS1034 cell proliferation. In contrast, higher concentrations of TGF-beta 1 are inhibitory for proliferation of LS513 cells, whereas TGF-beta 2 has no effect on the growth of these cells in liquid assay. On this basis, using appropriate anti-TGF-beta 1 and anti-TGF-beta 1 IgY, we developed a bioassay for TGF-beta 1 and TGF-beta 2. Two of the three lines have indeed been shown to produce latent-TGF-beta 1 activity.

[Visceral surgery]. / Chirurgie.

Visceral surgery has benefited from several significant therapeutical improvements in 2005. They involve more specifically endocrine surgery, obesity, ovarian cancer, rectocele and cystic pancreatic neoplasia. Minimal invasive surgery is increasingly used, for example in endocrine conditions and obesity treatment. New techniques also emerge, such as electrical gastric stimulation for obesity or Stapled Trans Anal Rectal Resection (STARR) for anterior rectocele. Accurate diagnosis criteria allow better management of cystic pancreatic neoplasia, especially to choose the best treatment of this condition.

[Surgery]. / Chirurgie.

The evolution of visceral surgery is characterized by defining with ever increasing precision the real role of new techniques. Hernia repair, abdominal compartment syndrome, pancreatic and colorectal cancers, as well as haemorrhoids, confirm this reality. Although laparoscopy has clear indications in hernia repairs, many still prefer open approach. The abdominal compartment syndrome, now better understood thanks to laparoscopy, is increasingly important in intensive care. The role of laparoscopy for pancreatic and colorectal cancers is still limited. The development of minimally invasive techniques has led to a reduced morbidity of surgery for haemorrhoids and better results. The economic impact of new technologies must remain a primary concern.

Interferon alpha and 5'-deoxy-5-fluorouridine in colon cancer: effects as single agents and in combination on growth of xenograft tumours.

Interferon-alpha (IFN-alpha) enhances the activity of the 5-fluorouracil (5-FU) prodrug 5'-deoxy-5-fluorouridine (5'-dFUrd) in colorectal cancer cells in vitro by upregulating the enzyme pyrimidine nucleoside phosphorylase (PNPase), which is responsible for converting 5'-dFUrd to 5-FU. We examined whether such enhancement also occurs in vivo using human colorectal xenografts in nude mice. The Co-115 line has high basal levels of PNPase and the enzyme level was increased in tumours from mice treated for 3 weeks with 50,000 IU/day (5 days/week) of IFN-alpha A/D. The prodrug 5'-dFUrd (200 mg/day, 5 days/week) had a much greater antitumour activity than 5-FU had when it was used at an approximately equitoxic dose (20 mg/day, 5 days/week). However, because of the high activity of 5'/dFUrd as a single agent, no enhancement by IFN-alpha A/D was observed. Studies on xenografts of WiDr cells indicated that this line is much less sensitive to 5'-dFUrd. However, treatment of animals with IFN-alpha A/D at doses of 75,000 IU/day or 150,000 IU/day resulted in significant inhibition of WiDr tumour growth. Combination treatment with 75 mg/kg/day or 150 mg/kg/day of 5'-dFUrd resulted in enhanced antitumour activity, particularly at the higher dose of IFN-alpha A/D. Synergy of this drug combination was confirmed by isobologram analysis. Analysis of PNPase levels in WiDr tumours, excised from mice treated with IFN-alpha A/D, demonstrated that the enzyme activity was increased by IFN-alpha in a dose-dependent manner. Slight increases were also seen in normal liver and intestine from the same animals. Our results indicate that modulation of converting enzymes for anticancer prodrugs by cytokines could be a novel therapeutic strategy for combination therapy of colorectal cancer.

Interactions of interferon-alpha 2a with 5'-deoxy-5-fluorouridine in colorectal cancer cells in vitro.

The biological activity of 5'-deoxy-5-fluorouridine (5'-dFUrd) depends upon intracellular enzymatic cleavage by pyrimidine phosphorylase to form 5-fluorouracil (5-FU). Interferon-alpha 2a (IFN-alpha) effect was analysed alone and combined with 5-FU or 5'-dFUrd, on proliferation inhibition of eight human colorectal cancer cell lines. The toxicity of 5-FU was enhanced by IFN-alpha in only one line (SW-480). In contrast, interactive enhancement of IFN-alpha was observed with 5'-dFUrd in five lines (WiDr, HT-29, 513, SW-480 and Co-115). In each of the lines showing potentiation by IFN/5'dFUrd but not by IFN/5-FU, cytoplasmic pyrimidine phosphorylase activity was increased after 5 days' incubation with IFN-alpha in a dose-dependent manner. Two lines (LISP-1 and SW-620) showed no potentiation of either 5-FU or 5'-dFUrd toxicity by IFN-alpha, and no change in pyrimidine phosphorylase activity. Potentiation of 5'-dFUrd effect by IFN-alpha may thus be explained by an enhancement of its conversion to 5-FU through stimulation of pyrimidine phosphorylase activity.

Expression of homeobox-containing genes in primary and metastatic colorectal cancer.

Homeobox genes are a network of genes encoding nuclear proteins functioning as transcriptional regulators. Human and murine homeobox genes of the HOX family are organised in four clusters on different chromosomes. Gene order within each cluster is highly conserved, perhaps in direct relation to their expression. Homeobox genes have recently been involved in normal development and oncogenesis. We have analysed HOX gene expression in normal human colon and in primary and metastatic colorectal carcinomas. The majority of HOX genes are active in normal adult colon and their overall expression pattern is characteristic of this organ. Furthermore, the expression of some HOX genes is identical in normal and neoplastic colon indicating that these genes may exert an organ-specific function. In contrast, other HOX genes exhibit altered expression in primary colon cancers and their hepatic metastases which may suggest an association with colon cancer progression.

Growth stimulation of a human colorectal carcinoma cell line by interleukin-1 and -6 and antagonistic effects of transforming growth factor beta 1.

We analysed the effect of interleukin-1 (IL-1), IL-6 and transforming growth factor beta 1 (TGF beta 1) on the growth of a panel of eight colorectal carcinoma cell lines. IL-1 stimulated growth of two lines (LS411N and LS1034) up to 20-fold and IL-6 enhanced proliferation of LS1034 more than 5-fold. Both cytokines also augmented colony-formation of LS1034 in methylcellulose. Under both growth conditions IL-1 was the most potent stimulator. However, the addition of IL-6 to IL-1 synergistically enhanced proliferation of LS1034 in monolayer culture and additively augmented the number of colonies formed in methylcellulose. Furthermore, TGF beta 1 strongly reduced the growth rate of LS1034. Low amounts of TGF beta 1 markedly inhibited the response of LS1034 to IL-1 and totally abrogated proliferation induced by IL-6. We conclude that different cytokines can provide distinct signals for the regulation of growth of colorectal carcinoma cells.

p53 and Ki-ras as prognostic factors for Dukes' stage B colorectal cancer.

Mutations of the TP53 and Ki-ras genes have been reported to be of prognostic importance in colorectal carcinomas. An increased intracellular concentration of the p53 protein, although not identical to, is sometimes seen in tumours with TP53 mutation and has been correlated with poor prognosis in some tumour types. Previous colorectal cancer studies, addressing the prognostic importance of Ki-ras mutation and TP53 aberrations, yielded contradictory results. The aim of this study was to determine in a clinically and therapeutically homogeneous group of 122 sporadic Dukes' B colorectal carcinomas with a median follow-up of 67 months (3-144 months) whether or not p53 protein expression, TP53 mutation and K-ras mutation correlated with prognosis. p53 staining was performed by immunohistochemistry, using the monoclonal antibody DO7 on paraffin-embedded tissue. Mutations in exons 5-8 of the TP53 gene and in codons 12 and 13 of the K-ras gene were assayed in paraffin-embedded tissue by the single-strand conformation polymorphism (SSCP) assay. Nuclear p53 staining was found in 57 (47%) tumours. Aberrant migration patterns indicating mutation of the TP53 gene were found in 39 (32%) tumours. Forty-six carcinomas (38%) showed a mutation of the Ki-ras codons 12 or 13. In a univariate analysis, patients with wild-type TP53 status showed a trend towards better survival, compared with those with mutated TP53 (log-rank test, P = 0.051). Likewise, tumours immunohistochemically positive for p53 showed a worse prognosis than p53-negative tumours (P = 0.010). The presence or absence of mutations in Ki-ras did not correlate with prognosis (P = 0.703). In multivariate analysis, only p53 immunoreactivity emerged as an independent marker for prognosis hazard ratio (HR) = 2.16, 95% confidence interval (CI) 1.12-4.11, P = 0.02). Assessment of p53 protein expression is more discriminative than TP53 mutation to predict the outcome of Dukes' stage B tumours and could be a useful tool to identify patients who might benefit from adjuvant therapy.

Clinical value of immunoscintigraphy in colorectal carcinoma patients: a prospective study.

Fifty-seven patients with suspected CEA-producing tumors were studied prospectively by radioimmunoscintigraphy (RIS) using a 123I-labeled anti-CEA monoclonal antibody (MAb) (essentially the F(ab')2 or Fab fragments) and emission computed tomography (ECT). Results of RIS were compared to those of a comprehensive diagnostic study. Final diagnosis was based on surgery, biopsy and autopsy (n = 39) or follow-up findings (n = 18). Three groups of patients were defined: Group A with suspected primary tumors (n = 11), Group B with probable (n = 19) and Group C with questionable (n = 27) tumor relapse. Eighty-eight per cent, 93% and 71% of the anatomic regions studied were correctly identified as being involved, and 97%, 97%, and 87% as being free from tumor in Groups A, B, and C, respectively. In the 27 patients from Group C with no definite diagnosis of relapse, and in whom diagnosis was most difficult, 38 tumor sites were involved. Of these, 21 were detected by both prospective RIS and repeated comprehensive study, six by RIS only and seven by conventional methods only. Four sites remained undetected by both approaches. Ten of the 21 lesions were detected by RIS more than 1 mo earlier than by any other method. Among the seven tumor sites detected by other diagnostic modalities only, three were identified at the time of RIS and four became positive more than 6 mo later. Overall diagnosis was entirely correct in 30, partially correct in 16 and incorrect in six patients studied. RIS with ECT and 123I-labeled anti-CEA MAb allows early detection of recurrence or metastasis of colorectal cancer. It thus contributes to reduced delay between diagnosis and treatment.

Prognostic factors in colorectal cancer.

Prognosis of patients after colorectal cancer resection is predominantly influenced by the extent of local tumour growth and the presence or absence of nodal or distant metastasis. However, many factors have been used to generate numerous classification systems, leading to some debate and confusion. The effects on survival of 7 clinical and pathological parameters were reviewed in 801 consecutive patients operated upon with locally curative intent for colorectal cancer over a ten-year period. Age less than 50 or more than 70 years, poor cellular differentiation, high mucous secretion by tumour cells and Dukes' staging were the parameters significantly correlated to poor overall survival (p<0.001 for each). The Cox's regression analysis identified the same parameters as independent prognostic factors. The value of age as a prognostic factor remains debatable, but the other three parameters must be considered when evaluating prognosis after curative surgery for colorectal cancer and when considering adjuvant therapy.

Potential value of biliary CEA assay in early detection of colorectal adenocarcinoma liver metastases.

Elevation of the biliary CEA level in patients with liver metastases from colorectal carcinoma has been reported. The aim of this study is to determine the potential value of biliary CEA assay in the early detection of liver metastases. Biliary and serum CEA levels were determined in patients operated on for a colorectal cancer and in control groups. Among 13 patients with liver metastases from colorectal carcinomas, biliary CEA levels were markedly elevated (> 40 ng/ml) in nine, moderately elevated (5-40 ng/ml) in two and normal (arbitrarily defined as < 5 ng/ml) in two. Of 28 patients with primary colorectal carcinoma without detectable hepatic secondaries, three had marked CEA elevation in the bile, 10 had moderate CEA elevation and 15 had normal levels. Among nine patients with non-malignant hepatobiliary pathology, there was one marked biliary CEA elevation, one moderate elevation and seven normal levels. None of the 13 individuals with no identified hepatobiliary pathology had elevated biliary CEA levels. The follow-up of patients with a primary colorectal tumour, no evidence of hepatic secondaries and a biliary CEA elevation is of particular interest. If subsequent appearance of liver metastases is found in such cases, intra-operative biliary CEA assay could be considered a valuable diagnostic test. Further studies will then have to prove the possible benefit of a specific treatment for this group of patients.

Esophageal cancer as second primary tumor after breast cancer radiotherapy.

BACKGROUND: An increased risk of esophageal cancer has been reported in survivors of breast cancer treated with radiotherapy. This study further characterizes this association. METHODS: Through hospital databases, 118 patients (109 men, 9 women) treated for esophageal cancer between 1985 and 1993 were identified, of whom 37 had 60 synchronous or metachronous cancers. 5 women had primary esophageal cancer after having breast cancer, and are the subjects of this case-control study. RESULTS: All 5 women had been treated with radical mastectomy and adjuvant radiotherapy; none received chemotherapy. Their ages at the time of breast cancer ranged from 36 to 82 years; at esophageal cancer, 61 to 95 years. Time between radiotherapy and esophageal cancer varied from 13 to 31 years. All esophageal cancers were squamous cell carcinomas. Mean survival after esophageal cancer was 14.2 months. CONCLUSIONS: Radio-induced esophageal cancer can occur as a second primary cancer in women who survive at least 1 decade after mastectomy and adjuvant radiotherapy.

The type of K-ras mutation determines prognosis in colorectal cancer.

BACKGROUND: Mutations involving the oncogene K-ras in colorectal cancer may be related to tumor aggressiveness. However, the value of K-ras gene determination as a prognostic marker has not been clearly established. PATIENTS AND METHODS: The results from 98 patients recruited in a prospective study analyzing the effect of a K-ras mutation as a prognostic factor in colorectal cancer are reported. RESULTS: Disease-free (P = 0.02) and overall survival (P = 0.03) were significantly reduced for patients harboring a K-ras mutation. Two specific mutations demonstrated a significantly increased risk of disease recurrence, namely, 12-TGT (P = 0.04) and 13-GAC substitutions (P = 0.002). Patients with either of these substitutions had a 2-year disease-free survival rate of 37% compared with that of 67% for the group of patients harboring any other mutation type or a wild-type status (P = 0.01). CONCLUSIONS: The results herein presented suggest that K-ras acts as a prognostic factor in colorectal cancer and that this effect is probably related to a limited number of defined mutations.