Benoit Lefebure

Prognostic value of circulating mutant DNA in unresectable metastatic colorectal cancer.

Objective:No validated biologic prognostic marker is presently available in metastatic colorectal cancer (MCRC). We prospectively evaluated the prognostic value of circulating mutant DNA in 31 patients presenting an unresectable MCRC treated by chemotherapy, and we used, as tumor markers, KRAS mutations and methylation of the RASSF2A promoter. Methods:Detection in the serum of KRAS mutation and RASSF2A methylation were performed using sensitive methods, respectively, real-time polymerase chain reaction (PCR) performed in the presence of a peptide nucleic acid specific of the wild-type sequence and methyl-specific PCR after bisulfite treatment. Results:Among 29 MCRC patients for whom DNA from the primary tumor was available, 23 (79%) presented at least one of the markers in their primary tumor, and 12 of them presented the same alteration in serum. For the 2 remaining patients, RASSF2A methylation was detected in serum indicating that this alteration was present in the primary tumor. These 14 patients with a detectable tumor marker in their serum were designed sDNA+ patients. After 6 months of follow-up, 11/14 (79%) sDNA+ and 1/11 (9%) sDNA− patients presented a progressive disease (P = 0.001). The median progression free survival was 5 months in sDNA+ patients versus 14 months in sDNA− patients (P = 0.004). After 1 year of follow-up, 2 of 14 (14%) sDNA+ and 8 of 11 (73%) sDNA− patients presented no signs of disease progression (P = 0.005). Conclusions:This study suggests that the presence of circulating mutant DNA in unresectable MCRC patients, which can be detected using simple methods such as methylation-specific PCR or real-time PCR, is highly predictive of clinical outcome.

Clinical interest of KRAS mutation detection in blood for anti-EGFR therapies in metastatic colorectal cancer

Sir, We reported last year, in the British Journal of Cancer, in a series of 59 metastatic colorectal cancer (MCRC) patients treated with cetuximab-based chemotherapy (CT), that KRAS mutation was highly predictive of treatment resistance and that progression-free survival was significantly increased in wild-type KRAS compared with mutant KRAS patients (Di Fiore et al, 2007). All the studies published so far have unambiguously confirmed that the presence of somatic KRAS mutation is indeed highly predictive of resistance to anti-EGFR antibodies in MCRC patients (Lievre et al, 2006, 2008; Benvenuti et al, 2007; Frattini et al, 2007; Khambata-Ford et al, 2007; De Roock et al, 2008). Moreover, a large randomised controlled trial on panitumumab integrating KRAS genotyping has recently shown that, among 208 patients receiving panitumumab, 0 out of 84 mutants and 21 out of 124 (17%) wild-type patients were, respectively, responders (Amado et al, 2008). Therefore, KRAS genotyping should now be performed on a routine basis in patients with MCRC. In most of these studies, KRAS genotyping has been performed on primary colorectal tumours, whereas anti-EGFR antibodies are used to treat the metastatic disease. This strategy might, at least in certain circumstances, present two limitations. First, systematic KRAS genotyping in MCRC patients might be hampered in the future, at least for some patients, by the difficulty of obtaining tumour samples suitable for molecular analyses (and this might limit the use of anti-EGFR antibodies). Second, considering the genetic heterogeneity of colorectal cancers, the absence of detectable KRAS mutations in the primary tumour cannot formally exclude the presence of a KRAS mutation in metastases. For these two reasons, we think that detection of KRAS mutation in the blood of patients with MCRC may have a clinical interest in the context of anti-EGFR therapies and we would like to highlight in this letter the potential interest of such a strategy. Although several studies have shown the presence of mutant DNA in blood from patients with colorectal neoplasia, only positive results are informative. Therefore, one should consider the development of combined tests indicating in blood, first the presence of tumour DNA, then the status of KRAS. In MCRC, hypermethylated DNA can be used as a blood tumour molecular marker. For instance, hypermethylation of the RASSF2 gene has frequently been detected in colorectal adenoma and invasive carcinoma (Park et al, 2007), and we found, in a series of 32 patients with MCRC, that RASSF2 was hypermethylated in 79% of the tumours (unpublished results). In addition to RASSF2, other targets may be used to ensure a sensitive detection of tumour DNA, if RASSF2 is not found hypermethylated. For sensitive detection on a routine basis of KRAS mutation, several methods, shown to be more sensitive than conventional dye-labelled dideoxynucleotide sequencing, are now available, such as, SNaPshot or PCR-LCR assays (Di Fiore et al, 2007), or allele-specific real-time PCR (De Roock et al, 2008; Lievre et al, 2008). We used this strategy of combined blood assays to analyse two patients who received cetuximab-based CT, one responder and the other showing a progressive disease after anti-EGFR therapy. We screened the plasma of these patients for the presence of methylated DNA, using a classical methyl-specific assay exploring the RASSF2A promoter after bisulphite treatment, and then for the presence of KRAS mutation using real-time PCR, performed in the presence of a peptide nucleic acid (PNA) sequence specific for the wild-type KRAS codons 12 and 13, which inhibits amplification from the wild-type template. The first patient, a 67-year-old man, received cetuximab and irinotecan regimens for a peri-hepatic lymph node tumour recurrence 12 months after surgery for liver metastases, and after 3 months, evaluation revealed disease progression. In patient plasma collected before the beginning of cetuximab CT, the combined assays revealed the presence of hypermethylated RASSF2 (Figure 1A) and the presence of mutant KRAS. Sequencing analysis of the PCR product obtained in the presence of the PNA revealed the same KRAS mutation (Figure 1B), as the one previously detected in the colorectal tumour and liver metastases. The second patient, a 76-year-old man, received, in second line, cetuximab plus irinotecan CT for hepatic metastasis occurring 4 years after curative surgery for a bifocal CRC adenocarcinoma, and this treatment allowed control of the disease with the duration of response of 10 months. In this patient, the combined assays performed on the plasma collected before cetuximab treatment showed the presence of hypermethylated RASFF2A (Figure 1) but the absence of mutant KRAS. Figure 1 Detection of methylated RASSF2A promoter in the primary tumour (T), liver metastases (M) and plasma (P) from patients 1 and 2. For patient 2, T1 and T2 correspond to the right and left colon adenocarcinoma, respectively. Genomic DNA was modified by bisulphite ... We therefore suggest that, in the forthcoming clinical trials on anti-EGFR antibodies in MCRC, which integrate KRAS genotyping, it is probably useful to collect blood samples before treatment and that the clinical interest of such combined blood tests, using the presence of hypermethylated DNA, as tumour DNA marker, and a sensitive method for KRAS mutation detection, should be evaluated on large series of MCRC patients.

Complications Associated With Two Laparoscopic Procedures Used in the Management of Rectal Endometriosis

This study suggests that bladder and rectal dysfunction occur more frequently with colorectal resection in rectal endometriosis compared with excision of the nodules alone.

Artificial anal sphincter for severe fecal incontinence implanted by a transvaginal approach: experience with 32 patients treated at one institution.

PURPOSE: Our aim was to evaluate medium-term results of transvaginal implantation of an artificial anal sphincter in a large series of patients. METHODS: Women undergoing treatment for severe fecal incontinence at Rouen University Hospital, Rouen, France, from January 2003 through December 2007 were eligible for the study if the fecal incontinence had lasted for 6 months and if they had attempted other therapies without success. All patients received implantation of an artificial anal sphincter via a transvaginal approach. Incontinence was assessed with the Cleveland Clinic Florida Fecal Incontinence Scale (Wexner score). RESULTS: A total of 32 women entered the study. Their median age was 63 (range, 26–79) years. At entry, 20 (63%) had severe destruction and scarring of the perineum, which was a contraindication for implantation via a perineal approach. Nine patients (28.1%) had previously undergone implantation of an AAS which had been removed because of complications, and 5 had had a Pickrell procedure for anal agenesia. No deaths occurred during the study. The device was removed in a total of 9 patients (28.1%): in 7 because of septic adverse events within the first 6 months after the operation, in 1 because of poor function, and in 1 for psychological reasons despite good functional results. Implantation was successful in 23 patients (71.9%), and the device remained activated for a mean follow-up of 41 (range, 18–75) months, with a mean decrease in Cleveland Clinic incontinence score from 18.4 to 6.8 (P < .0001). None of the patients complained of dyspareunia. CONCLUSIONS: The transvaginal approach for implantation of an artificial anal sphincter permits treatment of women with fecal incontinence who have severe damage and scarring of the anterior perineum. This route provides an alternative for patients whose only therapeutic option would previously have been a defunctioning stoma.

Combined Resection of the Pancreas and Inferior Vena Cava for Pancreatic Metastasis from Renal Cell Carcinoma

Indications for pancreatic resections for metastatic disease have not yet been defined to date, and few guidelines exist for the management of these lesions. However, most authors recommend surgery as the treatment of choice for pancreatic metastasis (PM). Resection of the inferior vena cava (IVC) is rarely done during removal of peripancreatic cancer. This report presents the first case of metachronous PM from renal cell carcinoma (RCC) with IVC involvement successfully treated by en-bloc resection in a 70-year-old asymptomatic woman. The abdominal computed tomography (CT) scan showed a 4.0-cm mass in the tail and a 5.0-cm mass in the head of the pancreas with a suspected involvement of vena cava. An en-bloc total pancreatectomy was performed with excision of the involved portion of the cava vein. Histology confirmed the presence of two metastases from RCC with neoplastic infiltration of the IVC and without lymph node involvement. All surgical margins were tumor-free. At most recent follow-up 12 months after pancreatectomy, the patient has no evidence of disease. We believe that a multidisciplinary approach and careful evaluation and treatment of these patients is a mandatory component for patient selection. IVC resection should be performed only when a margin-negative resection is expected to be achieved.

Reporting on Quality of Life in Randomised Controlled Trials in Gastrointestinal Surgery

BackgroundAlthough health-related quality of life (HRQOL) has become an important outcome measure in surgical trials, questions still remain about the quality of its reporting. The aim of this study was to evaluate HRQOL assessment methodology of randomised clinical trials concerning gastrointestinal surgery.MethodsAll articles published in the calendar years 2006 and 2007 that purported to assess quality of life as end points or make some conclusion about quality of life were chosen for review from eight general surgical journals and four medical journals. Identified eligible studies were selected and then evaluated on a broad set of predetermined criteria.ResultsTwenty-four published randomised controlled clinical trials (RCTs)s with an HRQOL component were identified. Although most trials exhibited good-quality research, some methodological limitations were identified: Only 21% of the studies gave a rationale for selecting a specific HRQOL measure, 46% of the studies failed to report information about the administration of the HRQOL measure, and 37% did not give details on missing data.ConclusionsAlthough it is clear that HRQOL is an important end point in surgical RCTs because the information helps to influence treatment recommendations, a number of methodological shortcomings have to be further addressed in future studies.

Small-bowel adenocarcinoma in patient with Crohn's disease: Report of a series of three cases

Patients affected with Crohns disease (CD) have a recognized, but low relative risk of developing small-bowel adenocarcinoma (SBA). In fact, SBA develops in 2.2% of patients who have long-standing CD and it is seldom diagnosed preoperatively because of its rarity. A retrospective analysis of all cases of SBA in CD patients since 1980 was carried out in Rouen University Hospital. Three patients with known or unknown CD who presented with SBA with long-term follow-up were analysed. In our first case, the occlusive syndrome revealed SBA and CD simultaneously. Most ileal carcinomas in CD are located in strictures and are often incidentally diagnosed postoperatively, as in our three cases. Digestive surgeons and gastroenterologists must be aware that the diagnosis of SBA in CD is often made fortuitously on histological examination after surgical resection for an occlusive syndrome. Failure to detect SBA in patients with CD results in late diagnosis, with poor survival.