Preoperative geriatric assessment and tailored interventions in frail older patients with colorectal cancer: a randomized controlled trial.

AIM: Colorectal cancer (CRC) is prevalent in the older population, and surgery is the mainstay of curative treatment. A preoperative geriatric assessment (GA) can identify frail older patients at risk for developing postoperative complications. In this randomized controlled trial we wanted to investigate whether tailored interventions based on a preoperative GA could reduce the frequency of postoperative complications in frail patients operated on for CRC. METHOD: Patients > 65 years scheduled for elective CRC surgery and fulfilling predefined criteria for frailty were randomized to either a preoperative GA followed by a tailored intervention or care as usual. The primary end-point was Clavien-Dindo Grade II-V postoperative complications. Secondary end-points included complications of any grade, reoperation, length of stay, readmission and survival. RESULTS: One hundred and twenty-two patients with a mean age of 78.6 years were randomized. We found no statistically significant differences between the intervention group and the control group for Grade II-V complications (68% vs 75%, P = 0.43), reoperation (19% vs 11%, P = 0.24), length of stay (8 days in both groups), readmission (16% vs 6%, P = 0.12) or 30-day survival (4% vs 5%, P = 0.79). Grade I-V complications occurred in 76% of patients in the intervention group compared with 87% in the control group (P = 0.10). In secondary analyses adjusting for prespecified prognostic factors, there was a statistically significant difference in favour of the intervention for reducing the total number of Grade I-V complications (P = 0.05). CONCLUSION: A preoperative GA and tailored interventions did not reduce the rate of Grade II-V complications, reoperations, readmission or mortality in frail older patients electively operated on for CRC.

Navigating the mesentery: part II. Vascular abnormalities and a review of the literature.

AIM: Vascular abnormalities present advantages and/or disadvantages for the patient undergoing surgery. The aims of this study were to define, classify and demonstrate the courses, and to assess the clinical value, of arterial and venous abnormalities in the central mesentery. METHOD: We conducted a review of the anatomy of 340 patients planned for enrolment in the 'Safe Radical D3 Right Hemicolectomy for Cancer through Preoperative Biphasic MDCT Angiography' trial, 312 of whom were submitted to surgery. Vascular abnormalities were analysed in context with surgical notes and images. A meta-analysis of the literature was performed. RESULTS: Arterial Abnormalities were found in 28 (8.2%) of the 340 patients and were classified into the following three groups based on anticipated surgical difficulty: group 1, accessory or replaced arteries to solid organs [14 (4.1%)]; group 2, arterial shunts [11 (3.2%)] between the coeliac trunk and the superior mesenteric artery, which resulted in bleeding in three patients; and group 3, common stem abnormalities [3 (0.9%)]. Two groups of superior mesenteric vein abnormalities were noted. The first included morphological abnormalities in a single vein [4 (1.2%)]: aneurysm [1 (0.3%)]; and ring variants of principal tributaries [3 (0.9%)]. The second included double superior mesenteric vein trunks [31 (9.1%)]: genuine bifid [10 (2.9%)]; and pseudo bifid [21 (6.2%)]. The meta-analysis revealed 26 articles, including 10 series of anatomical dissections or angiographies [1970 cases with 205 (10.4%) arterial abnormalities] and 16 case reports, none of which described a clinical or surgical setting. CONCLUSION: Vascular abnormalities occur frequently. Arterial abnormalities are a hazard when inadvertent injury occurs during surgery. Preoperative knowledge of a bifid superior mesenteric vein is useful.

Navigating the mesentery: a comparative pre- and per-operative visualization of the vascular anatomy.

AIM: Awareness of anatomy is critical for performing safe surgery within the root of the mesentery. Our aim was to investigate the anatomical relationship between the superior mesenteric artery (SMA) and vein (SMV) and their branches within a predefined D3 area of the right colon and to compare preoperatively established three-dimensional (3D) mesenteric vessel anatomy from CT with that found at surgery. METHOD: Prospective data were collected on 139 patients included in the 'Safe Radical D3 Right Hemicolectomy for Cancer Through Preoperative Biphasic Multi-detector Computed Tomography (MDCT) Angiography' trial. CT data sets were 3D reconstructed before surgery and compared with photographs taken during the operation. RESULTS: The ileocolic artery was present and correctly identified in all patients and crossed the SMV anteriorly in 58 (41.7%). Seventeen patients had a right colic artery at surgery and there were three false-negative and one false-positive CT findings, yielding a diagnostic accuracy of 97.1%, sensitivity of 85.7% and specificity of 95.2%. Positive and negative predictive values were 94.7% and 97.5%, respectively. The middle colic artery was absent in one (0.7%) patient and multiple (nine double and one triple) in 10 (7.2%) patients. A mean of 3.8 ± 1.2 jejunal arteries and 2.0 ± 0.8 jejunal veins arose from the SMA and SMV. Jejunal veins crossed the SMA in the D3 area anteriorly in 30.9% of patients. In 26 (18.7%) patients, additional veins drained into the SMV, including pancreaticoduodenal in 16, right colic in six and both in two. The inferior mesenteric vein entered the SMV in 58 (41.7%) patients and crossed the D3 area in three (2.2%). CONCLUSION: CT-reconstructed anatomy has high specificity, sensitivity, accuracy and reliability.

CLC and IFNAR1 are differentially expressed and a global immunity score is distinct between early- and late-onset colorectal cancer.

Colorectal cancer (CRC) incidence increases with age, and early onset of the disease is an indication of genetic predisposition, estimated to cause up to 30% of all cases. To identify genes associated with early-onset CRC, we investigated gene expression levels within a series of young patients with CRCs who are not known to carry any hereditary syndromes (n=24; mean 43 years at diagnosis), and compared this with a series of CRCs from patients diagnosed at an older age (n=17; mean 79 years). Two individual genes were found to be differentially expressed between the two groups, with statistical significance; CLC was higher and IFNAR1 was less expressed in early-onset CRCs. Furthermore, genes located at chromosome band 19q13 were found to be enriched significantly among the genes with higher expression in the early-onset samples, including CLC. An elevated immune content within the early-onset group was observed from the differentially expressed genes. By application of outlier statistics, H3F3A was identified as a top candidate gene for a subset of the early-onset CRCs. In conclusion, CLC and IFNAR1 were identified to be overall differentially expressed between early- and late-onset CRC, and are important in the development of early-onset CRC.

Rapid secretion of prestored interleukin 8 from Weibel-Palade bodies of microvascular endothelial cells.

Interleukin (IL)-8, a C-X-C chemokine, activates integrin-mediated adhesion of neutrophils. Presentation of IL-8 on the endothelial cell surface may promote leukocyte extravasation. We found that cultured human microvascular endothelial cells from the intestine (HIMEC) and from nasal polyps (PMEC), but not human umbilical vein endothelial cells (HUVEC), contained IL-8 in intracellular granules that coexpressed von Willebrand factor (vWf ). This observation was corroborated by the immunohistochemical observation of double-positive granules (IL-8(+)vWf+) in vessels of small and large intestine, nasal mucosa, and skin, whereas umbilical cords revealed no endothelial IL-8. After treatment of HIMEC or PMEC with histamine or thrombin, a dramatic increase in supernatant IL-8 concentration was observed within 3 min, whereas no increase in IL-8 was detected in supernatants of identically treated HUVEC cultures. Histamine or thrombin treatment also caused IL-8-containing granules to rapidly disappear from HIMEC. In HUVEC, IL-8-containing granules were inducible by treatment with recombinant human IL-1beta for 24 h; additional histamine treatment doubled IL-8 secretion from HUVEC in the same rapid manner observed for mucosal EC. These data suggested that IL-8 prestored in microvascular endothelial cells may provide a rapid pathway for specific activation of neutrophil adhesion at sites of acute inflammation.

Increased resistance to chlorambucil in cultured cells with a high concentration of cytoplasmic metallothionein.

Cultured cells with elevated levels of cytoplasmic metallothionein (MT), a small-molecular-weight protein extremely rich in cysteine, showed resistance against the alkylating drug chlorambucil. One human epithelial line (HE) and one mouse fibroblast line (Cl 1D) were used, as well as substrains of both cell lines (HE100 and Cl 1D100). The substrains contain large amounts of MT. Dose-survival curves obtained from cloning studies with the murine cells after exposure to chlorambucil for 1 hr revealed that Cl 1D100 was approximately 3-fold more resistant than were Cl 1D cells (D0 = 32.9 and 11.6 micrograms/ml, respectively); this difference was highly significant (p less than 0.001; t test). In growth rate studies, both MT-containing strains showed resistance against chlorambucil over the total dose range of 0.5 to 100 micrograms/ml compared to the parent strains. After 4 days treatment with 25 micrograms/ml, the growth inhibition of Cl 1D was 67%, but only 13% in Cl 1D100. For HE and HE100, 50 micrograms/ml gave growth inhibitions of 83 and 65%, respectively. Following 1- and 24-hr incubations of cells with [14C]chlorambucil and subsequent ultracentrifugation and gel filtration of the cytosols, about 20 to 40% of the 14C-derived radioactivity coeluted with the MT from the resistant strains. The results indicate that intracellular MT sequesters chlorambucil or its toxic metabolites and that the protein thus contributes to the resistance against this drug.

Expression and gene amplification of primary (A, B1, D1, D3, and E) and secondary (C and H) cyclins in colon adenocarcinomas and correlation with patient outcome.

BACKGROUND/AIMS: Deregulation of cell cycle control is a hallmark of cancer. The primary cyclins (A, B1, D1, D3, and E) are crucial for cell cycle progression. Secondary cyclins (C and H) have putative indirect effects on cell cycle progression and have not previously been evaluated in colon cancer. This study examined cyclin protein expression and gene amplification in colon adenocarcinoma and the correlation with patient outcome. METHODS: Immunohistochemistry and real time quantitative polymerase chain reaction were used to determine cyclin expression and gene amplification in 219 tumours. The results were compared with clinical variables and patient outcomes. RESULTS: Cyclin H was overexpressed in all tumours, cyclin C in 88%, cyclin B1 in 58%, cyclin A in 83%, cyclin D3 in 36%, cyclin E in 25%, and cyclin D1 in 11% of the tumours. Extra gene copies of cyclin A were seen in 6.2% of the tumours, cyclin B1 in 9%, cyclin C in 26.9%, cyclin D1 in 55%, cyclin D3 in 20.5%, cyclin E in 19.1%, and cyclin H in 5.1%. A significant correlation between protein overexpression and gene amplification was seen for cyclin C only. High expression of cyclin A was independently associated with improved survival. Amplification of cyclin C was independently associated with an unfavourable prognosis. CONCLUSIONS: Amplification of the cyclin C gene was related to an unfavourable prognosis and high protein expression of cyclin A was associated with a better outcome in colon adenocarcinoma.

Surgical treatment as a principle in patients with advanced abdominal carcinoid tumors.

Seventy-five patients with advanced abdominal carcinoid tumors (65 midgut, 10 others) have been examined retrospectively to evaluate the role of surgical treatment as a principle, irrespective of stage of disease. Eighteen of 52 patients (35%) exhibited the carcinoid syndrome. Two or more primaries were found in 39% of patients with midgut lesion, 81% of these patients had regional metastases, 5% of these patients had distant lymph node metastases, and 74% of the patients had liver secondaries. All patients underwent operation, an additional 34% of the patients had a further reoperation, 9% of the patients had a second reoperation, 3% of the patients had a third reoperation, and one patient (2%) had a fourth reoperation. Intraoperative debulking (liver excluded) was performed in 33% of the patients, and 48% of the patients had treatment (resection, hepatic artery ligation, embolization) directed at the liver. The postoperative mortality rate was 2% after the primary operation for midgut lesions. The median survival for midgut tumors was 92 months, compared to 40 months for other lesions (not significant). A significantly higher survival rate was revealed for those patients with midgut lesion who were undergoing intraabdominal debulking procedures (liver excluded); median survival was 139 months versus 69 months without debulking. For those patients with liver metastases, median survival after intervention was 216 months and 48 months without such treatment (p less than 0.001). It is concluded that resection of intraabdominal carcinoid tumor masses can be performed in a high proportion of patients. Despite the retrospective, uncontrolled nature of this study, the difference in survival probabilities in favor of aggressive surgical therapy is so marked that it is not unreasonable to conclude that surgery has played a role in prolonging life in these patients.

Presence of isolated tumour cells in mesenteric lymph nodes predicts poor prognosis in patients with stage II colon cancer.

AIM: Most patients with stage I and stage II colon adenocarcinomas do not have disseminated disease, and the group is not offered adjuvant therapy. However, more than 30% of stage II colon adenocarcinoma patients get metastases to remote organs. Thus, it is important to identify patients in this group at risk of disease relapse. PATIENTS AND METHODS: We have examined the prognostic value of isolated tumour cells (ITC) in mesenteric lymph nodes in a consecutive series of 156 colon carcinoma patients with stage II disease. Immunohistochemistry, using antibodies to cytokeratins, and morphology were used to identify presence of ITC. RESULTS: ITC were detected in 59 (37.8%) patients. Presence of ITC in mesenteric lymph nodes was independently associated with reduced relative survival both in univariate (p=0.0199) and in a multivariate analysis (p=0.041). CONCLUSION: The results strongly suggest that presence of ITC in mesenteric lymph nodes is associated with reduced relative survival in colon carcinoma patients stage II, and that detection of ITC may be important in treatment of these patients.

Assessment of Mucosal Inflammation and Circulation in Response to Probiotics in Patients Operated with Ileal Pouch Anal Anastomosis for Ulcerative Colitis.

BACKGROUND: Pouchitis is a common and troublesome condition, and a disturbed microbiological flora and mucosal blood flow in the pouch have been suggested as possible causes. Laser Doppler flowmetry (LDF) has been used successfully to measure gastric and colonic mucosal perfusion in humans. The aim of this study was to evaluate the effect of intervention with probiotics on ileal pouch inflammation and perfusion in the pouch, assessed by endoscopy, histology, fecal calprotectin and LDF. METHODS: A fermented milk product (Cultura; 500 ml) containing live lactobacilli (La-5) and bifidobacteria (Bb-12) was given daily for 4 weeks to 10 patients operated with ileal-pouch-anal anastomosis (IPAA) for ulcerative colitis (UC). Mucosal perfusion was measured with LDF and the degree of inflammation was examined at predefined levels of the distal bowel by endoscopy and histology. Stool samples were cultured for lactobacilli and bifidobacteria and calprotectin were measured before and after intervention. RESULTS: The LDF measurements were reproducible in the pelvic pouch at each of the predefined levels, but did not change after intervention. The mucosal perfusion was reduced in the distal compared to the proximal part of the pouch. Calprotectin levels did not change significantly after intervention. The median endoscopic score for inflammation was significantly reduced by 50% after intervention, whereas the histological score did not change significantly. CONCLUSION: The results suggest that probiotics primarily act superficially, with change of gross appearance of the mucosa at endoscopy, but without significant effect on histological picture, mucosal perfusion or faecal calprotectin, during a relatively short period of 4 weeks.

Two simultaneously occurring hypopharyngo-oesophageal diverticula.

We report a case of two simultaneously occurring hypopharyngeal-oesophageal diverticula, one apparently originating above, the other below the cricopharyngeal muscle. The radiological and clinical findings of this rare condition are presented.

Endoscopic treatment of colorectal carcinoma.

All malignant pedunculated polyps of the colon can be removed totally by colonoscopy alone. Resection of the colon is only necessary in those few instances where the cancer portion is poorly differentiated and where there are cancer cells in lymphatic or vascular channels. Malignant well differentiated sessile polyps are adequately managed by the endoscopic technique as well if the polypectomy is believed to have been complete and this can be confirmed by follow-up biopsies after 4-8 weeks. In these patients Laser therapy may also be of value. Endoscopic Laser therapy may be of value as a symptomatic treatment in patients with advanced malignant disease with obstruction or bleeding.

Outcome of four weeks' intervention with probiotics on symptoms and endoscopic appearance after surgical reconstruction with a J-configurated ileal-pouch-anal-anastomosis in ulcerative colitis.

OBJECTIVE: Pouchitis is a common and troublesome condition in patients operated on with ileal-pouch-anal-anastomosis (IPAA). A disturbed microecology in the pouch has been suggested as one possible explanation. In a previous double-blind, randomized, controlled study we demonstrated clinical improvement of symptoms in patients with ulcerative colitis (UC) operated on with IPAA, during intervention with live probiotic microbes Lactobacilli and Bifidobacteriae. The aim of the present study was to confirm our previous results in a much larger material, including clinical symptoms, faecal flora and endoscopic evaluation, and to compare the results in UC/IPAA patients with those of patients with familial adenomatous polyposis (FAP) with IPAA and UC patients with ileorectal anastomosis (IRA). MATERIAL AND METHODS: Five hundred millilitres of a fermented milk product (Cultura) containing live lactobacilli (La-5) and bifidobacteriae (Bb-12) was given daily for 4 weeks to 51 UC patients and 10 patients with FAP, operated on with IPAA, and six UC patients operated on for IRA. Stool samples were cultured for examination of lactobacilli, bifidobacteriae, fungi and pH before, during and after intervention. Before, during and after intervention, endoscopic evaluation was performed. Categorized symptomatology was examined prospectively using diary cards in addition to an interview, before and on the last day of intervention. RESULTS: The number of lactobacilli and bifidobacteriae increased significantly during intervention in the UC patients operated on with IPAA and remained significantly increased one week after intervention. Involuntary defecation, leakage, abdominal cramps and the need for napkins (category I), faecal number and consistency (category II) and mucus and urge to evacuate stools (category III) were significantly decreased during intervention in the UC/IPAA group. In the FAP group there was a significant decrease in faecal leakage, abdominal cramps and use of napkins (category I) during intervention. The median endoscopic score of inflammation was significantly decreased during intervention in the UC/IPAA patients. Blood tests, faecal fungi and faecal pH did not change significantly during intervention. CONCLUSIONS: Results of this extended study, showing an effect of probiotics on symptoms and endoscopic inflammation in UC patients operated on with IPAA confirm our previously reported effect of probiotics on clinical symptoms and endoscopic score in a smaller, double-blind, randomized, controlled study. The significantly higher response to probiotics in families with increased risk of IBD will have to be repeated in future studies.

Effect of cadmium and colcemide on the mitoses of a human epithelial cell line with high content of cytoplasmic metallothionein.

Cultures of cell strains with and without metallothionein were exposed to CdCl2 in doses ranging from 10 mu mol/l to 200 mu mol/l . Cell growth parameters were monitored by flow cytometric DNA-measurements, cell counts and counting of mitoses during the first two days after exposure. CdCl2 inhibited cell growth in a dose dependent way. The cadmium resistant cells were inhibited with concentrations above 100 mu mol/l, the concentration which the metallothionein-containing cells had previously been adjusted to. Microscopy of the cell cultures showed a dose dependent accumulation of cells in the mitotic prophase, whereas the other phases of the cell cycle were unaffected as measured by flow cytometry. When exposed to colcemide, however, the two cell strains showed identical responsiveness.