Is suturing of the bladder defect in benign Enterovesical fistula necessary?

BACKGROUND: Enterovesical fistula (EVF) is a abnormal connection between the intestine and the bladder. The aim of the study was to analyze whether closure of the defect in the bladder wall during surgery is always necessary. METHODS: Fifty-nine patients with benign EVF undergoing surgical treatment were enrolled. A one-stage surgical procedure was performed in all patients. After the separation of the diseased bowel segment, methylene blue was introduced. Through a catheter into the bladder. Only patients with urinary bladder leakage were sutured. RESULTS: The most common intestinal fistula involving the urinary bladder was colovesical fistula, observed in 53% of cases. Two-thirds of patients had diverticular disease as the underlying pathology. There was no relationship between suturing of the bladder and perioperative complications. Recurrent EVF was observed in one patient with bladder suturing and in two patients without suture. CONCLUSIONS: These findings suggest that closure of the bladder defect is not necessary in cases where a leak is not demonstrated from the bladder intraoperatively. This study is limited by its retrospective design and small numbers and a randomized controlled trial is recommended to answer this question definitively.

Expression of vascular endothelial growth factor and its correlation with clinical symptoms and endoscopic findings in patients with chronic radiation proctitis.

AIM: The aim of this study was to assess the expression of vascular endothelial growth factor (VEGF) as a key proangiogenic factor and determine whether there is any correlation between its expression and clinical symptoms or endoscopic changes in patients with chronic radiation proctitis (ChRP). METHOD: Fifty patients who had all undergone radiotherapy for prostate, cervical or uterine cancer were included in the study (37 women, 13 men). There was a control group of 20 patients (9 women, 11 men). The Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer (RTOG/EORTC) scoring system was used for grading the severity of the proctitis. Endoscopic scoring of late rectal mucosal damage was performed using Gilinsky's classification. Serum levels of VEGF were analysed by the enzyme-linked immunosorbent assay method. RESULTS: Most patients presented with Grade 1 symptoms. Endoscopic assessment showed that most patients had Grade 1 late rectal mucosal damage. The predominant endoscopic finding was the presence of telangiectasia. Assessment of VEGF correlation between the control group and the degrees of endoscopic changes showed statistically significant differences for all three degrees (P < 0.0001, P = 0.0251 and P = 0.0005, respectively). Due to the small numbers of patients with Grades 2 and 3 symptoms using the RTOG/EORTC scoring system, they were grouped with Grades 1 and 4 respectively forming two groups for statistical purposes. VEGF expression differed significantly between controls and group I and between controls and group II (P = 0.0001, P = 0.0009, respectively). CONCLUSION: A significant increase in VEGF expression was found to correlate with clinical symptoms and endoscopic rectal mucosa changes in patients with ChRP, suggesting that it may play an important role in pathological angiogenesis.

Modulation of Colorectal Cancer Risk by Polymorphisms in 51Gln/His, 64Ile/Val, and 148Asp/Glu of APEX Gene; 23Gly/Ala of XPA Gene; and 689Ser/Arg of ERCC4 Gene.

Polymorphisms in DNA repair genes may affect the activity of the BER (base excision repair) and NER (nucleotide excision repair) systems. Using DNA isolated from blood taken from patients (n = 312) and a control group (n = 320) with CRC, we have analyzed the polymorphisms of selected DNA repair genes and we have demonstrated that genotypes 51Gln/His and 148Asp/Glu of APEX gene and 23Gly/Ala of XPA gene may increase the risk of colorectal cancer. At the same time analyzing the gene-gene interactions, we suggest the thesis that the main factor to be considered when analyzing the impact of polymorphisms on the risk of malignant transformation should be intergenic interactions. Moreover, we are suggesting that some polymorphisms may have impact not only on the malignant transformation but also on the stage of the tumor.

Does C-reactive protein monitoring after colorectal resection with anastomosis give any practical benefit for patients with intra-abdominal septic complications?

AIM: This study aimed to assess the influence of the C-reactive protein (CRP) level on the early outcome after elective colorectal resection. METHOD: Patients with colorectal cancer operated on between 2006 and 2013 were identified retrospectively. They were divided into a study group operated on between 2010 and 2013 when CRP was measured routinely on the fourth postoperative day and a control group operated on between 2006 and 2009 when the CRP level was not measured routinely. Mortality, intra-abdominal septic complications (IASC), abscesses and anastomotic leakage (AL), the need for reoperation, the interval from index surgery to relaparotomy, length of hospital stay and imaging studies were compared by multivariate analysis. RESULTS: A total of 1189 patients were assessed, including 598 (50.3%) in the study group (mean age 61.3 ± 13 years; 282 female) and 591 (49.7%) in the control group (mean age 61.8 ± 11 years; 267 female). There were seven (1.2%) postoperative deaths in the study group and nine (1.5%) in the control group (P = 0.598). Abdominal ultrasound (US) was performed more often in the study group [97 (16.2%) vs 71 (12.0%); P = 0.037]. In the study group the interval to diagnosis of IASC was shorter than in the control group (5.7 ± 1.5 days vs 7.3 ± 1.3 days; P = 0.029). The decision to reoperate was also made earlier in the study group (6.2 ± 1.7 days vs 7.4 ± 2.8 days; P = 0.043). CONCLUSION: Routine measurement of CRP can help to make an earlier diagnosis of IASC and earlier decision for relaparotomy, without any influence on mortality or length of hospital stay.

Efficiency of Base Excision Repair of Oxidative DNA Damage and Its Impact on the Risk of Colorectal Cancer in the Polish Population.

DNA oxidative lesions are widely considered as a potential risk factor for colorectal cancer development. The aim of this work was to determine the role of the efficiency of base excision repair, both in lymphocytes and in epithelial tissue, in patients with CRC and healthy subjects. SNPs were identified within genes responsible for steps following glycosylase action in BER, and patients and healthy subjects were genotyped. A radioisotopic BER assay was used for assessing repair efficiency and TaqMan for genotyping. Decreased BER activity was observed in lymphocyte extract from CRC patients and in cancer tissue extract, compared to healthy subjects. In addition, polymorphisms of EXO1, LIG3, and PolB may modulate the risk of colorectal cancer by decreasing (PolB) or increasing (LIG3 and EXO1) the chance of malignant transformation.

International quality assurance project in colorectal cancer-unifying diagnostic and histopathological evaluation.

PURPOSE: Several European countries are undertaking quality control projects in colorectal cancer. These efforts have led to improvements in survival, but a comparison between different projects reveals questionable results. The aim of this study is the presentation of results from hospitals in three different European countries participating in the International Quality Assurance in Colorectal Cancer (IQACC) project. METHODS: For this publication, patients with cancer of the colon or rectum treated in 2009 and 2010 and recorded in the IQACC (Germany, Poland and Italy) were analysed. The comparison included number of patients, age, preoperative diagnostics (CT of the abdomen and thorax, MRI, colonoscopy, ultrasound, tumour markers), surgical approach, metastasis, height of rectal cancer and histopathological examination of a specimen (T stage, N stage and MERCURY classification for rectum resection). For short-term outcomes, general complications, wound dehiscence, tumour-free status at discharge, anastomotic leakage and in-hospital mortality were analysed. RESULTS: A total of 12,691 patients (6,756 with colon cancer, 5,935 with rectal cancer) were included in the analysis. Preoperative diagnostics differed significantly between countries. For pT and pN stages, several quality differences could be demonstrated, including missing stages (colon cancer: pT 5.7-12.5 %, pN 2.5-11.0 %; rectal cancer: pT 1.1-5.6 %, pN 1.1-15.5 %). The most relevant differences for short-term outcomes in colon cancer were found in general complications (4.2-22.8 %) and tumour-free status at discharge (74.5-91.7 %). In-hospital deaths ranged between 2.5 and 4.3 % and did not show significant differences. For rectal cancer, the country with the highest percentage of tumours localised less than 4 cm from the anal verge (16.0 %) showed the lowest frequency of amputation (8.5 %). Outcome differences were found for general complications (3.2-18.8 %), anastomotic leakage (0-4.3 %) and tumour-free status at discharge (72.9-87.6 %). In-hospital deaths ranged between 1.1 and 3.2 %. CONCLUSION: This study demonstrates the feasibility of an international quality assurance project in colorectal cancer. This concept ensures data analysis based on a comparable data input. Differences in preoperative diagnostics, completeness of histopathological evaluation and short-term outcomes for Germany, Poland and Italy might result from disparities in socioeconomic factors and implementation of existing guidelines. Further activities are necessary to warrant the use of common standards in outcome control.

Dendrimers in therapy for breast and colorectal cancer.

Current trends in research dealing with methods of developing effective chemotherapy for the two most dangerous killers - breast and colon cancers have been discussed. The input brought by nanotechnology is presented with particular stress on the use of dendrimers. These unique "polymeric compounds" after modification can form intelligent species, transporting drugs into specific areas and at the same time can be used for monitoring the state of organs attacked by cancer cells, as well as the progress of the curing process. They can help to limit the anticancer drugs delivery to designed goals only, eliminating many side effects of chemotherapy. Breast and colon cancer are major problem for public health care in many countries all over the world. During last twenty years a dramatic increase in incidence of both of them has been observed, especially in industrialized countries. Probably, both of them are caused, apart from the hereditary syndromes, by specific point mutation, some hormonal factors in breast cancer and by the strong co-influence of environmental factors and dietary exposure of a patient.

The EURECCA project: Data items scored by European colorectal cancer audit registries.

AIMS: The EURECCA (European Registration of Cancer Care) consortium is currently formed by nine independently founded national colorectal audit registrations, of which most already run for many years. The cumulative experience of EURECCA's participants could be used to identify a 'core dataset' that covers all important aspects needed for high quality auditing and at the same time lacking needless data items that only consumes administrative effort. The aim of this study is to compare the data items used by the nine registries participating in EURECCA to identify a core dataset and explore options for future research. METHODS: All colorectal outcome registrations participating in the EURECCA project were asked to supply a list with all the data items they score. Items were scored 'present' if they appeared literally in a registration or in case they could be calculated using other items in the same registration. The definition of a 'shared data item' was that at least eight of the nine participating registries scored the item. RESULTS: The number of registered data items varied between 254 (Belgium) and 83 (Norway). Among the 45 variables were patient data, data about preoperative staging, surgical treatment, pre- or postoperative radio- and/or chemotherapy, and follow-up. Items about tumour recurrence or quality of life were scored too little to become shared data items. CONCLUSIONS: A total of 45 items were collected by 8 or more of the participating registries and subsequently met the criteria for a shared data item.

The role of N-acetyltransferase 2 polymorphism in the etiopathogenesis of inflammatory bowel disease.

BACKGROUND AND PURPOSE: Inflammatory bowel disease (IBD) consists of ulcerative colitis (UC) and Crohn's disease (CD), which are complex genetic disorders resulting from the interplay between several genetic and environmental risk factors. The arylamine N-acetyltransferase 2 (NAT2) enzyme detoxifies a wide spectrum of naturally occurring xenobiotics including carcinogens and drugs. Acetylation catalyzed by NAT2 is an important process in metabolic activation of arylamines to electrophilic intermediates that initiate carcinogenesis. The aim of our study was to determine whether there is any association between the susceptibility to inflammatory bowel disease among the variations of NAT2 genotypes. METHODS: This study was carried out in 80 patients with IBD. The control group consisted of 100 healthy volunteers. The most common mutations found in the Caucasian population are at the positions 481T, 803G, 590A and 857A on the NAT2 gene. This was determined using the polymerase chain reaction-restriction fragment length polymorphism method with DNA extracted from peripheral blood. RESULTS: Risk of IBD development was 3.86 for the carriers of the NAT2*5/NAT2*7 genotype and 2.53 for the carriers with NAT2*6/NAT2*7, but it was not statistically significant. A statistically significant correlation between the NAT2*7 allele prevalence and the risk for developing IBD was found (OR = 5.8; P = 0.005). CONCLUSIONS: Higher prevalence of the NAT2*7 allele in patients with IBD and the obtained OR values could suggest that this mutation has the effect of increasing IBD development. Future studies are needed to confirm our assumptions on larger group of patients.

Resection of the primary tumour or other palliative procedures in incurable stage IV colorectal cancer patients?

OBJECTIVE: The aims of the study were to analyse the early and late results of surgical treatment in patients with stage IV colorectal cancer (CRC) and to evaluate the effect of primary tumour resection and other clinical factors on survival. METHOD: A group of 134 patients with stage IV CRC was electively operated on between 1996 and 2000. The first group underwent resection of the primary tumour (52 patients; mean age 63.4 +/- 10.3) and the second group of patients underwent procedures without resection (82 patients; mean age 62.6 +/- 10.6). RESULTS: Postoperative morbidity occurred significantly more often (P = 0.041) in the first group--in 26 patients (50%) than in the second group - 19 patients (23.1%). The resection of the primary tumour increased the survival probability; hazard ratio (HR): 1.78; 95% confidence interval (CI): 1.21-2.78%; P = 0.004. Bi-lobar metastases increased mortality risk compared with uni-lobar; HR 2.32; 95% CI: 1.47-3.68; P = 0.0003. The 2-year survival rate in patients with uni-lobar metastases in the first group was 44.2%, in the second group: 30.7%; P = 0.023. CONCLUSION: Primary tumour resection in stage IV CRC increases the risk of postoperative complications. In the given setting, however, it results in an increased 2-year survival rate but it may not influence the 5-year survival rate. In patients with bi-lobar liver metastases resection of the primary tumour does not prolong survival time.

Genetic polymorphisms of CYP2D6 oxidation in patients with inflammatory bowel disease.

Inflammatory bowel disease (IBD) consists of ulcerative colitis and Crohn's disease, both of which are associated with increased colorectal cancer risk. The relationship between genetically determined polymorphic metabolism of exogenous substances by oxidation catalyzed by CYP2D6 isoenzyme and susceptibility to cancer has aroused great interest. We determined whether there was an association between susceptibility to inflammatory bowel disease and particularly to CYP2D6 genotypes. The study was carried out in 39 patients with IBD. The control group consisted of 129 healthy volunteers. The CYP2D6 genotypes were analyzed by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method with DNA extracted from peripheral blood. Among 39 patients with inflammatory bowel disease, extensive metabolizer (EM) genotype constituted 97.4%. One patient (2.6%) was poor metabolizer with CYP2D6*4/CYP2D6*4 genotype. Results obtained in the inflammatory bowel disease group did not differ significantly from those of the control group. Although the odds ratio for EM metabolizers was about 3.8-fold greater in the group of patients with inflammatory bowel disease, this association was not statistically significant. This data also showed no overall statistically significant association between alleles and incidence risk of inflammatory bowel disease [odds ratio (OR) of 1.36 for CYP2D6*1 allele, 0.83 for CYP2D6*3 allele, and 0.74 for CYP2D6*4 allele]. The present results suggest that EM genotype may be the risk factor of inflammatory bowel disease. Future studies are needed to confirm our assumptions on larger group of patients.

Open and closed haemorrhoidectomy for fourth degree haemorrhoids--comparative one center study.

AIM: We compared results of two techniques of haemorrhoidectomy: open Milligan-Morgan (MM) and closed Ferguson (CF) techniques. Length of hospitalization, pain complaints, return to full activity, wound healing time were considered. METHODS: We included the group of 63 patients: 29 patients (16 women) were randomly allocated to MM operation and 34 patients (15 women) to CF operation. Follow-up study was performed after 2, 4, 24 weeks and six and eighteen months postoperatively. RESULTS: We did not note any statistically significant differences in relation to hospitalization time 30.9 days (MM) and 30.8 days (CF). Postoperative urine retention was similar: 5 (17.2%) patients (MM) and 7 (20.6%) patients (CF). No differences in the intensity of postoperative pain was observed. Patients returned to work after 293 days (MM) and 342 days (CF) (p = 0.059). We observed no infection of the wound in MM group but in four patients from CF group (11.8%); (p = 0.053). However overall wound healing time was shorter after CF method than after MM method: 233 vs. 274 days, respectively (p = 0.053). CONCLUSIONS: Our study confirms that the results after MM and CF haemorrhoidectomy are similar. We found a trend towards faster wound healing after CF procedure, however there was a trend towards higher wound infection in that group. There was also a trend towards shorter recovery time in patients after MM operation.

Chemoprevention of colorectal cancer - a new target needed?

OBJECTIVE: Novel treatments for colorectal cancer (CRC) include chemoprevention. Nonsteroidal anti-inflammatory drugs (NSAIDs) were the first to be studied and an inverse association was proven between their use and the development of invasive CRC. The numerous side effects of NSAIDs led, however, to the search for safer drugs. These have included Coxibs (selective COX-2 inhibitors). In this study, the role of coxibs in the chemoprevention of CRC is reviewed. RESULTS: Numerous in-vitro and in-vivo experiments have shown the effectiveness of coxibs in the chemoprevention of CRC. These have led to the registration of celecoxib by the USA Food and Drug Administration for the treatment of familial adenomatous polyposis. Further studies of coxibs have revealed an increased risk of serious cardiovascular events when compared with placebo. This finding has considerably decreased the opportunities for chemoprevention of CRC. CONCLUSION: The multi-directional activity of coxibs, which was the reason for their effectiveness against CRC development may be the key to proposing a new target area for chemoprevention. It has been shown that celecoxib partly inhibits the activity of NF-kappaB, transcription factor involved in inflammation and carcinogenesis pathways. Modulation of its activation may be the future of effective CRC chemoprevention.

Late results of treatment of anal fistulas.

OBJECTIVE: The aim of this paper was to analyse the results of treatment of anal fistulas retrospectively. METHODS: Between 1992 and 2004, 407 patients were operated on for perianal fistula. In the follow-up period, 107 patients were lost, so 300 patients were analysed in the study. The mean follow-up time was 4.2 years. Analysed parameters included: types of surgical procedures in different kinds of fistulas and postoperative complications. Various types of surgical procedures and their effectiveness were described. Late results were assessed taking into account healing time, duration of sick leave, recurrence rate and incidence of anal sphincter dysfunction. Severity of gas and stool incontinence was assessed according to the Cleveland Clinic Incontinence Score. RESULTS: In our study, subcutaneous fistula was diagnosed in 23.3%, inter-sphincteric in 18%, trans-sphincteric in 37.7%, supra-sphincteric in 16% and extra-sphincteric in 5% of patients. Single-tract fistulas were present in 88.7% and multi-tract fistulas were present in 11.3%. Overall, 242 patients had primary fistulas and 58 patients had recurrent fistulas. The most frequently performed procedures were cutting seton (139 patients) and radical fistulectomy (104 patients). Recurrent fistulas developed in 14.3%. Postoperative gas and/or stool incontinence was noticed in 10.7%. The recurrence rate was 5.4% in patients with primary fistula and in 51.7% patients presenting with a recurrent fistula. Gas and stool incontinence developed in 3.7% of patients with primary fistulas and in 39.7% of patients presenting with recurrent fistulas. Recurrence rate was 12% in the patients of single-tract fistulas and 32.4% in the patients of multi-tract fistulas. Postoperative gas and/or stool incontinence occurred in 8.3% of patients of single-tract fistulas and in 29.4% of patients of multi-tract fistulas. CONCLUSIONS: The complication rate was 10-fold higher in patients presenting with a recurrent fistula than in those with primary fistulas and threefold higher in patients with multi-tract fistulas than in those with single-tract fistulas.

The T/G mutation in exon 8 of hMSH2 gene in the sporadic colon cancer patients.

The DNA mismatch repair (MMR) system guards against genomic instability, therefore the mutations in the human MMR genes cause the majority of the hereditary nonpolyposis colorectal cancer (HNPCC) and a small percentage of the sporadic colon cancer. hMSH2 is one of MMR genes involved in the correction of mispairing during replication and its mutations are associated with both--microsatellite instability and the hereditary and sporadic colon tumourgenesis. The aim of this study was to analyse the T/G mutation (codon 458) in exon 8 of hMSH2 gene in the sporadic colon cancer cells. We also examined the relationship between the T/G mutation of hMSH2 gene, and the selected prognostic factors such as Dukes' stage, histological grade and lymph node metastasis. We analysed samples of tumour from 75 patients with sporadic colorectal cancers. The mutation in the hMSH2 gene ware determined by the RFLP-PCR. We found T/G mutation in exon 8 of hMSH2 gene in 5 patients (6,7%). There was no statistically significant difference between this mutation and selected clinical parameters. The results of our studies revealed that mutations of hMSH2 gene may lead to development of colorectal cancer. No dependence between the mutation of hMSH2 gene and clinical parameters, suggests that the mutation of hMSH2 gene may have a critical significance for the first steps of carcinogenesis in colon epithelial.

Crohn's disease--when to operate?

Crohn's disease is a chronic bowel condition, which can present as a number of different clinical and pathological presentations, depending on localization and activity of the inflammatory process. The aethiology of the disease has not been explained. In each case the treatment should be individually tailored depending on the type of the changes. The indications for surgical intervention are continuous bleedings, recurrent ileus, perforation of the intestine, abscesses, fistulas, failure of pharmacological treatment, resistance to steroids and steroid dependence. In case of the mild type of the disease with few symptoms pharmacological treatment is the right choice In case of the mild type of the disease with few symptoms pharmacological treatment is the right choice process. In malign form of Crohn's disease lack of improvement after 7-10 days of intensive treatment is generally accepted indication for surgical treatment. Fulminant form of the disease is still a clear-cut indication for immediate surgical intervention. Decision on surgical intervention is more difficult and controversial when patient presents with series of subileus recurrences subsiding after conservative treatment. Patients with stenotic form of Crohn's disease usually require multiple operations most of which are bowel resections. Patients with stenotic form of Crohn's disease usually require multiple operations most of which are bowel resections therapy. External and internal asymptomatic fistulas should be treated conservatively. The timing of surgical treatment is essential in Crohn's disease however the prevention from recurrences is also fundamental. It is well proved that preventive administration of 5-ASA (especially mesalazine) and metronidazol can reduce the risk of early recurrences after surgery.

Antigen levels of the urokinase-type plasminogen activator and its gene polymorphisms in colorectal cancer.

We analysed the distribution of genotypes of two polymorphisms in the urokinase-type plasminogen activator (uPA) gene: C-->T substitution in exon 6 and T-->C substitution in intron 7 in 52 subjects with colorectal cancer. Genotypes were determined in tumour tissue and distant mucosa samples by allele-specific polymerase chain reaction. The antigen levels of uPA in cancer tissue were higher than in distant mucosa as measured by enzyme-linked immunosorbent assay. The level of uPA antigens in cancer samples with the C/C genotype of C-->T polymorphism in exon 6 was higher than in samples with C/T and T/T genotypes. No differences in the level of uPA antigens between the alleles of the intron 7 T-->C polymorphism were found. As uPA can be involved in cancer invasion and metastasis, C/C genotype in exon 6 of uPA gene can be further considered as being related to colorectal cancer progression.

Risk factors in the recurrence of the colorectal cancer.

Traditionally, the clinical outcome of colorectal cancer patients may be predicted by pathological staging by either Dukes staging or the UICC-TNM system. However, some of Dukes stage A (approximately 10% of patients) and Dukes B patients (30-40%) will develop local recurrence or distant metastasis years after receiving standard surgical treatments. Therefore it is important to find some other indicators that can predict for recurrence so that we can screen for high-risk early-stage patients who may need preventive chemotherapy or other adjuvant therapy. The aim of this study is determination of risk factor for local recurrence in rectal cancer. In this study there has been used and summarized also research records and publications from different clinical hospitals according to actual international literature. Part of elements connected with patient, tumor and genetic and immunological factors remains independent on curative procedures. However better investigation these factors might affect on therapy, frequency of follow-up examinations, and help to detect recurrence at very early phase. Concomitant treatment factors are able to be moderate by surgeons and therapeutics. Therefore precise definition of risk factors might be helpful in decrease recurrence rate in patients with rectal cancer.

New approaches to the treatment of anal fissure.

According to Antropoli, pathologies of the anal canal are extremely common. About 30 to 40 percent of the population suffers from proctologic pathologies at least once in their lives. In most cases they are more annoying than dangerous. Anal fissure (AF) was recognized as a clinical entity in 1934. It is a longitudinal defect of the anal canal mucosa and anoderm extending usually from the dentate line to the external verge of the anal canal. This defect exposes the lower half or even most of the fibres of internal anal sphincter. AF is almost always accompanied by extensive tension of this muscle. Anal fissures affect all age groups but predominantly occur in the 3rd and 4th decades of life (2, 8, 23). Gathright states that fissure disease causes from 6 to 15% of office visits and 10% of operative procedures in a colorectal practice. The etiology of anal fissure has only been partially explained and remains controversial although spasm of the internal anal sphincter has been recognized to play a main role in the pathogenesis of this disease. Recent studies have cast new light on the pathogenesis of anal fissures.