Chronic wounds treated with cold atmospheric plasmajet versus best practice wound dressings: a multicenter, randomized, non-inferiority trial.

The use of phase-adapted wound dressings represents best practice (BP) in chronic wound treatment. However, efficacy is often limited and associated care requirements are high. Cold atmospheric plasmajet (CAP-jet) is a promising new therapeutic tool for these wounds. In the present multicenter, randomized, open-label, prospective, clinical trial, non-inferiority of the CAP-jet versus BP was assessed in 78 patients with infected or non-infected chronic wounds of different etiology. Primary outcome measure was the sum of granulation tissue, furthermore wound area reduction, healing rate, time to complete healing, changes in wound pH value, infection score, exudate level and local tolerability were assessed. In CAP-jet treated wounds compared to control, the sum of granulation tissue was significantly higher (p < 0.0001) and wound area reduced significantly faster (p < 0.001). Furthermore, wound pH value decreased significantly faster (p = 0.0123) and local infection was overcome more rapidly by CAP-jet therapy. In 58.97% CAP-jet- vs. 5.13% BP-treated patients, complete healing of chronic ulcers was documented after 6 weeks. Treatment with CAP-jet appeared not only non-inferior, but even superior to BP in all wound entities analyzed with a favorable tolerability profile. Thus, treatment with the CAP-jet provides beneficial effects in chronic wound treatment regarding promotion of the wound healing process.

Impact of Surgical Margins in Breast Cancer After Preoperative Systemic Chemotherapy on Local Recurrence and Survival.

BACKGROUND: While "no tumour on ink" is an accepted margin width for R0 resection in primary surgery, it's unclear if it's oncologically safe after neoadjuvant chemotherapy (NAC). Only limited data demonstrate that surgery within new margins in cases of a pathological complete response (pCR) is safe. We therefore investigated the influence of different margins and pCR on local recurrence and survival rates after NAC. METHODS: We retrospectively analysed data of 406 women with invasive breast cancer, treated with NAC and breast-conserving therapy between 1994 and 2014 in two certified Austrian breast health centres. We compared R ≤ 1 mm, R > 1 mm and RX (pCR) for local recurrence-free survival (LRFS), disease-free survival (DFS) and overall survival (OS). RESULTS: After a median follow-up of 84.3 months, the 5-year LRFS (R ≤ 1 mm: 94.2%, R > 1 mm: 90.6%, RX: 95.0%; p = 0.940), the 5-year DFS (R ≤ 1 mm: 71.9%, R > 1 mm: 74.1%, RX: 87.2%; p = 0.245) and the 5-year OS (R ≤ 1 mm: 85.1%, R > 1 mm: 88.0%, RX: 96.4%; p = 0.236) did not differ significantly between narrow, wide, nor RX resections. Regarding DFS and OS, a negative nodal status reduced the hazard ratio significantly. CONCLUSION: There is no significant difference in LRFS, DFS and OS comparing close, wide or unknown margins after pCR. We suggest that resection in new margins after NAC is safe according to "no tumour on ink". Resection of the clipped area in cases of pCR is emphasized.

Assessing the TP53 marker type in patients treated with or without neoadjuvant chemotherapy for resectable colorectal liver metastases: a p53 Research Group study.

The type of a biomarker - whether it is prognostic or predictive - is frequently not known, although such information is crucial for assessing the clinical value of a marker. In order to evaluate the type of marker TP53 is, we identified a cohort of 76 patients with colorectal liver metastases (CLM), homogeneously staged as resectable, who had been treated either with or without fluorouracil-based neoadjuvant chemotherapy. The TP53 genotype was assessed retrospectively from paraffin-embedded, diagnostic tumour biopsies using a standardised, p53 gene-specific sequencing protocol (mark53(®) kit). The overall median survival was 44.2 months, and the overall TP53 mutation frequency was 55%. A significant interaction was observed between chemotherapy and TP53 status (P = 0.045). To illustrate this effect, the 51 patients with and the 25 patients without neoadjuvant chemotherapy were described separately. In patients with neoadjuvant chemotherapy, mutated TP53 was significantly associated with poor survival (P = 0.0025), resulting in five-year survival rates of 22%, compared to 60% in patients with normal TP53. The hazard ratio was 3.12 (95% confidence intervals (CI): 1.46-6.95) to the disadvantage of TP53-mutated patients and 5.49 (P = 0.0001; 95% CI: 2.28-13.24) after adjustment for known prognostic factors. In patients treated with surgery alone, a mutated TP53 did not have a negative effect on survival (P = 0.54). A mutated TP53 status independently predicted survival disadvantage in CLM patients in the presence, but not in the absence, of neoadjuvant chemotherapy. Our data suggest that TP53 might be a pure predictive marker.

Surgical recurrence after primary ileocolic resection for Crohn's disease.

BACKGROUND: The current study was conducted to assess long-term outcomes after primary ileocolic resection for Crohn's disease (CD) and to identify factors associated with surgical relapse in the era of immunosuppressive medications. METHODS: Data were collected retrospectively on 116 consecutive patients, who underwent primary ileocolic resection for CD at a tertiary referral center between 1997 and 2006. Medical records were reviewed, and the use of immunomodulators was noted. The cumulative probability for a second operation due to recurrent CD was described by Kaplan-Meier curves. RESULTS: Ten patients (8.6 %) developed surgical recurrence after a mean follow-up period of 8.1 (±2.6) years. The percentage of patients not requiring further surgery was 96.5% and 88.0 % at 5 and 10 years, respectively. An urgent indication for surgery was significantly associated with the necessity of repeated intestinal resection (hazard ratio 5.6, 95 % confidence interval 1.2-27.0, p = 0.0145). In addition, postoperative exposure to azathioprine/6-mercaptopurine for more than 3 months decreased the probability of surgical recurrence significantly (hazard ratio 2.5, 95 % confidence interval 0.6-9.9, p = 0.0349). CONCLUSIONS: In contrast to previous studies, we observed a significant low surgical recurrence rate after primary ileocolic resection. Additionally, maintenance treatment with azathioprine/6-mercaptopurine after surgery may reduce the necessity for repeat surgical intervention.

Tissue expansion for correction of scars due to burn and other causes: a retrospective comparative study of various complications.

BACKGROUND: Tissue expansion is associated with a relatively high complication rate. The aim of this study was to quantify the complication risk of burn scar patients who underwent tissue expansion in comparison to patients with other indications such as skin tumors. Furthermore it was attempted to compare the complication rates in children and adults. METHODS: A retrospective analysis was performed on 148 expanders implanted in 73 patients during the years 1994-2011. Two patient cohorts (burn scar cohort n=31 and other indication cohort n=42) were identified and analyzed. RESULTS: 27 male and 46 female patients with a median age of 21 years were included. No statistically significant difference for complication risk between the burn and other indication cohorts could be found (p=0.1412). Statistical analyses revealed a higher complication rate (52%) in the lower limb compared to all other anatomic sites (29%) (p=0.1746). In addition, statistical analyses revealed a significantly higher total complication rate in children younger than 10 years (p=0.0043). Moreover a greater TBSA was accompanied by a higher complication rate (p=0.0258). CONCLUSION: This set of data suggests that the burn scar patient is at no greater risk to suffer complications from tissue expansion. Other factors like age, TBSA and anatomical site have far more influence on the expander complication rate than the initial indication for tissue expansion.

Sexual function and quality of life after surgical treatment for anal fistulas in Crohn's disease.

BACKGROUND: The aim of this study was to assess sexual function and quality of life (QoL) in patients after surgery for perianal Crohn's disease. METHODS: Eighty-eight consecutive patients with perianal Crohn's disease, operated on at the Medical University of Vienna, completed a self-administered questionnaire including the International Index of Erectile Function (IIEF), Female Sexual Function Index (FSFI), Short Form-12 Health Survey (SF-12), and the Inflammatory Bowel Disease Questionnaire (IBDQ). Patients with a current stoma were excluded from further analysis. The median follow-up time was 104 months (range 3-186 months). Healthy subjects served as controls for each case and were matched by age (±6 years) and gender. Forty-seven (68 %) female and 22 male patients with a median age of 46.5 years (range 18-64 years) were analyzed. Eleven (16 %) patients had simple and 58 (84 %) complex anal fistulas. RESULTS: The median SF-12 physical health score of the patients was significantly lower (47.9 (range 25.5-57.2)) than that of the controls (54.3 (range 34.6-61.8); p = 0.03). Not surprisingly, the median total sore of the IBDQ of the controls was significantly better than that of the patients (controls: 188.5 (range 125-206.5), patients: 157 (range 60-199.5); p < 0.0001). Analysis with the multiple logistic regression test showed that type of operation, >1 perianal fistula opening, and active Crohn's disease were independent risk factors for a worse IBDQ (p = 0.03, p = 0.015 and p < 0.0001). Interestingly, the median FSFI and IIEF score were not found to be significant different in any domain. CONCLUSIONS: QoL but not sexual function is significantly influenced by surgery for perianal Crohn's disease.

A two-step screening algorithm including fasting plasma glucose measurement and a risk estimation model is an accurate strategy for detecting gestational diabetes mellitus.

AIMS/HYPOTHESIS: It is currently not clear how to construct a time- and cost-effective screening strategy for gestational diabetes mellitus (GDM). Thus, we elaborated a simple screening algorithm combining (1) fasting plasma glucose (FPG) measurement; and (2) a multivariable risk estimation model focused on individuals with normal FPG levels to decide if a further OGTT is indicated. METHODS: A total of 1,336 women were prospectively screened for several risk factors for GDM within a multicentre study conducted in Austria. Of 714 women (53.4%) who developed GDM using recent diagnostic guidelines, 461 were sufficiently screened with FPG. A risk prediction score was finally developed using data from the remaining 253 women with GDM and 622 healthy women. The screening algorithm was validated with a further 258 pregnant women. RESULTS: A risk estimation model including history of GDM, glycosuria, family history of diabetes, age, preconception dyslipidaemia and ethnic origin, in addition to FPG, was accurate for detecting GDM in participants with normal FPG. Including an FPG pretest, the receiver operating characteristic AUC of the screening algorithm was 0.90 (95% CI 0.88, 0.91). A cut-off value of 0.20 was able to differentiate between low and intermediate risk for GDM with a high sensitivity. Comparable results were seen with the validation cohort. Moreover, we demonstrated an independent association between values derived from the risk estimation and macrosomia in offspring (OR 3.03, 95% CI 1.79, 5.19, p < 0.001). CONCLUSIONS/INTERPRETATION: This study demonstrates a new concept for accurate but cheap GDM screening. This approach should be further evaluated in different populations to ensure an optimised diagnostic algorithm.

The use of Suprathel(®) in deep dermal burns: first results of a prospective study.

INTRODUCTION: While autologous skin grafting has been the standard for coverage of full-thickness areas, several options for deep-partial-thickness defects exist. With regard to economising donor sites, we compared a copolymer based on DL-lactid acid (Suprathel(®)) as temporary wound dressing with autologous skin, and analysed time to healing and scar quality in matched areas of deep-partial-thickness burn. METHODS: We recruited 18 patients with a median age of 45 years (range: 25-83 years), for this prospective, non-blinded controlled non-inferiority study, suffering from deep-partial-thickness burns from November 2009 to July 2010. After early tangential excision, matched deep-partial-thickness areas were covered with 1:1.5 meshed autologous skin grafts and the copolymer for direct intra-individual comparison. Scars were evaluated by means of the Vancouver Scar Scale (VSS), the Patient and Observer Scar Assessment Scale (POSAS) and suction cutometry (MPA 580, Courage and Khazaka Electronic GmbH, Cologne, Germany) on days 30 and 90, postoperatively. RESULTS: Fifteen days after surgery, complete wound closure was present in 44.4% (8/18) of all areas covered with copolymer and 88.9% (16/18) in the split-thickness skin graft (STSG) area (p=0.008). Evaluation of the total VSS, POSAS and cutometry satisfied the criterion of non-inferiority for Suprathel(®) on day 30. Ninety days after surgery, only the Observer Scar Scale showed that Suprathel is non-inferior to STSG, albeit the mean total VSS and Patient Scar Scale were better in Suprathel(®) areas. CONCLUSION: Suprathel(®) represents a solid, reliable epidermal skin substitute with longer healing times in comparison to skin grafts but comparable results concerning early scar formation. Suprathel(®) can serve as a tool in treatment portfolio for adult patients suffering from deep dermal burns. Especially in patients with extensive burns, Suprathel(®) can be used to cover the deep dermal burn wounds to save STSGs and its donor sites for the coverage of full-thickness burned areas.

Objectively measured breast symmetry has no influence on quality of life in breast cancer patients.

AIMS: This study investigates how quality of life (QoL) of breast cancer patients is related to breast symmetry. METHODS: We objectively measured breast symmetry using the breast analyzing tool (BAT) in 101 patients after breast conserving surgery for breast cancer at different time points during follow up. We correlated the results with the quality of life measured at the same time using the breast image scale (BIS), the EORTC QLQ-BR23 scale and a not validated sexual score scale. Age, tumour size, tumour/breast relation and the use of oncoplastic surgery were also correlated with symmetry and quality of life scales. Using multivariate analyses, independent parameters for an improved quality of life were identified. RESULTS: Mean age was 56 (±11.6), and 75.2% of patients had T1 or T2 tumours. Patient age (p = 0.03) and tumour size (p = 0.01) significantly influenced objectively measured breast symmetry. The cosmetic result was important for 53% of patients while 48% found it not important. Independent from this, neither overall quality of life nor breast self esteem was influenced by breast symmetry in our patients. CONCLUSIONS: After breast cancer surgery, breast symmetry is not a major factor for patients' quality of life and breast self esteem. Cosmetic result seems to be less important than oncologic outcome in patients with breast cancer.

Haemorrhoids, constipation and faecal incontinence: is there any relationship?

AIM: Little is known about the association of haemorrhoids and anorectal function. Moreover, available data on the impact of constipation on the presence of haemorrhoids are conflicting. The present study aimed to assess any potential relationship between haemorrhoids and anorectal dysfunction. METHOD: All participants who attended the Austrian nationwide healthcare programme for colorectal cancer screening at four medical institutions were enrolled prospectively between 2008 and 2009. A colonoscopy and detailed anorectal examination were performed on all patients. Haemorrhoids were classified according to an international grading system. Faecal incontinence was defined as the involuntary loss of solid stool, liquid stool or gas, at least once a month. Constipation was recorded by a constipation scoring system. RESULTS: Of 976 participants, 380 (38.9%) were found to have haemorrhoids. There was an association between healthy individuals, patients with symptomatic and patients with asymptomatic haemorrhoids and incontinence of liquid stool. No association was found regarding incontinence for solid stool and gas. The median constipation score was significantly higher in those patients with haemorrhoids (grade I-IV) compared with patients without haemorrhoids (2.5 points (range, 0-19) and 3 points (range, 0-19); P = 0.0113). 'Painful evacuation effort' and 'assistance for defaecation (stimulant laxatives, digital assistance or enema)' showed a significant correlation with haemorrhoids (P = 0.0394 and P = 0.0143). CONCLUSION: Although the median constipation score was low in both groups, there was a significant association between constipation and haemorrhoids in adult patients.

Oncologic safety of breast conserving surgery after tumour downsizing by neoadjuvant therapy: a retrospective single centre cohort study.

The objective of this study is to analyse local recurrence rates in patients receiving neoadjuvant chemotherapy (nCT) comparing mastecomized (MX) patients with those undergoing breast conserving therapy (BCT). Patients undergoing breast cancer surgery after nCT (3xCMF or 3-6xED) between 1995 and 2007 at our department were retrospectively analysed. The median follow up was 60 months for 308 patients. Patients who were downsized from MX to BCT with partial or complete response (n = 104) had a similar local recurrence free survival (LRFS) compared to patients who did not experience successful downsizing (n = 67) and finally undergoing MX (LRFS MX-BCT 81% vs. MX-MX 91%; P = 0.79). Uni- and multivariate analyses demonstrated that BCT itself was not an independent prognostic factor for a worse LRFS (P = 0.07 and 0.14). After no pathologic change or progressive disease the risk of local recurrence was increased in patients undergoing BCT (MX-BCT; n = 6 LRFS 66%) compared with MX (n = 44; LRFS 90%; P = 0.04). Overall survival in general was better for the BCT group (n = 197) compared with MX group (n = 111) regardless of clinical response (92% vs. 72%; P < 0.0001). Breast conservation, nodal negativity and low or medium grade histology were prognostic factors for an improved OS (P = 0.02, 0.01, 0.004). In conclusion, our study suggests that BCT is oncologically safe after tumour downsizing by nCT in patients primarily scheduled for mastectomy. These patients, however, should not be treated with breast conservation in the absence of any proven response after nCT.

Haemorrhoids and quality of life.

AIM: There are few studies into the quality of life of patients with haemorrhoids. The aim of this study was to assess the quality of life of patients with haemorrhoids in an adult general population. METHOD: Participants, who attended the Austrian nationwide healthcare programme for colorectal cancer screening at four medical institutions, were enrolled prospectively between 2008 and 2009. A colonoscopy was performed in all patients. Haemorrhoids were classified according to an international grading system and defined as symptomatic in cases with bleeding, itching, soiling or pain. Quality of life was measured by the Short Form-12 Health Survey. RESULTS: Of 976 participants, 380 patients (39%) had haemorrhoids. The median physical health score was 52.6 (range 20.6-61.3) in the symptomatic and 53.2 (range 16.2-61.3) in the asymptomatic group (P = 0.7993). The median mental health score showed also no significant difference between both groups [symptomatic group, 52.8 (range 12.4-62.6); asymptomatic group, 54.8 (range 18.7-67.2); P = 0.0738]. CONCLUSION: Haemorrhoids, irrespective of their degree, do not influence quality of life measured by the Short Form-12 Health Survey.

Short-term complications of wide-lumen stapled anastomosis after ileocolic resection for Crohn's disease: who is at risk?

AIM: There is growing evidence that stapled anastomoses are similarly effective compared to hand-sewn anastomoses in Crohn's patients. This study was designed to assess safety and limitations of wide-lumen stapled ileocolic anastomoses. METHOD: All patients with ileocolic resections for Crohn's disease perfomed between 1998 and 2006 were studied. A stapled anastomosis was constructed whenever possible. Potential risk factors for postoperative complications were recorded, retrospectively. Univariate and multivariate analyses were performed. RESULTS: In 209 out of 220 cases (95%, 132 primary operations) stapled anastomoses were performed. Eleven patients underwent a hand-sewn anastomosis owing to massive bowel dilatation (n = 7) or increased wall thickness (n = 4). There were 10 major (4.5%; surgical: 8, medical: 2) complications including two anastomotic leaks and one anastomotic bleed (all from stapled anastomoses) and one death not related to the anastomosis. Minor complications occurred in 25 patients. In multivariate analysis, major surgical postoperative complications were significantly associated with a low level of albumin (P = 0.0113) and previous resections for Crohn's disease (P = 0.0144). CONCLUSION: Stapled ileocolic anastomosis was safe in the majority of Crohn's patients. The most important limitation was technical impracticability. A low level of albumin and a history of previous resection increased the risk of postoperative complications.

Proposals for sample size calculation programs.

OBJECTIVES: Numerous sample size calculation programs are available nowadays. They include both commercial products as well as public domain and open source applications. We propose modifications for these programs in order to even better support statistical consultation during the planning stage of a two-armed clinical trial. METHODS: Directional two-sided tests are commonly used for two-armed clinical trials. This may lead to a non-negligible Type III error risk in a severely underpowered study. In the case of a reasonably sized study the question for the so-called auxiliary alternative may evolve. RESULTS: We propose that sample size calculation programs should be able to compute i) Type III errors and the so-called q-values, ii) minimum sample sizes required to keep the q-values below pre-specified levels, and iii) detectable effect sizes of the so-called auxiliary alternatives. CONCLUSIONS: Proposals i and ii are intended to help prevent irresponsibly underpowered clinical trials, whereas the proposal iii is meant as additional assistance for the planning of reasonably sized clinical trials.

Gastric emptying of glucose solution and associated plasma concentrations of GLP-1, GIP, and PYY before and after fundoplication.

BACKGROUND: This study was designed to assess the relationship between gastric emptying of glucose solution and the ensuing plasma concentrations of glucagon-like peptide-1 (GLP-1), peptide YY (PYY), and glucose-dependent insulinotropic polypeptide (GIP) in patients having undergone fundoplication for gastroesophageal reflux (GERD). SUBJECTS AND METHODS: In 10 male patients the emptying of 50% glucose solution was determined scintigraphically and its relationship with plasma glucose, GLP-1, PYY, and GIP concentrations was studied before and 3 months after fundoplication. RESULTS: In the first 30 min after glucose ingestion, emptying was significantly (p = 0.048) faster after fundoplication than before. Emptying and GLP-1 and GIP correlated: the faster the emptying during the first 30 min the greater the concentrations integrated over that period (p = 0.04; p = 0.01; p = 0.02). Emptying and PYY concentrations were unrelated. In the 120-180 min. period, blood glucose concentrations were lower the faster the emptying in the initial 30 min (p = 0.06) and the entire 50-min recording period (p = 0.03) had been. The GLP-1 concentrations integrated over the first 30 min correlated inversely with the integrated plasma glucose during the third hour after ingestion (p = 0.004). CONCLUSIONS: After fundoplication, gastric emptying may, if accelerated in its initial phases, give rise to greater and earlier increases in plasma glucose, GLP-1, and GIP concentrations and thus to reactive hypoglycemia.

A simulation study comparing properties of heterogeneity measures in meta-analyses.

The assessment of heterogeneity or between-study variance is an important issue in meta-analysis. It determines the statistical methods to be used and the interpretation of the results. Tests of heterogeneity may be misleading either due to low power for sparse data or to the detection of irrelevant amounts of heterogeneity when many studies are involved. In the former case, notable heterogeneity may remain unconsidered and an unsuitable model may be chosen and the latter case may lead to unnecessary complex analyses strategies. Measures of heterogeneity are better suited to determine appropriate analyses strategies. We review two measures with different scaling and compare them with the heterogeneity test. Estimates of the within-study variance are discussed and a new total information measure is introduced. Various properties of the quantities in question are assessed by a simulation study. Heterogeneity test and measures are not directly related to the amount of between-study variance but to the relative increase of variance due to heterogeneity. It is more favourable to base the within-study variance estimate on the squared weights of individual studies than on the sum of weights. A heterogeneity measure scaled to a fixed interval needs reference values for proper interpretation. A measure defined by the relation of between- to within-study variance has a more natural interpretation but no upper limit. Both measures are quantifications of the impact of heterogeneity on the meta-analysis result as both depend on the variance of the individual study effects and thus on the number of patients in the studies.

Intra-individual comparison between open and 2-portal endoscopic release in clinically matched bilateral carpal syndrome.

Based upon bilateral carpal tunnel syndrome (CTS) we undertook a prospective randomised intra-individual comparison between open (OR) and 2-portal endoscopic release (2-PER) to establish if there is any demonstrable advantage in undertaking either technique in a 1 year follow-up. Ten patients with bilateral CTS were enrolled in this study and underwent a 2-PER on the one and an OR with two minimised incisions on the contralateral hand. Both hands were examined pre- and postoperatively after 2, 4, 6 and 12 weeks and after 6 and 12 months, respectively. Preoperatively both hands revealed statistically no significant differences in all the parameters recorded. Comparing both techniques no significant differences could be detected in the follow-up period. Nevertheless, both techniques showed significant improvements in the severity of symptoms and pain, in sensory nerve testing and in electro-diagnostic parameters, when comparing pre- with postoperative data after 1 year. The endoscopic approach revealed no distinct advantages over the open technique not only in the late but also in the early postoperative follow-up period when performing intra-individual comparison. Considering the higher complication rate and costs when performing 2-PER the OR with two minimised incisions seems to be a good alternative in order to keep the recovery period as short as possible.

A prospective randomised trial to study the role of levamisole and interferon alfa in an adjuvant therapy with 5-FU for stage III colon cancer.

The purpose of this trial was to examine the efficacy of the addition of levamisole (LEV) or interferon alfa (IFN) to an adjuvant chemotherapy with 5-fluorouracil (5-FU) in patients with stage III colon cancer. According to a 2 x 2 factorial study design, 598 patients were randomly assigned to one of four adjuvant treatment arms. Patients in arm one received 5-FU weekly for 1 year, patients in arm two 5-FU plus LEV, in arm three 5-FU plus IFN and patients in arm four 5-FU, LEV and IFN. The relative risk of relapse and the relative risk of death were significantly higher for patients treated with LEV compared with those without LEV treatment (HR 1.452, 95% CI 1.135-1.856, P=0.0028; HR 1.506, 95% CI 1.150-1.973, P=0.0027, respectively). No significant impact on survival was observed for therapy with IFN in the univariate analysis. The addition of LEV to adjuvant 5-FU significantly worsened the prognosis of patients with stage III colon cancer. Interferon alfa had no significant influence on survival when combined with adjuvant 5-FU, but increased the toxicity of therapy substantially.