Hypofractionated accelerated radiotherapy, cytoprotection and capecitabine in the treatment of rectal cancer: a feasibility study.

BACKGROUND: This is a report on the feasibility and efficacy of hypofractionated accelerated radiotherapy combined with amifostine cytoprotection (hypoARC) and capecitabine in the treatment of rectal adenocarcinoma. PATIENTS AND METHODS: Twenty-seven patients (pts) received pre- (14 pts) or postoperative (13 pts) conformal radiotherapy with 10 consecutive fractions of 3.4 Gy in 12 days, supported with subcutaneously administered high-dose amifostine (up to 1000 mg) and capecitabine (daily dose of 600 mg/m2 twice a day, 5 days per week for 4 weeks). Ten additional patients with inoperable tumors received a higher dose (15 fractions of 3.4 Gy) as a radical intervention and 5 received a lower dose for palliation. RESULTS: Chemotherapy-related toxicity was minimal and radiation grade 2 diarrhoea and proctitis was noted in 3/42 and 4/42 cases, respectively. No peri- or postoperative complications were noted in patients receiving pre-operative radiochemotherapy. Significant tumor regression was confirmed in post- RT CT-imaging and major histological responses were noted in 85% of cases treated before surgery. Late toxicity (median follow-up 26 months) was negligible. The 2-year local relapse-free survival was 85-90% in patients treated with pre- or postoperative radiotherapy and 35% in patients with inoperable tumors. CONCLUSION: Capecitabine-based hypoARC is feasible with only minimal early and late toxicity and encouraging efficacy.

Early antivascular effects of bevacizumab anti-VEGF monoclonal antibody on colorectal carcinomas assessed with functional CT imaging.

BACKGROUND: The complex effect on anti-VEGF (vascular endothelial growth factor) monoclonal antibodies on the tumor vasculature urges studies to identify the optimal time frames for the administration of such agents with chemotherapy and radiotherapy. PATIENTS AND METHODS: Using CT scan functional imaging, we examined the perfusion changes of contrast medium induced 7 days following administration of bevacizumab (5 mg/kg iv) in 12 patients with colorectal cancer. RESULTS: CT imaging 7 days after the administration of bevacizumab confirmed tumor shrinkage in 3 of 12 cases. The mean Haunsfield units after the injection of contrast medium were significantly lower 7 days following the administration of bevacizumab (P = 0.002). The "perfusion score" significantly decreased after the administration of bevacizumab (P = 0.01). In 5 of 12 cases the perfusion score was by 45% to 75% decreased, in 3 of 12 minor drop of the perfusion score was noted, in 1 of 12 a slight increase was noted, and in 3 of 12 remained unchanged. CONCLUSION: It is concluded that the antivascular effects of bevacizumab are evident within 7 days from administration in 40% of colorectal carcinomas. The mechanisms by which this early antivascular effect may favor the antitumor efficacy of radiotherapy and chemotherapy require further investigation.

Corticotropin-releasing factor (CRF) receptor type 2 in the human stomach: protective biological role by inhibition of apoptosis.

Corticotropin-releasing factor agonists exert inhibitory effects in stomach functions possibly through peripheral routes. We have previously reported the expression of Urocortin (Ucn) I, an endogenous ligand of both CRF receptor types CRF(1) and CRF(2), in the human stomach. We examined CRF(1) and CRF(2) expression in the same tissue. Using RT-PCR, CRF(2) but not CRF(1) transcripts were detected in RNA extracts from normal human stomach. In addition, immunohistochemical analysis revealed receptor protein in epithelial gastric cells. In order to investigate the biological role of CRF(2) in these cells, an in vitro model was established, using the gastric cancer cell line AGS transiently transfected to express functional CRF(2). The effect of the CRF(2) endogenous ligands CRF, Ucns I and II on the growth parameters of the AGS/CRF(2) was examined. After 1 day of exposure, all three ligands reduced the degree of apoptosis (16%-19%, n = 9, P < 0.05) compared to non-treated controls and this effect was observed for 3 days of treatment. No such effect was detected in non-transfected cells, suggesting mediation through CRF(2) receptors. Administration of CRF, Ucns I and II had no effect on the proliferation rate of AGS/CRF(2) cells or on the release of PGE(2) by them. Our results demonstrate CRF(2) expression in the human gastric mucosa and indicate a physiological role of this receptor type in regulating apoptosis, an important parameter of gastric cell regeneration. Paracrine effects exerted by locally expressed endogenous ligands, such as Ucn I, support a significant role of the peripheral CRF system in gastric physiology. J. Cell. Physiol. 209: 905-911, 2006. (c) 2006 Wiley-Liss, Inc.

Lateral subcutaneous internal sphincterotomy in the treatment of chronic anal fissure: our experience.

BACKGROUND: Chronic anal fissure is the most common cause of anal pain associated with internal anal sphincter hypertonia. Reduction of hypertonia favours fissure healing. Temporary reduction in sphincter tone can be achieved by conservative treatment. Surgical sphincterotomy achieves permanent reduction of sphincter hypertonia and is very successful at healing anal fissures, but requires an operation with associated small morbidity. METHODS: A study was undertaken on 246 patients (120 men, 126 women, mean age 48.3 years), undergoing subcutaneous lateral internal sphincterotomy for a chronic fissure-in-ano from January 1, 1981 to December 31, 2004. Therapeutical outcome, postoperative course and early and long-term results were recorded. RESULTS: During the study period, the 246 patients underwent total subcutaneous lateral internal sphincterotomy, 62 of them under general anesthesia (1981-1991), and the remainder under local anesthesia. Two-hundred-forty-two patients returned for their postoperative visits at 2, 6, 24 and 48 weeks, while four patients were lost to follow-up. At 3 months postoperatively, 97.5% of fissures had healed; 224 fissures were healed by 6 weeks, 10 by 7 weeks and 2 by 3 months. Pain was significantly reduced in all patients at Day 1 postoperative. Minor complications included hematoma (0.8%) and pain (0.4%). New minor incontinence was seen in 7.02% of patients at 48-week follow up. Patients' satisfaction was 91.7%. CONCLUSIONS: Total subcutaneous internal sphincterotomy is a safe and effective treatment for chronic anal fissures, that only rarely impairs continence to flatus.

Angiogenesis and p53 at the invading tumor edge: prognostic markers for colorectal cancer beyond stage.

BACKGROUND: Angiogenesis has emerged as a major prognostic factor in many human malignancies and it is a prospective target for cancer therapy. MATERIALS AND METHODS: In this study, we investigated immunohistochemically the angiogenic activity and the expression of p53 and bcl-2 proteins in a series of 170 operable colorectal carcinomas, stage B and C. RESULTS: A high vascular density at the invading tumor front was directly related to nuclear p53 accumulation, and inversely to cytoplasmic expression of bcl-2. Furthermore, high angiogenic activity was significantly associated with lymph node metastasis. Survival analysis showed that Dukes stage and vascular density were the most important and independent prognostic factors in colorectal cancer. DISCUSSION: It is believed that angiogenesis at the invading tumor edge can be used as an independent prognostic marker to identify subgroups of colorectal cancer patients with an unfavorable post-operative outcome.

Both early-onset and late-onset ventilator-associated pneumonia are caused mainly by potentially multiresistant bacteria.

OBJECTIVE: To compare the causative pathogens of early-onset and late-onset ventilator-associated pneumonia (VAP) diagnosed by bronchoalveolar lavage quantitative cultures. Most previous reports have been based on endotracheal aspirate cultures and gave uncertain findings. DESIGN: Prospective evaluation of consecutive patients with clinical suspicion for VAP. SETTING: Multidisciplinary intensive care unit of a university hospital. PATIENTS AND PARTICIPANTS: During a 3-year period 473 patients with clinical suspicion of VAP entered the study. Diagnosis of VAP was confirmed by cultures of bronchoalveolar lavage (> 10(4) cfu/ml) specimens in 408 patients. INTERVENTIONS: Protected bronchoalveolar lavage samples were taken. Initial antibiotic therapy was modified upon bronchoalveolar lavage culture results. MEASUREMENTS AND RESULTS: Among 408 patients 191 had early-onset (< 7 days mechanical ventilation) and 217 late-onset (> or = 7 days) VAP. Potentially multiresistant bacteria, mainly Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus (MRSA), were the most commonly isolated pathogens in both types of VAP. No difference was noted in the contribution of potentially multiresistant pathogens (79% vs. 85%), P. aeruginosa (42% vs. 47%), or MRSA (33% vs. 30%) between early-onset and late-onset VAP. Initial antibiotic therapy was modified in 58% of early-onset VAP episodes and in 36% of late-onset VAP episodes. No difference in mortality was found between the two types of VAP. CONCLUSIONS: Both early-onset and late-onset VAP were mainly caused by potentially multiresistant bacteria, most commonly P. aeruginosa and MRSA. Antimicrobial agents against these pathogens should be prescribed empirically, at least in our institution.

Gastroesophageal reflux disease and Helicobacter pylori: lack of influence of infection on oesophageal manometric, 3-hour postprandial pHmetric and endoscopic findings.

AIM: To investigate the relationship between Helicobacter pylori and gastro-oesophageal reflux disease according to manometric and pHmetric findings. METHOD: Fifty-nine consecutive patients with reflux symptoms and endoscopic evidence of mild oesophagitis, were recruited. Manometry and ambulatory pHmetry were performed in all patients, as well as the 3-hour postprandial pHmetry, as a more flexible and well tolerable test. RESULTS: There were no significant differences between Helicobacter pylori positive and negative patients regarding age, sex ratio and endoscopic severity of oesophagitis. There was no difference in prevalence of abnormal oesophageal peristalsis between the two groups (Fisher's exact test, p=NS). Differences were also not found regarding lower oesophageal sphincter pressure between the two groups (mean PLOS 12.86+/-4.39 mmHg and 13.1+/-4.61 mmHg respectively; p=0.840). Finally, the mean values of DeMeester score were 60.38+/-48.04 and 67.64+/-51.04 respectively (p=0.576). CONCLUSION: Helicobacter pylori infection does not influence oesophageal peristalsis, the lower oesophageal sphincter pressure and the acidity of refluxates into the oesophageal lumen, in patients with established gastro-oesophageal reflux disease (esophagitis grade A and B).

Infliximab for treatment of pyoderma gangrenosum associated with clinically inactive Crohn's disease. A case report.

We report the case of a 57-year old female patient with refractory to treatment pyoderma gangrenosum associated with clinically inactive Crohn's disease. Pyoderma gangrenosum was successfully treated with Infliximab, a chimeric monoclonal antibody that inhibits tumour necrosis factor alpha (TNF-alpha). Our case report suggests that Infliximab, a therapeutic agent for refractory and fistulizing Crohn's disease, may also be safe and effective in the treatment of Crohn's disease associated pyoderma gangrenosum, even though the inflammatory bowel disease is clinically inactive and repeated infusions may be required for successful treatment.

Effects of Helicobacter pylori infection on gastric emptying rate in patients with non-ulcer dyspepsia.

AIM: The pathogenesis of delayed gastric emptying in patients with non-ulcer dyspepsia (NUD) remains unclear. We aimed to examine whether gastric emptying rate in NUD patients was associated with Helicobacter pylori (H pylori) infection and whether it was affected by eradication of the infection. METHODS: Gastric emptying rate of a mixed solid-liquid meal was assessed by the paracetamol absorption method in NUD patients and asymptomatic controls (n=17). H pylori status was assessed by serology and biopsy urease test. H pylori-positive NUD patients (n=23) received 10-day triple eradication therapy. H pylori status was re-assessed by biopsy urease test four weeks later, and if eradication was confirmed, gastric emptying rate was re-evaluated. RESULTS: Thirty-three NUD patients and 17 controls were evaluated. NUD patients had significantly delayed gastric emptying compared with controls. The mean maximum plasma paracetamol concentration divided by body mass (Cmax/BM) was 0.173 and 0.224 mg/L.kg respectively (P=0.02), the mean area under plasma paracetamol concentration-time curve divided by body mass (AUC/BM) was 18.42 and 24.39 mg.min/L.kg respectively (P=0.01). Gastric emptying rate did not differ significantly between H pylori-positive and H pylori-negative NUD patients. The mean Cmax/BM was 0.172 and 0.177 mg/L.kg respectively (P=0.58), the mean AUC/BM was 18.43 and 18.38 mg.min/L.kg respectively (P=0.91). Among 14 NUD patients who were initially H pylori-positive, confirmed eradication of the infection did not significantly alter gastric emptying rate. The mean Cmax/BM was 0.171 and 0.160 mg/L.kg before and after Hp eradication, respectively (P=0.64), the mean AUC/BM was 17.41 and 18.02 mg.min/L.kg before and after eradication, respectively (P=0.93). CONCLUSION: Although gastric emptying is delayed in NUD patients compared with controls, gastric emptying rate is not associated with H pylori status nor it is affected by eradication of the infection.

Impact of Helicobacter pylori infection on histological changes in non-erosive reflux disease.

AIM: The evidence for an association between Helicobacter pylori (H pylori) and gastroesophageal reflux disease, either in non- erosive (NERD) or erosive esophagitis (ERD) remains uncertain. The available data on the histological changes in NERD and the effect on H pylori infection on them are elusive. The aim of this study therefore was to prospectively evaluate the histological findings and the impact of H pylori infection on a group of symptomatic patients with NERD. METHODS: Fifty consecutive patients were prospectively evaluated for symptoms compatible with GORD. In all cases, routine endoscopy and lugol directed biopsies were performed and assessed histologically in a blinded manner. RESULTS: The overall prevalence of H pylori infection was 70%. Twenty-nine patients out of 50 (58%) were NERD patients. No statistical significance was observed between the H pylori status and NERD. The remaining 21 (42%) were diagnosed as follows: 13 (26%), 6 (12%), 2(4%) with esophagitis grade A, B and C respectively. A statistically significant correlation was observed between the H pylori+ and esophagitis grade A, as well as between H pylori- and grade B. Biopsies from 2 patients were not included because of insufficient materials. Histologically, a basal zone hyperplasia was found in 47 (97.91%) patients, alterations of glycogen content in 47 (97.91%), papillae elongation in 33 (68.75%), blood vessels dilatation in 35(72.91%), chronic inflammation in 21 (43.75%), infiltration with eosinophils, neutophils and T-lymphocytes in 4 (8.33%), 6 (12.5%) and 39 (81.25%) respectively. No correlation was observed between the H pylori status and the histological parameters studied either in NERD or GERD. CONCLUSION: Histological assessment can not differentiate symptomatic patients with erosive versus non-erosive reflux disease. Moreover, H pylori infection may not act as an important factor in patients with NERD.

Amifostine before chemotherapy: improved tolerance profile of the subcutaneous over the intravenous route.

INTRODUCTION: The i.v. administration of the cytoprotective agent amifostine is associated with reversible clinical hypotension, protracted emesis, and malaise in a various percentage of patients. We evaluated, prospectively, whether the s.c. route is a better tolerated alternative to the i.v. route in patients receiving chemotherapy. PATIENTS AND METHODS: Fifty-nine patients treated with "once every 2 weeks" regimens received 1000 mg of amifostine i.v. before chemotherapy. Patients who developed protracted vomiting and malaise and/or clinical hypotension for two consecutive i.v. administrations received the same dose of amifostine s.c. for the subsequent cycles (i.v./s.c. study). In an additional cohort of 12 patients (s.c. study), 1000 mg of amifostine were given s.c. since the first chemotherapy cycle. RESULTS: In the i.v./s.c. study, 8 (13.5%) patients showed protracted emesis/malaise and/or clinical hypotension during the first two cycles. An additional 4 (6.6%) patients developed similar side effects during the subsequent cycles. Switching to the s.c. route, an improved tolerance was noted. In the s.c. study, a total of 76 injections was administered. Protracted vomiting or clinical hypotension was absent, and this tolerance profile was significantly better than the i.v. one (P = 0.001). There were no other systemic side effects related to the s.c. administration. CONCLUSIONS: Amifostine, at a dose of 1000 mg, is better tolerated when administered s.c. Switching to the s.c. route in patients with poor tolerance using the i.v. administration allows the continuation of cytoprotection with minor side effects. Although preliminary, 1000 mg of amifostine effectively protected against the lower, still more frequently administered doses of chemotherapy given once every 2 weeks.

Angiogenesis relates to estrogen receptor negativity, c-erbB-2 overexpression and early relapse in node-negative ductal carcinoma of the breast.

Tumor angiogenic activity is an important process linked to tumor growth, metastasis, and invasion. In the present study we investigated whether intratumoral microvessel density (MVD), as assessed with immunohistochemistry, is of prognostic relevance in a series of 77 breast cancer patients with node-negative disease. The mean MVD in the hot spots ranged from 9 to 106 (median 31) vessels per x200 optical field. Patients were grouped into 3 categories of low (27 pts), medium (26 pts), and high (24 pts) MVD. Angiogenesis was not related to the primary tumor dimensions (T-stage) or the histology differentiation. An inverse association of MVD with estrogen receptor (ER) expression was noted (p=0.0007), while high MVD was directly related to c-erbB-2 overexpression (p=0.04) and high MIB1 proliferation index (p=0.02). In univariate and multivariate analysis of relapse-free survival, MVD was the only variable significantly and independently linked to relapse. It is concluded that high intratumoral angiogenic activity is linked with early relapse in node-negative breast cancer.

Differential assessment of vascular survival ability and tumor angiogenic activity in colorectal cancer.

BACKGROUND: The process of new vessel formation during neoplastic transformation and growth (neoangiogenesis) comprises proliferation, sprouting, and migration of endothelial cells within normal tissues adjacent to the tumor. These new vessels are directed toward the tumor invading edge and provide the bed for the subsequent growth of new tumor layers. We previously showed various degrees of decreasing vascular density in tumor layers once these lose contact with the normal tissue. This suggests that, apart from angiogenic factors, vascular survival factors contribute equally to the structure of the tumoral vasculature. This "vascular survival" potential can be assessed by comparatively examining the vascular density in peripheral and inner tumor areas. EXPERIMENTAL DESIGN: Using immunohistochemistry with the anti-CD31 monoclonal antibody, we assessed the tumor angiogenic activity (TAA) and vascular survival ability (VSA) in a sample of 242 patients with Dukes' stage A (90 patients), B (73 patients), and C (79 patients) colorectal cancer treated with surgery alone. RESULTS: Overall, High TAA and VSA were significantly related with poor prognosis (P = 0.03; hazard ratio, 1.9 and P = 0.001; hazard ratio, 2.7, respectively). In multivariate analysis, VSA was revealed as the most potent and independent prognostic factor (P = 0.0001; t ratio, 4.5), followed by vascular invasion (P = 0.0001; t ratio, 4.4) and stage (P = 0.01; t ratio, 2.5). Tumors with high TAA and high VSA had a significantly higher risk to develop liver metastasis (P = 0.0003). CONCLUSIONS: Assessment of VSA in addition to TAA provides additional important prognostic information in patients with colorectal cancer and can be a useful tool in the recruitment of patients who would benefit from angiostatic versus angiotoxic therapies.