Alois Fürst

Multicenter Phase II Trial of Chemoradiation With Oxaliplatin for Rectal Cancer

PURPOSE To evaluate the activity and safety of preoperative radiotherapy (RT) and concurrent capecitabine and oxaliplatin (XELOX-RT) plus four cycles of adjuvant XELOX in patients with rectal cancer. PATIENTS AND METHODS One hundred ten patients with T3/T4 or N+ rectal cancer were entered onto the trial in 11 investigator sites and received preoperative RT (50.4 Gy in 28 fractions). Capecitabine was administered concurrently at 1,650 mg/m2 on days 1 to 14 and 22 to 35, and oxaliplatin was administered at 50 mg/m2 on days 1, 8, 22, and 29. Surgery was scheduled 4 to 6 weeks after completion of XELOX-RT. Four cycles of adjuvant XELOX (capecitabine 1,000 mg/m2 bid on days 1 to 14; oxaliplatin 130 mg/m2 on day 1) were administered. The main end points were activity as assessed by the pathologic complete response (pCR) rate and the feasibility of postoperative XELOX chemotherapy. RESULTS After XELOX-RT, 103 of 104 eligible patients underwent surgery; pCR was achieved in 17 patients (16%), one patient had ypT0N1 disease, and 53 patients showed tumor regression of more than 50% of the tumor mass. R0 resections were achieved in 95% of patients, and sphincter preservation was accomplished in 77%. Full-dose preoperative XELOX-RT was administered in 96%. Grade 3 or 4 diarrhea occurred in 12% of patients. Postoperative complication occurred in 43% of patients. Sixty percent of patients received all four cycles of adjuvant XELOX, with sensory neuropathy (18%) and diarrhea (12%) being the main grade 3 or 4 toxicities. CONCLUSION Preoperative XELOX-RT plus four cycles of adjuvant XELOX is an active and feasible treatment. This regimen is proposed for phase III evaluation comparing standard fluorouracil-based treatment with XELOX- based multimodality treatment.

Neorectal reservoir is not the functional principle of the colonic J-pouch: The volume of a short colonic J-pouch does not differ from a straight coloanal anastomosis

AbstractBACKGROUND: Low anterior resection with coloanal anastomosis prevents a definitive stoma in patients with distal rectal cancer. However, imperative stool urge, stool fragmentation, prolonged stooling sessions, and minor problems of incontinence are frequently observed in the postoperative situation and negatively affect quality of life. Therefore, the colonic J-pouch was originally constructed to create a stool reservoir. In a randomized, prospective study, the short (5 cm) colonic J-pouch was tested for function and continence vs. straight coloanal anastomosis. METHODS: Over a period of 30 months, 74 consecutive patients (55 males) with rectal cancer in the lower and middle third of the rectum were included and randomized into two groups. Anastomosis was performed either as a coloanal or a colon-pouch-anal anastomosis. The standardized surgical procedure included mobilization of the left hemicolon, central ligation of the inferior mesenteric artery and vein, preaortal lymph node dissection, autonomic nerve preservation, and total mesorectal excision. The anastomosis was performed at the upper anal canal or at the intersphincteric level. All patients were evaluated preoperatively and six months postoperatively for fecal continence, including sphincter manometry and defecation habits. In addition, quality of life was determined by use of a standardized questionnaire (European Organization for Research and Treatment of Cancer, EORTC-QLQ-C30). RESULTS: Thirty-seven patients were randomized into each group. In general, problems with continence for liquids or gas occurred less frequently in the colonic J-pouch group 6 months after surgery. The frequency of bowel movements was lower in the J-pouch group (2.5 per day) than in the coloanal group (4.7 per day). Importantly, in a manometric study at the same postoperative point, neorectal capacity was decreased to a similar degree in both groups compared with the preoperative rectal volume. Thus, the expected and postulated reservoir effect could not be achieved by forming a 5-cm colonic J-pouch. CONCLUSION: The colonic J-pouch was superior with regard to continence for gas and liquids compared with a straight coloanal anastomosis. Furthermore, stool frequency was significantly lower in the J-pouch group than in the coloanal reconstruction group. However, because neorectal capacity decreased equally in both groups, we speculate that the advantage of the colonic J-pouch is not in the creation of a larger neorectal reservoir but rather may be related to decreased motility.

Evidence for a role of epithelial mesenchymal transition during pathogenesis of fistulae in Crohn's disease

Background: The pathogenesis of fistulae in Crohns disease (CD) patients is barely understood. We recently showed that more than two‐thirds of CD fistulae are covered with flat, mesenchymal‐like cells (transitional cells [TC]) forming a patchy basement membrane. Epithelial‐to‐mesenchymal transition (EMT) is a process of reprogramming epithelial cells, allowing them to migrate more effectively and giving epithelial cells an “invasive” potential. EMT has been suggested to be crucial in fibrosis found in different tissues and diseases. We therefore investigated whether EMT could be involved in the pathogenesis of fistulae formation in CD. Methods: In all, 18 perianal fistulae, 2 enteroenteric, and 1 enterovesical fistulae from 17 CD patients were analyzed. In addition 2 perianal fistulae of non‐CD patients were studied. Hematoxylin and eosin staining, immunohistochemistry for the expression of cytokeratins 8 and 20, &bgr;6‐integrin, E‐cadherin, &bgr;‐catenin, vimentin, and TGF‐&bgr;1 and 2 were performed according to standard techniques. Results: The TC covering perianal or enteroenteric fistulae were strongly positive for cytokeratins 8 and 20 but negative for vimentin, indicating their epithelial origin. &bgr;6‐Integrin and TGF‐&bgr; had the highest staining intensities in the transitional zone between the epithelium and the TC. Expression of junctional proteins such as E‐cadherin was reduced in TC as compared to regular fistulae epithelium. In addition, a translocation of &bgr;‐catenin from the membrane to the cytoplasm was observed. Conclusions: Our data for the first time indicate an expression pattern of epithelial and mesenchymal markers in TC associated with fistulae formation that is characteristic for EMT. Studying the pathways of EMT during intestinal fistulae formation may help to develop new therapeutic strategies.

Colonic J-Pouch vs. Coloplasty Following Resection of Distal Rectal Cancer

AbstractPURPOSE: In terms of functional outcome, there is evidence of the superiority of the colonic J-pouch over a straight coloanal anastomosis. Even though the colonic J-pouch was created to restore a neorectal reservoir, manometric data show that the volume of a short colonic J-pouch does not differ from a straight coloanal anastomosis. We speculate that the advantage of the colonic J-pouch is not in creating a larger neorectal reservoir, but rather related to decreased motility. Maurer and Z’graggen recently described a new colonic pouch design, performing a “transverse coloplasty” pouch. The purpose of this pilot study was to compare the feasibility and functional outcome of the 5-cm colonic J-pouch vs. the coloplasty pouch. METHODS: From February 2000 to June 2001, we randomized 40 consecutive patients with distal rectal cancer (<12 cm from the anal verge) into the J-pouch or coloplasty group. A low rectal resection and coloanal anastomosis was performed in all patients. Functional data were collected by a standardized questionnaire and anorectal manometry, preoperatively and six months postoperatively. Primary end points of the study were potentially differences of both groups regarding technical feasibility, stool frequency, and anorectal manometry. RESULTS: The construction of a coloplasty pouch was feasible in all cases of the coloplasty group, but not in 5 of 20 (25 percent) patients of the J-pouch group, because of colonic adipose tissue. Six months after operation or stoma closure, respectively, stool frequency was 2.75 ± 1 per day in the J-pouch group and 2 ± 2 per day in the coloplasty group. There was no significant difference in resting and squeeze pressure and neorectal volume between both groups, but an increased neorectal sensitivity in the coloplasty group. CONCLUSION: We found similar functional results in the coloplasty group compared to the J-pouch group. The neorectal sensitivity was increased in the coloplasty group. Therefore, the colonic coloplasty seems to be an attractive pouch design because of its feasibility, simplicity, and effectiveness.

Preoperative radiotherapy is associated with worse functional results after coloanal anastomosis for rectal cancer.

PURPOSE: This study was designed to evaluate functional outcome in patients treated with preoperative radiotherapy after low anterior resection and a coloanal anastomosis for low rectal cancer. METHODS: Functional outcome data from patients enrolled in a prospective randomized trial comparing 3 reconstructive procedures were evaluated with respect to administration of preoperative radiotherapy. Incontinence was assessed with a questionnaire on bowel function including the Fecal Incontinence Severity Index; sexual function was assessed with the Sexual Health Inventory for Men and a gender-specific questionnaire for women. Quality of life was assessed with SF-36 scores. RESULTS: Of 364 patients enrolled, 153 (42%) had no radiotherapy or chemotherapy, and 211 (58%) had preoperative radiotherapy; 186 (51%) had chemotherapy in addition to radiotherapy. Comparison of irradiated vs. nonirradiated patients showed no significant differences in postoperative morbidity (29.9% vs. 35.3%; P = 0.27). Two-year follow-up of 297 patients showed greater impairment of bowel function in irradiated patients (n = 170) vs. nonirradiated patients (n = 127): e.g., mean number of daily bowel movements at 12 months, 4.2 ± 3.5 vs. 3.5 ± 2.6, P = 0.032; urgency, 85% vs. 67%, P = 0.002). Antidiarrheal use was significantly higher in irradiated patients vs. nonirradiated patients at 4 (P = 0.043), 12 (P = 0.002), and 24 (P = 0.001) months. Sexual Health Inventory for Men scores indicated poorer function in irradiated patients at 24 months (P = 0.039). Preoperative radiotherapy had no deleterious effects on quality of life. Multivariate analyses showed that negative effects of preoperative radiotherapy on urgency at 4 months (P = 0.002) and antidiarrheal use at 24 months were independent of reconstruction technique, but a positive effect of reconstruction with a J-pouch was still observed in patients who received radiotherapy. CONCLUSION: Preoperative radiotherapy does not increase overall morbidity but is associated with poorer functional outcome after low anterior resection with coloanal anastomosis. Preoperative radiotherapy and the J-pouch are nonconfounding predictors of functional outcome up to 24 months after surgery.

Health-related quality of life after laparoscopic and open surgery for rectal cancer in a randomized trial

Previous studies comparing laparoscopic and open surgical techniques have reported improved health‐related quality of life (HRQL). This analysis compared HRQL 12 months after laparoscopic versus open surgery for rectal cancer in a subset of a randomized trial.

German S3 guideline: anal abscess

BackgroundThe incidence of anal abscess is relatively high, and the condition is most common in young men.MethodsA systematic review of the literature was undertaken.ResultsThis abscess usually originates in the proctodeal glands of the intersphincteric space. A distinction is made between subanodermal, intersphincteric, ischioanal, and supralevator abscesses. The patient history and clinical examination are diagnostically sufficient to establish the indication for surgery. Further examinations (endosonography, MRI) should be considered in recurrent abscesses or supralevator abscesses. The timing of the surgical intervention is primarily determined by the patients symptoms, and acute abscess is generally an indication for emergency treatment. Anal abscesses are treated surgically. The type of access (transrectal or perianal) depends on the abscess location. The goal of surgery is thorough drainage of the focus of infection while preserving the sphincter muscles. The wound should be rinsed regularly (using tap water). The use of local antiseptics is associated with a risk of cytotoxicity. Antibiotic treatment is only necessary in exceptional cases. Intraoperative fistula exploration should be conducted with extreme care if at all; no requirement to detect fistula should be imposed. The risk of abscess recurrence or secondary fistula formation is low overall, but they can result from insufficient drainage. Primary fistulotomy should only be performed in case of superficial fistulas and by experienced surgeons. In case of unclear findings or high fistulas, repair should take place in a second procedure.ConclusionIn this clinical S3 guideline, instructions for diagnosis and treatment of anal abscess are described for the first time in Germany.

Magnetic resonance imaging based colonography for diagnosis and assessment of diverticulosis and diverticulitis.

Background and aimsMRI-based colonography is a new minimally invasive imaging modality to assess the colon and abdomen. This new method which is applied mainly for polyp screening could be an integrative approach for colonic diverticulitis assessment. This study evaluated the feasibility of MRI-based colonography to assess diverticulosis or diverticulitis.Patients and methodsFourteen consecutive patients with clinically suspected diverticulitis were examined by MRI colonography on a 1.5-T scanner. All patients underwent abdominal CT as gold standard. N-Butyl-scopalamin was given intravenously to reduce bowel peristalsis. After rectal administration of a T1-positive enema T1- and T2-weighted acquisitions with additional intravenous contrast were obtained. A 3D FLASH sequence was acquired for virtual colonography. The results were compared with CT and biological parameters such as white blood cell count and C-reactive protein.ResultsOf 56 bowel segments (sigmoid colon, descending colon, transverse colon, ascending colon) in all 14 patients 54 were assessed to have good to fair image quality. Having CT as standard of reference, all sigmoid diverticula were diagnosed based on MRI. Inflammation as judged by CT was identically assessed on MRI. 3D models of the colon revealed further diverticula in the remaining colon; additionally, the 3D models gave a comprehensive image for surgical planning.ConclusionIn our preliminary study MRI colonography revealed the same diagnosis as CT in all patients without ionizing radiation. Additionally, 3D-rendered models and virtual colonoscopy can be performed. This comprehensive 3D models could replace presurgical planning barium enema with concurrent assessment of the residual colon.

Hallmarks of epithelial to mesenchymal transition are detectable in Crohn's disease associated intestinal fibrosis

BackgroundIntestinal fibrosis and subsequent stricture formation represent frequent complications of Crohn’s disease (CD). In many organs, fibrosis develops as a result of epithelial to mesenchymal transition (EMT). Recent studies suggested that EMT could be involved in intestinal fibrosis as a result of chronic inflammation. Here, we investigated whether EMT might be involved in stricture formation in CD patients.MethodsHuman colonic tissue specimens from fibrotic areas of 18 CD and 10 non-IBD control patients were studied. Immunohistochemical staining of CD68 (marker for monocytes/macrophages), transforming growth factor-β1 (TGFβ1), β-catenin, SLUG, E-.cadherin, α-smooth muscle actin and fibroblast activation protein (FAP) were performed using standard techniques.ResultsIn fibrotic areas in the intestine of CD patients, a large number of CD68-positive mononuclear cells was detectable suggesting an inflammatory character of the fibrosis. We found stronger expression of TGFβ1, the most powerful driving force for EMT, in and around the fibrotic lesions of CD patients than in non-IBD control patients. In CD patients membrane staining of β-catenin was generally weaker than in control patients and more cells featured nuclear staining indicating transcriptionally active β-catenin, in fibrotic areas. In these regions we also detected nuclear localisation of the transcription factor, SLUG, which has also been implicated in EMT pathogenesis. Adjacent to the fibrotic tissue regions, we observed high levels of FAP, a marker of reactive fibroblasts.ConclusionsWe demonstrate the presence of EMT-associated molecules in fibrotic lesions of CD patients. These findings support the hypothesis that EMT might play a role for the development of CD-associated intestinal fibrosis.

Cryptoglandular Anal Fistulas

BACKGROUND Cryptoglandular anal fistula arises in 2 per 10 000 persons per year and is most common in young men. Improper treatment can result in fecal incontinence and thus in impaired quality of life. METHOD This S3 guideline is based on a systematic review of the pertinent literature. RESULTS The level of evidence for treatment is low, because relevant randomized trials are scarce. Anal fistulae are classified according to the relation of the fistula channel to the sphincter. The indication for treatment is established by the clinical history and physical examination. During surgery, the fistula should be probed and/or dyed. Endo-anal ultrasonography and magnetic resonance imaging are of roughly the same diagnostic value and may be useful as additional studies for complex fistulae. Surgical treatment is with one of the following operations: laying open, seton drainage, plastic surgical reconstruction with suturing of the sphincter, and occlusion with biomaterials. Only superficial fistulae should be laid open. The risk of postoperative incontinence is directly related to the thickness of sphincter muscle that is divided. All high anal fistulae should be treated with a sphincter-saving procedure. The various plastic surgical reconstructive procedures all yield roughly the same results. Occlusion with biomaterials yields a lower cure rate. CONCLUSION This is the first German S3 guideline for the treatment of cryptoglandular anal fistula. It includes recommendations for the diagnostic evaluation and treatment of this clinical entity.