Surgical treatment of trans-sphincteric anal fistulas with the Fat GRAFT technique: a minimally invasive procedure.

AIM: Anal fistulas are common pathologies with a significant social impact; however, their treatment is often complex and the recurrence rate can be significant. Some surgical treatments for fistula are also associated with the risk of sphincter injury. In this technical note, we aim to evaluate the feasibility and efficacy of the Fat GRAFT technique (Fat Grafting in Anal Fistula Treatment) in the treatment of recurrent anal fistulas. METHOD: All patients presenting with recurrent trans-sphincteric anal fistulas over an 18-month period were included. After abdominal fat harvesting and fat preparation, fat grafting was performed in the track and peripheral area of the fistula. The internal and external openings of the fistula were closed to maximally preserve the retention of the adipocyte graft in the fistula. RESULTS: Eleven patients underwent the Fat GRAFT procedure (seven men, four women). The average re-injected volume for each fistula was 21 ml (range 10-30 ml). The postoperative course was uneventful. At 6 months three patients developed recurrence (73% healed). There were no postoperative complications. CONCLUSION: The Fat GRAFT technique appears to be a promising technique with a low risk of anal incontinence, in contrast to other techniques. This method was effective in > 70% of patients in a single session.

Mejor rendimiento de la PET/TC con 18F-FDOPA para la detección de metástasis de un tumor neuroendocrino del íleon / Best sensitivity of 18F-FDOPA PET/CT to detect metastasis in one case of neuroendocrine tumour of the ileum

Los tumores neuroendocrinos (TNE) son un grupo de tumores muy heterogéneos y de distribución variable, lo que dificulta su localización anatómica. En medicina nuclear, durante décadas se han propuesto diferentes técnicas de imagen PET o SPECT con diversos radiotrazadores para el estudio de estos tumores, no existiendo consenso actualmente sobre la más adecuada, incluso al considerar solamente los TNE digestivos. Presentamos el caso de una mujer de 67 años con un TNE bien diferenciado del íleon en la que se sospechó una recidiva y ninguna técnica de imagen fue capaz de detectar la enfermedad, excepto la PET/TC con 18F-FDOPA. El seguimiento posterior mostró progresión de la enfermedad, confirmándose la positividad de este primer hallazgo. A raíz del caso se discuten y comparan los radiofármacos posibles para el diagnóstico de TNE digestivos, haciendo énfasis en los derivados embriológicamente del intestino medio (AU)

Neuroendocrine tumours (NET) are heterogeneous and frequently spread over the body, making their imaging difficult. With this aim, nuclear medicine imaging, using PET or SPECT with different tracers, has been proposed for decades, but there is currently no consensus on the most appropriate technique, even when only considering gastrointestinal NET. The case is presented of a 67year old woman with a well differentiated NET of the ileum with suspected recurrence, which was not detected by any imaging technique except 18F-FDOPA PET/CT. Subsequent follow up showed disease progression, which confirmed the true positivity of 18F-FDOPA. Using this case, we discuss and compare different radiotracers for the diagnosis of gastrointestinal NET, focusing on those embryologically originating from the mid-gut (AU)

Best sensitivity of 18F-FDOPA PET/CT to detect metastasis in one case of neuroendocrine tumour of the ileum. / Mejor rendimiento de la PET/TC con 18F-FDOPA para la detección de metástasis de un tumor neuroendocrino del íleon.

Neuroendocrine tumours (NET) are heterogeneous and frequently spread over the body, making their imaging difficult. With this aim, nuclear medicine imaging, using PET or SPECT with different tracers, has been proposed for decades, but there is currently no consensus on the most appropriate technique, even when only considering gastrointestinal NET. The case is presented of a 67year old woman with a well differentiated NET of the ileum with suspected recurrence, which was not detected by any imaging technique except 18F-FDOPA PET/CT. Subsequent follow up showed disease progression, which confirmed the true positivity of 18F-FDOPA. Using this case, we discuss and compare different radiotracers for the diagnosis of gastrointestinal NET, focusing on those embryologically originating from the mid-gut.

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.

[Inguinal hernia repair: time interval between surgical repair and recurrence]. / Hernies inguinales: délais d'apparition des récidives.

This study seeks to evaluate the time interval between initial inguinal hernia repair and the appearance of recurrent hernia in patients undergoing re-operation. Recurrent hernia was identified in 94 (6.4%) of 1,474 patients having undergone initial hernia repair at our institution. Recurrence appeared within two years in 40 patients (42%). Recurrences were noted beyond five years in 32 patients (34%), and after 20 years in 18 patients (19%). 75% of recurrences had occurred within 15 years. We conclude that almost two-thirds of recurrences occur later than five years after the initial intervention and a quarter occur at an interval of more than fifteen years. Most studies underestimate hernia recurrence due to an insufficient period of post-operative observation.

Prognosis of stage II colon cancer by non-neoplastic mucosa gene expression profiling.

We have assessed the possibility to build a prognosis predictor (PP), based on non-neoplastic mucosa microarray gene expression measures, for stage II colon cancer patients. Non-neoplastic colonic mucosa mRNA samples from 24 patients (10 with a metachronous metastasis, 14 with no recurrence) were profiled using the Affymetrix HGU133A GeneChip. Patients were repeatedly and randomly divided into 1000 training sets (TSs) of size 16 and validation sets (VS) of size 8. For each TS/VS split, a 70-gene PP, identified on the TS by selecting the 70 most differentially expressed genes and applying diagonal linear discriminant analysis, was used to predict the prognoses of VS patients. Mean prognosis prediction performances of the 70-gene PP were 81.8% for accuracy, 73.0% for sensitivity and 87.1% for specificity. Informative genes suggested branching signal-transduction pathways with possible extensive networks between individual pathways. They also included genes coding for proteins involved in immune surveillance. In conclusion, our study suggests that one can build an accurate PP for stage II colon cancer patients, based on non-neoplastic mucosa microarray gene expression measures.

[Epidermoid carcinomas of anal canal treated with radiation therapy and concomitant chemotherapy (5-fluorouracil and cisplatin)]. / Carcinomes épidermoïdes du canal anal traités par association concomitante de radiothérapie et de chimiothérapie. Evaluation des résultats fonctionnels.

PURPOSE: To evaluate our results after radiation therapy and concomitant chemotherapy in terms of local control, survival and toxicity in patients with anal cancer. METHODS AND PATIENTS: Between November 1990 and January 2002, 60 patients (pts) were treated with radiation therapy and concomitant chemotherapy. The T-stage according to the 2001 UICC classification were: 2 T1, 26 T2, 25 T3, and 7 T4. There were 20 pts with nodal involvement at presentation. The treatment started with external beam RT (median dose: 45 Gy) and concomitant chemotherapy using 5-fluorouracil and cisplatin during the first week and the fifth week of external beam RT (EBRT). After a rest period of 4 to 6 weeks, a boost of 20 Gy was delivered by EBRT in 58 pts and by interstitial (192)Ir brachytherapy in 2 pts. Mean follow-up were 78.5 months. RESULTS: At the end of RT with concomitant chemotherapy local tumor clinical complete response rate was 83%. Out of 10 non responders or local progression, 5 (50%) were salvaged with abdominoperineal resection (APR). Out of 5 local tumor relapses, 3 were salvaged with APR. The overall local tumor control (LC) rate with or without salvage local treatment were 88%. LC rate with a good anal function scoring (score 0 and 1) was 70%. Among 43 pts who preserved their anus, 98% had a good anal function scoring. The 5-year disease-free survival was 75%. After multivariate analysis, 2 independent predicting factors significantly influenced the disease-free survival: HIV-positive pts (negative vs positive, P=0.032) and clinical tumor response after the first course of radiotherapy (<50% vs >or=50%, P=0.00032). Acute grade 2 or 3 toxicities were low: haematological toxicity in 4 pts and intestinal complication corresponding to diarrhea in 10 pts. Late severe complication was observed in 3 pts: 2 pts with painful necrosis of the anus requiring colostomy and 1 pt with grade 3 rectal bleeding. CONCLUSION: We confirm the good results with RT and concomitant chemotherapy. The clinical tumor response after the first course of RT and concomitant chemotherapy is probably the most important predictive factor on the disease-free survival. For patients with T3 or T4 lesion and tumor regression

[Retroviral restriction factors : from Fv1 to TRIM5α]. / Les facteurs de restriction rétrovirale : de Fv1 à TRIM5α.

During their evolution, mammals have developed cellular factors interfering with retroviral replication, known as « restriction factors ¼. The prototype of these factors, Fv1, was characterized in the late 60's and blocks MLV infection. Some Fv1-like factors interfering with complex retroviruses, including HIV, have recently been discovered in primate cells. These restriction factors are referred to as Ref1, which blocksMLVreplication in human cells, and Lv1, which blocks the infection of non-human primate cells by various retroviruses, including MLV and HIV. These factors are all saturable by an excess of virus, target the viral capsid and interfere with an early step of viral replication. Lv1 and Ref1 have recently been found to be species-specific variants of a single protein called TRIM5α, a member of the TRIM protein family. The mechanism of action of these factors is still unknown. The existence of natural inhibitors of retroviral infection raises new hopes for the development of therapeutic tools against HIV infection.

Gemcitabine combined with oxaliplatin (GEMOX) in advanced biliary tract adenocarcinoma: a GERCOR study.

BACKGROUND: Since gemcitabine-oxaliplatin (GEMOX) has been used in pancreatic adenocarcinoma, we studied its activity and tolerability in advanced biliary tract adenocarcinoma (ABTA). PATIENTS AND METHODS: Consecutive adult patients with confirmed ABTA were recruited from four centers. Those in group A had performance status (PS) 0-2, bilirubin <2.5x normal and received GEMOX as first-line chemotherapy. Those in group B had PS >2 and/or bilirubin >2.5x normal and/or prior chemotherapy. All received gemcitabine 1000 mg/m2 as a 10 mg/m2/min infusion on day 1, followed by oxaliplatin 100 mg/m2 as a 2-h infusion on day 2, every 2 weeks. RESULTS: Tumor sites were gallbladder (19), extrahepatic bile ducts (5), ampulla of vater (3) and intrahepatic bile ducts (29). Results for group A (n = 3) were: objective response 36% [95% confidence interval (CI) 18.7% to 52.3%], stable disease 26%, progressive disease 39%, median progression-free survival (PFS) 5.7 months and overall survival (OS) 15.4 months. Results for group B (n = 23) were: objective response 22% (95% CI 6.5% to 37.4%), stable disease 30%, progressive disease 48%, PFS 3.9 months and OS 7.6 months. National Cancer Institute Common Toxicity Criteria grade 3-4 toxicities were neutropenia 14% of patients, thrombocytopenia 9%, nausea/vomiting 5% and peripheral neuropathy 7%. CONCLUSION: The GEMOX combination is active and well tolerated in ABTA.

[Epidermoid carcinomas of the anal canal treated with definitive radiation therapy in a series of 305 patients]. / Carcinomes épidermoïdes du canal anal traités par irradiation à visée curative: à propos de 305 patients.

PURPOSE: To identify prognostic factors and treatment toxicity in a serie of epidermoid cancers of the anal canal without evident metastasis. PATIENTS AND METHODS: Between June 1972 and January 1997, 305 patients (pts) were treated with curative-intent radiation therapy (RT). The T-stages according to the 1987 UICC classification were: 26 T1, 141 T2, 104 T3, and 34 T4. There were 49 pts with nodal involvement at presentation. Pretreatment anal function scoring according to our in-house system was: 22 scored 0, 182 scored 1, 74 scored 2, 7 scored 3, 11 scored 4, and 9 not available pts. The treatment started with external beam RT (EBRT) in 303 pts (median dose: 45 Gy). After a rest period of 4 to 6 weeks, a boost of 20 Gy was delivered by EBRT in 279 pts and by interstitial 192Ir brachytherapy (Bcy) in 17 pts. Seven pts received only one course of EBRT (mean dose: 49.5 Gy) and 2 pts were treated with interstitial 192Ir Bcy alone (55 and 60 Gy, respectively). Concomitant chemotherapy (5-fluoro-uracil and either mitomycin C or cisplatin) was delivered to 19 pts. Mean follow-up was 103 months. RESULTS: At the end of RT local tumor clinical complete response (cCR) rate was 80%. Out of 61 non responders or local progressive tumors 27 (44%) were salvaged with abdominoperineal resection (APR). The rate of local tumor relapse (LR) was 12%. Out of 37 LTR, 20 (54%) were salvaged with APR and one with interstitial 192Ir Bcy. The orevall local tumor control (LC) rate with or without salvage local treatment was 84%. LC rate with a good anal function scoring (score 0 and 1) was 56.5%. Among 181/186 available pts who preserved their anus, 94% had a good anal function scoring. For a subgroup of 15 pts with length tumor <2 cm-N0, the LC rate after the end of RT was 100%, the LC rate with or without local salvage treatment was 100%, and among 13 available pts who preserved their anus, the anal function scoring was good in 12 pts (92%). The 10-years disease-free survival was 74%. After multivariate analysis, 3 independent predicting factors significantly influenced the disease-free survival: gap duration between 2 courses of RT (>38 days vs < or =38 days, P =0.0025), pretreatment anal function scoring (0 vs 1 vs 2 vs 3 vs 4, P =4.4 10(-6)), and cCR after the end of RT (no complete response vs complete response, P =2.5 10(-14)). CONCLUSION: We confirm excellent results with RT in T1 and T2 lesions. However, chemoradiotherapy should be prefered to improve survival free of colostomy with a good anal sphincter function for tumors more than or equal to 2 cm in length and locally advanced tumors.

[Self-expandable metallic stent for palliative treatment of colorectal malignant obstructions: risk of perforation]. / Prothèse métallique expansive dans le traitement palliatif des occlusions colorectales malignes : risque de perforation.

OBJECTIVE: The self-expandable metallic stents are a good alternative to surgery for the palliative treatment of malignant colonic obstructions. The aim of this paper was to emphasize the causes which could increase the risk of perforation. PATIENTS AND METHODS: From November 2000 to November 2001, 6 patients with malignant colonic obstruction, to whom surgery was denied due to tumor extension and/or poor general condition, have had a palliative treatment (N = 5) or an attempt (N = 1) with self-expandable metallic stents placed by endoscopy. RESULTS: Only one patient did not developed any complication and died 5 months later of cancer. Five out of the 6 patients (83%) developed a colonic perforation following stenting (N = 4) or the attempt to place the stent (N = 1), two into the first 24 h after the procedure, and three 3, 5, and 10 months later. Subsequent colostomy was done in 2 patients while the 3 others have had an external drainage of the perforation and died postoperatively. CONCLUSION: The self-expandable metallic stents seems to be a less aggressive alternative therapy to surgery for malignant colonic obstructions. Nevertheless, the high rate of colonic perforations, suggests reconsidering the indications in the definitive palliation of malignant colonic obstructions.

[Radiotherapy of carcinomas of the anal canal. Tenon Hospital experience]. / Traitement des cancers du canal anal par irradiation. Expérience de l'hôpital Tenon.

Since 1980, curative-intent radiation therapy of epidermoid carcinoma of the anal canal is the standard first line treatment. The combined concomitant chemotherapy and radiation therapy is presently established for locally advanced tumors more than 4 cm in length and/or with nodal involvement. We report the Tenon hospital experience since 1972 concerning the long term results after radiation therapy, the modifications of the radiation technique, and the evolution of treatment strategy.

[Surgical treatment of gastroesophageal reflux disease in adults]. / Le traitement chirurgical du reflux gastro-oesophagien chez l'adulte.

Pathological gastroesophageal reflux is common. The aim of this review was to compare the results of different surgical techniques. Papers were selected on Medline from 1990 to April 2001. A critical analysis was performed, concerning definitions of included patients, surgical techniques, and criteria of evaluation. For comparison, the results of 23 randomized studies were mainly selected. Their heterogeneity has not allowed a meta-analysis. A few techniques had poorer results than others: simple closure of His angle, Hill operation, Belsey Mark IV technique, and Angelchik prosthesis. In most studies, results of partial fundoplication on reflux were as good as those of total Nissen fundoplication and fewer patients had postoperative dysphagia. In a double blind trial, immediate advantages of laparoscopic approach were less important than those observed in non comparative studies. Another trial was interrupted after inclusion of 103 patients because of the higher rate of side-effects in the laparoscopic group. These results may help the surgeon in the choice of a technique. Patients have to be informed of potential adverse effects of the different techniques chosen by their surgeon.

Local recurrence of cancer of the rectum.

BACKGROUND: [corrected] Although radiotherapy or total mesorectal excision decreases the risk of local recurrence of rectal cancer, this risk remains around 10%. METHODS: Of 80 patients having a local recurrence, 38 (48%) underwent a re-resection combined in 10 cases with resection of mestastases. RESULTS: The incidence of asymptomatic detected recurrence was higher after anterior resection (39%) than after abdominoperineal resection (18%). Re-resection was performed more often (P <0.01) in the past 2 decades after anterior or Hartman first procedure than after abdominoperineal resection (67% versus 21%), and more often in asymptomatic patients than in symptomatic patients (71% versus 38%). The actuarial 5-year survival rate after re-resection was 20%. CONCLUSIONS: Early detection of local recurrence, with PET scan using (18)F-fluorodeoxyglucose (8 cases in the present series), leads to an improved re-resection rate. In patients who did not undergo radiotherapy (all patients but 1) re-resection can be achieved safely (no postoperative mortality). The place for radiation in the treatment of rectal cancer has to be revaluated and compared with total mesorectal excision and results of re-resection for local recurrence.

Irradiation therapy for gallbladder carcinoma: recent advances.

PURPOSE: Gallbladder carcinomas were usually considered to be radioresistant. So far, the role of radiotherapy has not been adequately evaluated. The aim of this report is to assess the value of radiotherapy in carcinoma of the gallbladder. METHODS: We reviewed publications concerning the role of radiation therapy in gallbladder carcinoma from 1974 to 2000. External radiation therapy, intraoperative radiation therapy, and brachytherapy were evaluated in two different groups: one group of patients underwent surgery, with apparently complete resection of the tumor; and another group underwent palliative treatment. RESULTS: Local control of the tumor and reduction of tumor size were reported in several publications. Collected data suggested a slight improvement in survival after adjuvant or palliative radiotherapy. The best benefit was obtained in tumors resected with only microscopic residual tissue. If possible an intraoperative "boost" (15 Gy) is recommended on the gross lesion, residual lesion, or tumor bed. Additional postoperative external radiotherapy (45-50 Gy) must be delivered. CONCLUSION: Radiotherapy appears to be a safe procedure that slightly improves the survival time of patients treated for gallbladder carcinoma. Further trials are needed to assess the role of combined radiotherapy and chemotherapy.

Combined radiotherapy and chemotherapy (cisplatin and 5-fluorouracil) as palliative treatment for localized unresectable or adjuvant treatment for resected pancreatic adenocarcinoma: results of a feasibility study.

PURPOSE: To evaluate a cisplatin-containing chemoradiotherapy (CRT) regimen followed by chemotherapy for unresectable (locally advanced group, n = 32) and resected (adjuvant group, n = 10) pancreatic adenocarcinoma. The quality of palliation and percentage of secondary resections were also studied for unresectable disease. METHODS AND MATERIALS: The protocol comprised CRT (45 Gy over 5 weeks), combined with 5-fluorouracil and cisplatin during the first and fifth weeks, followed, 3 weeks later, by 4 cycles of the same chemotherapy plus leucovorin. RESULTS: All patients completed CRT but only 50% of each group finished the entire protocol. Gastrointestinal toxicity and weight loss were the major side effects during CRT. Enhanced hematological toxicity limited the post-CRT chemotherapy. For the locally advanced group, median survival was 9 months; 1- and 2-year survival rates were 31 and 12. 5%, respectively. The overall response rate was 16% and 50% had stable disease. A lasting palliative effect defined as improved performance status and decreased analgesic consumption, was recorded for 43% of the patients. Only three secondary resections have been performed. For the adjuvant group, median survival was 17 months. CONCLUSIONS: Although toxic in advanced disease, this regimen significantly lowered pain and analgesic consumption, but had poor impact on secondary resectability. In an adjuvant setting, although equally toxic, this series was too small to allow conclusions to be drawn.