Frequent intragenic rearrangements of DPYD in colorectal tumours.

Dihydropyrimidine dehydrogenase is a crucial enzyme for the degradation of 5-fluorouracil (5FU). DPYD, which encodes dihydropyrimidine dehydrogenase, is prone to acquire genomic rearrangements because of the presence of an intragenic fragile site FRA1E. We evaluated DPYD copy number variations (CNVs) in a prospective series of 242 stage I-III colorectal tumours (including 87 patients receiving 5FU-based treatment). CNVs in one or more exons of DPYD were detected in 27% of tumours (deletions or amplifications of one or more DPYD exons observed in 17% and 10% of cases, respectively). A significant relationship was observed between the DPYD intragenic rearrangement status and dihydropyrimidine dehydrogenase (DPD) mRNA levels (both at the tumour level). The presence of somatic DPYD aberrations was not associated with known prognostic or predictive biomarkers, except for LOH of chromosome 8p. No association was observed between DPYD aberrations and patient survival, suggesting that assessment of somatic DPYD intragenic rearrangement status is not a powerful biomarker to predict the outcome of 5FU-based chemotherapy in patients with colorectal cancer.

Molecular patterns in deficient mismatch repair colorectal tumours: results from a French prospective multicentric biological and genetic study.

BACKGROUND: To test the prognostic value of tumour protein and genetic markers in colorectal cancer (CRC) and examine whether deficient mismatch repair (dMMR) tumours had a distinct profile relative to proficient mismatch repair (pMMR) tumours. METHODS: This prospective multicentric study involved 251 stage I-III CRC patients. Analysed biomarkers were EGFR (binding assay), VEGFA, thymidylate synthase (TS), thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD) expressions, MMR status, mutations of KRAS (codons 12-13), BRAF (V600E), PIK3CA (exons 9 and 20), APC (exon 15) and P53 (exons 4-9), CpG island methylation phenotype status, ploidy, S-phase, LOH. RESULTS: The only significant predictor of relapse-free survival (RFS) was tumour staging. Analyses restricted to stage III showed a trend towards a shorter RFS in KRAS-mutated (P=0.005), BRAF wt (P=0.009) and pMMR tumours (P=0.036). Deficient mismatch repair tumours significantly demonstrated higher TS (median 3.1 vs 1.4) and TP (median 5.8 vs 3.5) expression relative to pMMR (P<0.001) and show higher DPD expression (median 14.9 vs 7.9, P=0.027) and EGFR content (median 69 vs 38, P=0.037) relative to pMMR. CONCLUSIONS: Present data suggesting that both TS and DPD are overexpressed in dMMR tumours as compared with pMMR tumours provide a strong rationale that may explain the resistance of dMMR tumours to 5FU-based therapy.

Ankle brachial index using an automatic blood pressure device in occupational medicine: relevance in routine examination and comparison with Framingham cardio-vascular risk score.

AIM: The aim of this study was to assess the feasibility and relevance of determining ankle brachial index (ABI) using an automatic blood pressure device in subjects seen for their annual routine examination by occupational physicians and to compare the obtained ABI with the Framingham score. PATIENTS AND METHODS: Sixteen physicians randomly recruited 634 subjects in 12 departments of occupational medicine. Subjects aged between 40 and 60 years underwent a determination of ABI using an OMRON HM 722 device and the analysis of Framingham score. Other analysed variables were: sex, age, smoking habit, hypertension, diabetes, hypercholesterolemia, glycaemia, total cholesterol, HDL and LDL cholesterol and triglycerides levels. RESULTS: Mean age of the population studied was 48.1 ± 6.0 years; 73% were men, 36% were smokers, 14% had hypertension, 3.3% diabetes and 22% hypercholesterolemia. Biochemical values were glycaemia 0.90 ± 0.30 g/l, total cholesterol 2.10 ± 0.4 g/l, HDL cholesterol level 0.50 ± 0.20 g/l, LDL cholesterol level 1.30 ± 0.40 g/l, and triglycerides 1.40 ± 1.0 g/l. Mean ABI were 1.1 ± 0.1 in both legs. Mean Framingham score was 8.2 ± 5.4%. Only 20 subjects (3%) had an ABI < 0.90. No relation was found between pathological ABI and Framingham score (abnormal ABI : 9.9 ± 5.5 vs. normal ABI : 8.2 ± 5.4, NS). CONCLUSION: The determination of ABI using a simple commercially available automatic blood pressure device is feasible and easy to implement by preventive or general physicians in all kinds of routine examinations. In our opinion automatic ABI very easy and quick to determine provides, in addition to Framingham score, a simple and useful tool to detect subjects at high cardio-vascular risk.

The agreement between magnetic resonance imaging and arthroscopic findings in temporomandibular joint disorders.

The aim of this retrospective observational study was to assess the potential agreement between independent magnetic resonance imaging (MRI) and arthroscopic findings and their respective contributions to a final diagnosis in patients with refractory temporomandibular joint disorders. Two dentomaxillofacial radiologists and two oral and maxillofacial surgeons scored 50 joints. All observers, who were blinded to additional clinical information, used a specific scoring form and selected one or more diagnostic labels. Agreement between MRI and arthroscopy and their contributions to the final diagnosis were assessed as primary outcomes using Fleiss' kappa. Intra-modality agreement and the correlation between signal intensity ratio (SIR) measurements on MRI and synovitis grading on arthroscopy were assessed as secondary outcomes. Agreement between MRI and arthroscopy was poor. A fair level of agreement was only reached for reduction capacity of the disc and disc perforation. Arthroscopic diagnostic labels matched better with the final diagnosis, suggesting a bigger contribution to that diagnosis. Higher SIR measurements correlated with higher synovitis grading scores for the retrodiscal tissue and the posterior band of the disc. Intra-modality agreement was better in arthroscopy. When blinded to clinical information, arthroscopy and MRI observations can lead to different conclusions. The diagnostic outcomes of both examinations should be considered and integrated into a final diagnosis.

Epidermal growth factor receptor (EGFR) status and K-Ras mutations in colorectal cancer.

BACKGROUND: In advanced colorectal cancer, K-Ras somatic mutations predict resistance to mAbs targeting epidermal growth factor receptor (EGFR). Relationships between K-Ras mutations and EGFR status have not been examined so far. We analyzed relationships between K-Ras mutations and EGFR tumoral status based on EGFR germinal polymorphisms, gene copy number and expression. METHODS: Eighty colorectal tumors (stage 0-IV) and 39 normal mucosas were analyzed. K-Ras mutations at codons 12 and 13 were detected by a sensitive enrichment double PCR-restriction fragment length polymorphism (RFLP) assay. EGFR gene polymorphisms at positions -216G>T, -191C>A and 497Arg>Lys were analyzed (PCR-RFLP), along with CA repeat polymorphism in intron 1 (fluorescent genotyping) and EGFR gene copy number (PCR amplification). EGFR expression was quantified by Scatchard binding assay. RESULTS: The number of EGFR high-affinity sites, dissociation constant (Kd), gene copy number, intron 1, -216G>T, -191C>A or 497Lys>Arg genotypes was not different between K-Ras-mutated or K-Ras-non-mutated tumors. No relationship was observed between any of the analyzed EGFR genotypes and EGFR expression. EGFR expression was not related to gene copy number. EGFR gene copy number in tumor and normal tissue was not correlated. The mean value of the tumor/normal mucosa gene copy number ratio was 1.16. CONCLUSIONS: Present data clearly show that EGFR status is independent of K-Ras mutations in colorectal tumors.

[Feasibility and preliminary experiment of a routine use of Da-VinciS in fertility surgery]. / Faisabilité et expérience préliminaire de l'utilisation du robot Da-VinciS dans la chirurgie de l'infertilité féminine.

OBJECTIVES: The goal of our study is to evaluate the use of Da-Vinci S in the field of fertility laparoscopic surgery. MATERIALS AND METHODS: Ten successive patients were included for a laparoscopic fertility surgery using the Da-Vinci S. Surgical feasibility, operating time, length of hospital stay and postoperative complications have been analyzed. RESULTS: All procedures have been completed using Da-Vinci S. CONCLUSION: In our preliminary surgical experience, the Da-Vinci S can be technically used in the field of fertility surgery.

Open inguinal hernia repair by plug and patch: the value of fibrin sealant fixation.

BACKGROUND: Prosthetic meshes give excellent results in groin hernia repair. However, although recurrence rates are very low, chronic pain remains frequent and mesh fixation may play a role in the occurrence of this complication. The use of fibrin sealant to secure the mesh may represent a useful alternative for the prevention of chronic pain. The aim of this study is to confirm that the mesh may be secured by spraying fibrin sealant and to assess the reduction in the incidence of chronic pain. METHODS: Seventy hernias were operated on in 57 patients and were evaluated on a prospective basis. The procedure involved placement of a plug and patch mesh which was secured with fibrin sealant alone. These patients were compared to a matched retrospective series of 57 patients who underwent the same procedure, except that conventional non-absorbable suture was used to secure the mesh. RESULTS: The two groups were equivalent for inclusion criteria and preoperative data. The complication rate was similar in the two groups. The operative time was shorter in the fibrin sealant group: 7 min for unilateral hernia (p=0.0017) and 16 min for bilateral hernia (p=0.0008). The length of hospital stay was also shorter in the fibrin sealant group (1.8 days vs. 2.5 days: p < 0.0001). There was no recurrence in the fibrin sealant group after a minimum follow-up of 12 months and no recurrence in the suture group after a minimum follow-up of 25 months. Finally, a significant reduction in chronic pain was observed in the fibrin sealant group (3.5% vs. 22.8%: p=0.042). CONCLUSION: This study confirms the effectiveness of fibrin glue in securing prosthetic meshes and reducing chronic inguinal pain.

[Bening enterogenital fistulas arising from the digestive tract: three cases]. / Fistules entérogénitales d'origine digestive bénigne: à propos de trois cas.

Fistulas between the female genital tract and the digestive tract occur after obstetrical, oncological, or post-operative complications. We report herein 3 rare cases of enterogenital fistulas: one colouterine fistula and one colotubal fistula in a patient with diverticulitis, and one ileovaginal fistula in a patient with Crohn's disease. Vaginal discharge was frequent and incited patients to consult a gynecologist. Better knowledge of enterogenital fistulas is necessary to enable earlier diagnosis and apply specific treatment. The incidence of colovaginal fistulas is increasing in diverticular disease because of increased prevalences of hysterectomies and diverticular disease.

Gastrojejunocolic fistula after gastric surgery for duodenal ulcer: case report.

Gastrojejunocolic fistulae, a late complication of gastroenterostomy, are presently uncommon. Patients can present with symptoms of a fistula 20 years or more after their original gastric surgery. The knowledge of this rare condition can allow prevention, through a better operative strategy and a medical treatment at the phase of stomal ulcer with proton pump inhibitor and Helicobacter pylori eradication. We present a case of gastrojejunocolic fistula and discuss the modern management of this condition. Its etiological, clinical, and surgical features were briefly discussed.

Concomitant leiomyoma and leiomyosarcoma of the oesophagus.

Leiomyosarcoma of the oesophagus is a malignant tumor that originates from smooth muscle cells. The filiation between oesophageal leiomyoma and leiomyosarcoma is controversial, with few cases reported in literature. The authors describe un uncommon situation with the simultaneous presence of a leiomyoma and a leiomyosarcoma of the oesophagus in a 75 year-old man, which have been successfully treated with surgical resection. It could probably be a case of a malignant transformation of a previous pre-existing multiple non-confluent leiomyoma.

[Rupture of a pancreaticoduodenal artery aneurysm with median arcuate ligament syndrome: report of a case]. / Rupture d'un anévrisme des arcades duodénopancréatiques associé à une sténose du tronc coeliaque: à propos d'un cas.

Aneurysms of pancreaticoduodenal arteries represent only 2% of all aneurysms of digestive arteries. Occurrence of these aneurysms are favoured by stenosis or occlusion of the celiac axis. Aneurysm rupture is frequent and carries a mortality rate of 20%. Computed tomography with intravenous contrast and selective coeliomesenteric arteriography can make the diagnosis of this disease which can be treated by either surgery or embolotherapy. We report the case of a patient with a ruptured aneurysm of the pancreaticoduodenal arcades mimicking a perforated duodenal ulcer, and successfully treated by surgical ligation.

Evaluation of the effective dose of cone beam CT and multislice CT for temporomandibular joint examinations at optimized exposure levels.

OBJECTIVES: To compare the effective dose to patients from temporomandibular joint examinations using a dental CBCT device and a multislice CT (MSCT) device, both before and after dose optimization. METHODS: A Promax(®) 3D (Planmeca, Helsinki, Finland) dental CBCT and a LightSpeed VCT(®) (GE Healthcare, Little Chalfont, UK) multislice CT were used. Organ doses and effective doses were estimated from thermoluminescent dosemeters at 61 positions inside an anthropomorphic phantom at the exposure settings in clinical use. Optimized exposure protocols were obtained through an optimization study using a dry skull phantom, where four observers rated image quality taken at different exposure levels. The optimal exposure level was obtained when all included criteria were rated as acceptable or better by all observers. RESULTS: The effective dose from a bilateral examination was 184 µSv for Promax 3D and 113 µSv for LightSpeed VCT before optimization. Post optimization, the bilateral effective dose was 92 µSv for Promax 3D and 124 µSv for LightSpeed VCT. CONCLUSIONS: At optimized exposure levels, the effective dose from CBCT was comparable to MSCT.

Risk factors for progression of atherosclerosis six months after balloon angioplasty of coronary stenosis.

To assess the possible progression of coronary artery disease after percutaneous transluminal coronary angioplasty (PTCA) and its relation to risk factors and restenosis, 124 patients who underwent a first successful PTCA were studied. All had routine follow-up angiography 5 to 8 months after PTCA. Restenosis was defined as a 30% decrease in diameter stenosis or a return to greater than 50% stenosis, and progression (in any nondilated site) as a 20% decrease in diameter stenosis, assessed by a video-densitometric computer-assisted technique. Univariate and multivariate analysis with respect to progression was carried out for age, sex, initial unstable angina, previous myocardial infarction, diabetes mellitus, hypertension, hypercholesterolemia (greater than or equal to 6.2 mmol), smoking habits, Jenkins' score, dilated artery and restenosis. Forty-one patients (33%) had restenosis, and 23 (19%) had evidence of progression; 20 (87%) of these latter patients had restenosis and 3 (13%) did not. Univariate correlates of progression were: previous myocardial infarction (p less than 0.05), higher Jenkins' score (p less than 0.0003) and restenosis (p less than 0.0001). Restenosis was the only multivariate correlate (p less than 0.00003). Progression at routine angiography after PTCA is not rare, and appears to be related to both the initial extent of coronary artery disease and restenosis.

Predictive value of hemostatic factors for sudden death in patients with stable angina pectoris.

To assess hemostatic risk factors for sudden death in patients with stable angina, 323 consecutive patients were recruited prospectively. Patients with clinical heart failure or recent myocardial infarction were excluded. The following clinical variables were recorded: age, gender, smoking habits, hypertension, previous myocardial infarction, left ventricular hypertrophy, and severe ventricular arrhythmia. Angiographic variables included coronary extent, assessed from Jenkins' and mean atherosclerotic scores, and left ventricular ejection fraction. Lipid variables included total cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and apolipoproteins A-I and B. Hemostatic factors included fibrinogen, fibrinopeptide A, antithrombin III, factor VIII antigen, factor VIII coagulant, protein C, plasminogen, alpha 2 antiplasmin, euglobulin clot lysis time, tissue plasminogen activator before and after venous occlusion, and plasminogen activator inhibitor. There were 34 deaths, 19 of which were sudden during the follow-up period (60 +/- 17 months). The association between each variable and the risk of sudden death was assessed by calculating the relative risk with the Cox univariate model. All significant predictors from the univariate analysis were then incorporated in a Cox multivariate model to select the independent predictors of sudden death. The independent predictors of sudden death were left ventricular hypertrophy (p < 0.04), lower left ventricular ejection fraction (p < 0.04), and shorter euglobulin clot lysis time after venous occlusion (p < 0.02), whereas fibrinogen (p < 0.07) and Jenkins' score (p < 0.08) were borderline. Determination of hemostatic variables, especially those pertaining to dynamic fibrinolysis, may thus be of value in assessing risk of sudden death.

Treatment of hepatic metastases of colorectal cancer by electrochemotherapy: an experimental study in the rat.

BACKGROUND: Electrochemotherapy, which consist of local or systemic administration of a cytotoxic agent followed by application of electric pulses to a tumor, has proved effective for various types of tumors in animals and for cutaneous and head and neck cancers in human beings. This is the first study to investigate the efficacy of electrochemotherapy for treatment of hepatic metastases of colorectal cancer in the rat. METHODS: After induction of a solitary hepatic metastasis in 36 male BDIX rats, the animals were randomized to one of four groups: B-E-(no treatment), B+E-(intratumoral bleomycin), B-E+ (application of electric pulses to the tumor), and B+E+ (electrochemotherapy: intratumoral bleomycin followed by application of electric pulses). RESULTS: Groups B-E and B-E+ had no tumor response. Group B+E had one partial response. Group B+E+ had seven partial responses and two complete responses. The difference in terms of response between group B+E+ and the other three groups was statistically significant (P < .05). Comparison of the mean posttherapy tumor volumes (B-E-, 50.6 mm3; B+E-, 58.7 mm3; B-E+, 46 mm3; and B+E+, 5.65 mm3) revealed a significantly smaller residual tumor in group B+E+ than in the other three groups (P < .05). CONCLUSIONS: Electrochemotherapy is an effective means to reduce the volume of hepatic metastases of colorectal cancer in the rat. Additional research is required to determine the optimum treatment duration, dose effects, volume of tumor that can be treated by electrochemotherapy, and impact on survival. Such experimental studies are indispensable prerequisites for clinical trials.

Jejunal versus ileal segmental allografts in the dog: comparison of immunologic and functional results.

Segmental small-bowel grafts have been advocated as a means of reducing the incidence of rejection and graft-versus-host disease in small-bowel transplant recipients. This study compared the results achieved with heterotopic segmental allografts of the jejunum and the ileum that used 120 cm Thiry-Vella loops in a dog model. Immunosuppressive therapy consisted of 25 mg cyclosporine/kg/day. Results were monitored by histologic examinations, function tests (maltose and xylose absorption), and brush-border enzyme assays. Thirty-three dogs were randomized for use as a donor (n = 11) or recipient of a jejunal allograft (n = 11) or an ileal allograft (n = 11). Eight allografts were technical failures and were excluded from analysis. Fourteen allografts were successful (eight ileal, six jejunal). No case of graft-versus-host disease was observed. Six allografts (42.5%, three jejunal [50%] and three ileal [37.5%]) were rejected during the first 3 months (not statistically significant). Eight allografts (five ileal, three jejunal) were tolerated for up to 3 months and were removed. Two ileal and two jejunal allografts appeared grossly normal at surgical removal, but two ileal and one jejunal allografts exhibited signs of chronic rejection, and one ileal allograft showed advanced rejection. The jejunal and ileal allografts had similar clinical courses, as were revealed by immunologic reactions and functional parameters. We conclude that there is no major difference between jejunal allografts and ileal allografts in the dog.

Technique for the repair of diaphragmatic eventration.

In contrast to the large thoracotomy incisions required by standard surgical techniques for repair of diaphragmatic eventration, the procedure we developed can be performed by video-assisted thoracoscopy, thus offering patients the advantages of a minimally invasive operation. Using two superposed series of transverse back-and-forth continuous sutures, the diaphragm is invaginated, then stretched. The first suture line holds the diaphragm down and maintains the excess within the abdomen; the second suture line places the desired tension on the diaphragmatic dome. Successful repair of 3 cases by this technique is described.

Regression of experimental liver tumor after distant intra-hepatic injection of cytosine deaminase-expressing tumor cells and 5-fluorocytosine treatment.

Cytosine deaminase (CD) gene of E. coli converts the non-toxic compound 5-fluorocytosine (5-FC) into 5-fluorouracil. We have introduced a vector expressing the CD gene in a rat colon carcinoma cell line. Expression of the CD gene confers 5-FC sensitivity to these cells in vitro and in vivo. In a bifocal model consisting in a simultaneous engrafment of a CD+ tumor on one lobe of the liver and a wild-type parental tumor on the opposite lobe, treatment with 5-FC results in regression of both type of tumors, indicating the existence of a distant bystander effect.

Biological risk factors for restenosis after percutaneous transluminal coronary angioplasty.

In an attempt to discern biological (such as thrombotic or fibrinolytic) risk factors in patients developing restenosis after percutaneous transluminal coronary angioplasty, the following factors were measured prior to angiography in a population of 23 patients (20 men, 3 women, mean age 57 +/- 5 yr) treated by a successful angioplasty (gain > 20% and residual stenosis < 50%) for stable angina pectoris and who had a routine angiographic restudy. The following factors were thus assessed: lipid factors: cholesterol, triglycerides, high density lipoprotein cholesterol, low density lipoprotein cholesterol, apolipoprotein AI, apolipoprotein B; coagulation factors: fibrinogen, antithrombin III, fibrinopeptide A, factor VIII coagulant, factor VIII antigen, protein C; factors of physiological fibrinolysis: plasminogen, alpha 2-antiplasmin, tissue plasminogen activator and euglobulin clot lysis time before and after venous occlusion, plasminogen activator inhibitor before venous occlusion; and factors of platelet release: beta-thromboglobulin, platelet factor 4. Also studied were clinical characteristics: age, gender, diabetes, hypertension, smoking habits, previous myocardial infarction; angiographic data: global extent of coronary artery disease, location of the stenosis in a bend or branch point, complexity of the lesion, initial and residual stenosis and treatment during follow-up. The coronary angiograms were analyzed by a computer-assisted method with automatic edge detection. On angiographic criteria, 6 patients (restenosis group) were judged to have developed a restenosis (30% decrease in diameter and/or return to a 50% stenosis). The other 17 patients (those without restenosis) were considered to have a persistent success. Apart from age (group without restenosis: 55 +/- 6; restenosis group 61 +/- 5, p < 0.04), there were no differences in clinical, angiographic or treatment variables. There were no differences in lipid factors, but significant differences were observed in hemostatic variables: fibrinogen (without restenosis: 3.18 +/- 0.83; restenosis: 3.83 +/- 0.51 milligrams, p = 0.05), tissue plasminogen activator before venous occlusion (without restenosis: 10.9 +/- 26.8; restenosis: 232.5 +/- 371.2 IU, p < 0.04), euglobulin clot lysis time after venous occlusion (without restenosis: 176.5 +/- 100.5; restenosis: 78.6 +/- 40.2 min, p < 0.05) and for marker of the platelet release: platelet factor 4 (without restenosis: 10.8 +/- 7.9; restenosis: 20.5 +/- 7.5 ng/l, p < 0.04). These findings indicate that patients developing restenosis after coronary angioplasty tend to have an imbalance in the prothrombotic-antithrombotic equilibrium prior to the procedure.

Restenosis or rapid progression in non-dilated sites are not predictors of late spontaneous coronary events.

The present study was designed to assess the prognostic value of clinical and angiographic factors, and especially restenosis or rapid progression in non-dilated sites, on major spontaneous coronary events at long-term follow-up after a first successful coronary angioplasty performed for angina pectoris. A second aim was to assess the prognostic factors and especially restenosis in asymptomatic patients after angioplasty. The first 352 consecutive patients undergoing a successful coronary angioplasty were selected and followed-up. The following variables: age, sex, unstable angina, previous myocardial infarction, diabetes, hypercholesterolemia, tobacco consumption, hypertension, fibrinogen, coronary extent, single or multiple dilatation, restenosis, new progression, clinical deterioration of anginal status just before angiographic restudy or asymptomatic status were subjected to a stepwise regression analysis. Restenosis (a loss of 30% in diameter and/or a return to a >50% stenosis) and progression in non-dilated segments (a 20% reduction in diameter) were assessed by a computer-assisted method. Cardiac death, new myocardial infarction or new unstable angina, at long-term follow-up after angiographic restudy, were regarded as spontaneous coronary events and pooled in a single dependent variable. Thus 41 patients had a coronary event. In the overall population, clinical deterioration of anginal status (p<0.001, relative risk: 3.65) and fibrinogen (p<0.05, relative risk: 1.03) were independent predictors of spontaneous coronary events. Restenosis or new progression were not predictors. In asymptomatic patients (n=187), fibrinogen (p<0.01, relative risk=1.06) was the only predictor and restenosis was not an independent predictor of spontaneous coronary events. The best predictor of spontaneous coronary events at long-term follow-up after a first successful coronary angioplasty is clinical deterioration in anginal status in the months following the procedure. Restenosis does not appear as an independent predictor. Rapid progression observed in non-dilated sites is not an important prognostic factor.