Gilles Manceau

Analysis of PTEN, BRAF, and EGFR Status in Determining Benefit From Cetuximab Therapy in Wild-Type KRAS Metastatic Colon Cancer

PURPOSE The occurrence of KRAS mutation is predictive of nonresponse and shorter survival in patients treated by anti-epidermal growth factor receptor (anti-EGFR) antibody for metastatic colorectal cancer (mCRC), leading the European Medicine Agency to limit its use to patients with wild-type KRAS tumors. However, only half of these patients will benefit from treatment, suggesting the need to identify additional biomarkers for cetuximab-based treatment efficacy. PATIENTS AND METHODS We retrospectively collected tumors from 173 patients with mCRC. All but one patient received a cetuximab-based regimen as second-line or greater therapy. KRAS and BRAF status were assessed by allelic discrimination. EGFR amplification was assessed by chromogenic in situ hybridization and fluorescent in situ hybridization, and the expression of PTEN was assessed by immunochemistry. RESULTS In patients with KRAS wild-type tumors (n = 116), BRAF mutations (n = 5) were weakly associated with lack of response (P = .063) but were strongly associated with shorter progression-free survival (P < .001) and shorter overall survival (OS; P < .001). A high EGFR polysomy or an EGFR amplification was found in 17.7% of the patients and was associated with response (P = .015). PTEN null expression was found in 19.9% of the patients and was associated with shorter OS (P = .013). In multivariate analysis, BRAF mutation and PTEN expression status were associated with OS. CONCLUSION BRAF status, EGFR amplification, and cytoplasmic expression of PTEN were associated with outcome measures in KRAS wild-type patients treated with a cetuximab-based regimen. Subsequent studies in clinical trial cohorts will be required to confirm the clinical utility of these markers.

MicroRNA and colorectal cancer

Colorectal cancer is still the third most common cancer in the world. Its carcinogenesis has been extensively studied at a molecular point of view, and has recently entered the era of microRNAs, a class small non-coding RNAs that post-transcriptionally regulate gene expression and control various cellular mechanisms. Because they control biological processes that are implicated in carcinogenesis (as developmental transitions, organ morphology, apoptosis and cell proliferation), microRNAs have been linked to cancer development, and these molecules have been recently studied as new potential biomarkers to better characterise tumour prognosis and to predict response to the different active chemotherapy. This review summarizes the potential roles of microRNAs as potential biomarkers for colorectal cancer diagnosis, prognosis and drug-response prediction. Through the literature there is evidence that some microRNA could be used as biomarkers in colorectal cancer; however, there are some discrepancies amongst the different studies. These differences could partially due to heterogeneity between the different series associated with tumour stage, tumour location, genetic background of the tumours and technical issues. More progress is needed before microRNAs can be used in clinical practice. Accumulation of further data will allow to determine the most relevant microRNAs as biomarkers and also to better understand their role in colorectal carcinogenesis.

Recurrent inactivating mutations of ARID2 in non-small cell lung carcinoma.

In eukaryotic cells, DNA is packaged into chromatin and this compact storage in the nucleus promotes transcriptional repression of genes. Chromatin remodeling complexes such as the SWI/SNF complex are involved in making DNA accessible to transcription factors and thereby are implicated in the regulation of gene expression. Mutations and altered expression of chromatin remodeling complex genes have been described in cancer cells. Indeed, non‐small cell lung cancer cell lines have been shown to harbor mutations in SMARCA4 (BRG1), a member of the SWI/SNF complex, but evidence has been less clear in primary tumors. Recently, inactivating mutations in AT‐rich interaction domain 2 (ARID2) were found in liver cancer related to HCV infection and in melanoma. Here, we explored, using a genome‐wide strategy and subsequent sequencing of targeted genes, whether chromatin remodeling is implicated in primary lung adenocarcinoma. Two genes were individualized from the genome screening as homozygously deleted in a set of samples: JARID2 and ARID2. Subsequent analysis of the entire coding sequences showed that ARID2 loss‐of‐function mutations were found in 5% of nonsmall cell lung cancers, thereby constituting one of the most frequently mutated genes in this cancer type after TP53, KRAS, EGFR, CDKN2A and STK11.

Response of liver metastases to preoperative radiochemotherapy in patients with locally advanced rectal cancer and resectable synchronous liver metastases.

BACKGROUND No standard treatment for advanced rectal cancer with synchronous resectable liver metastases (LM) has been defined. Radiochemotherapy prior to simultaneous or staged curative resection of both primary tumor and LM is one of the treatment options available. The response of LM to radiochemotherapy has never been evaluated and, in particular, the risk for progression of LM is unknown. METHODS Between 2000 and 2011, 20 patients underwent preoperative radiochemotherapy for advanced rectal cancer with synchronous limited but resectable LM. Imaging responses of LM to radiochemotherapy were analyzed on per-patient and per-lesion bases using Response Evaluation Criteria in Solid Tumors (RECIST) criteria. RESULTS Of the patients, 20 had 41 LM; 15 of the 20 patients (75%) had rectal cancer with expected circumferential margins <1 mm on magnetic resonance imaging (MRI), and 50% had a solitary LM before treatment. Of the patients, 13 received oxaliplatin-based chemotherapy, and 7 received fluorouracil (FU)-based chemotherapy in combination with radiation. Of the 41 LM, 7 showed complete response (17%); 7 showed partial response (17%); 20 remained stable (49%); and 7 progressed (17%). Of the 25 LM treated with oxaliplatin-based chemotherapy, only 1 LM (4%) progressed. All 20 patients were suitable for resection of LM with curative intent after the radiochemotherapy. CONCLUSION In patients with advanced rectal cancer and synchronous limited, but resectable LM, the risk for progression of LM during radiochemotherapy is low, especially if the chemotherapy regimen contains oxaliplatin. This low risk does not compromise a curative surgical approach to LM.

Primary tumor resection in colorectal cancer with unresectable synchronous metastases: A review

At the time of diagnosis, 25% of patients with colorectal cancer (CRC) present with synchronous metastases, which are unresectable in the majority of patients. Whether primary tumor resection (PTR) followed by chemotherapy or immediate chemotherapy without PTR is the best therapeutic option in patients with asymptomatic CRC and unresectable metastases is a major issue, although unanswered to date. The aim of this study was to review all published data on whether PTR should be performed in patients with CRC and unresectable synchronous metastases. All aspects of the management of CRC were taken into account, especially prognostic factors in patients with CRC and unresectable metastases. The impact of PTR on survival and quality of life were reviewed, in addition to the characteristics of patients that could benefit from PTR and the possible underlying mechanisms. The risks of both approaches are reported. As no randomized study has been performed to date, we finally discussed how a therapeutic strategys trial should be designed to provide answer to this issue.

How I do a colonic J-pouch prolapse repair after coloanal anastomosis with an aponeurotic graft: How to do it

Colonic prolapse (CP) is a rare complication after low coloanal anastomosis (CAA), with occurrence ranging from 1.3% to 10%. In addition to its exteriorization through the anus, CP is associated with worsening of anal function, anal pain, soiling, urgency, fragmentation or faecal incontinence. Advanced age, gender, obesity or extent of sphincter resection have been reported to be associated factors related to rectal prolapse. Because CP-related symptoms impair patients’ quality of life, surgical management is often required. We propose to use a novel surgical technique inspired from the Orr-Loygue mesh rectopexy approach for a full-thickness colonic J-pouch prolapse after proctectomy with CAA. A 74-year-old female, with no previous medical history, underwent neoadjuvant chemoradiation for a low T3N+ rectal cancer located 0.5 cm above the dentate line. Eight weeks later, a laparoscopic total mesorectal excision was performed with partial intersphincteric resection and CAA. Reconstruction with a colonic J-pouch was performed and a loop ileostomy was fashioned. She made an eventful recovery. Three months later, she developed a full-thickness colonic J-pouch prolapse, confirmed by an anal examination. Since the prolapse occurred under protective ileostomy and because it was disabling for the patient, surgical treatment was proposed. The surgical procedure was performed through an abdominal midline incision. Previous mobilized left colon was released to view the left and right ureter. The colonic J-pouch was mobilized from the pre-sacral space, then laterally and anteriorly until the pelvic floor was seen. Once the colonic J-pouch was fully mobilized, we took a 1-cm large aponeurotic graft of each side of the rectus muscle. We previously measured the necessary length of the graft from the sacral promontory to the lateral wall of the colonic J-pouch. We sutured with non-resorbable stitches each ‘graft’ to the sacral promontory and the other extremity to the lateral wall of the J-pouch, paying attention that the grafts kept the pouch out of the pelvis with smooth tension (Fig. 1). A pelvic suction drain was left in place. The patient made an uneventful recovery and left hospital on post-operative day 7. She performed biofeedback perineal kinesitherapy for 1 month after the surgery. Ileostomy was closed 3 months later. After a follow-up of 37 months, no recurrence of the CP occurred. She still has fragmentation managed by colonic irrigation with satisfactory result. Surgical management of CP after rectal resection and CAA remains controversial. Small published series reported transanal approaches (circumferential removal with or without posterior anal myorrhaphy, mucosal resection, transanal plication) with low recurrence rates. In all but one surgical details or post-operative outcome were lacking. The major drawback of the transanal approach is the need to remove the pouch and therefore to negatively impact the functional outcome. Through the abdominal ‘colopexy’ the pouch can be retained. Changchien et al. described an abdominal pouch pexy using biological mesh with no recurrence after 9-month follow-up. Given the price of the biological meshes and the logistical difficulties in obtaining them, we did not use this technique and replaced them by solid aponeurotic grafts. It is our hypothesis that non-foreign organic material decreases the risk of mesh migration and sepsis. The present modified Orr-Loygue aponeurotic graft ‘colopexy’ seems efficient, safe and reproducible and could become a useful tool in the colorectal surgeon’s armamentarium. For patients operated on for low rectal cancer with J-pouch CAA and intersphincteric resection, this might represent an alternative to the pouch removal.

Prise en charge des perforations coliques endoscopiques iatrogènes : le point de vue du chirurgien

Avec une incidence comprise entre 4,5 et 9,7 pour 10 000 procedures et une mortalite evaluee entre 0 et 25 % dans les series chirurgicales, la perforation colique endoscopique est la complication la plus redoutee du medecin gastroenterologueendoscopiste.La prise en charge d’une perforation colique est complexe et necessite une collaboration medico-chirurgicale etroite, elle a evolue ces dernieres annees avec l’essor de la chirurgie mini-invasive et le developpement des techniques de reparations endoscopiques. Toutefois, il n’existe pas d’attitude consensuelle tant les situations varient d’un cas a l’autre. Le role du chirurgien est donc de chercher des elements decisionnels et de retenir une solution chirurgicale lorsque celle-ci s’impose.Cette revue a pour but de preciser le role du chirurgien dans la prise en charge des perforations per-coloscopiques et d’exposer les differentes strategies chirurgicales et alternatives therapeutiques.

Remedial Surgery Following Failed Colorectal or Coloanal Anastomosis

Low colorectal (CRA) and coloanal (CAA) anastomosis are associated with early complications such as anastomotic leakage and late complications including chronic anastomotic stricture, leakage and fistula. In these situations, redo surgery with the aim to perform a new CRA or CAA may represent the last surgical option to avoid a permanent stoma. However, these procedures are challenging and technical with potentially high intraoperative and postoperative morbidity. One of the biggest challenges is to bring down a sufficient length of healthy colon in a scarred pelvis to perform a well-vascularized and tension-free anastomosis. The aim of the chapter is to provide abdominal surgeons a general overview of the means to overcome these intraoperative problems and to review the available literature on this particular subject.

Cancer colique asymptomatique avec métastases hépatiques synchrones non résécables : faut-il réséquer le primitif ?

Au moment du diagnostic, 25 % des patients avec un cancer colorectal ont des metastases synchrones, principalement hepatiques. Dans la majorite des cas, les metastases sont jugees non resecables et le traitement repose sur la chimiotherapie associee a une biotherapie. Chez ces patients, lorsque la tumeur colique est a- ou pauci-symptomatique, l’interet de la colectomie premiere avant de mettre en route le traitement reste controverse. Aucune etude prospective randomisee ne permet de repondre a cette question. Le but de ce travail est de faire le point sur les donnees disponibles dans la litterature pour guider le choix du traitement de premiere intention (colectomie oui vs non) chez un patient porteur d’un cancer colique metastatique avec des metastases synchrones non resecables en se focalisant sur trois elements de discussion : le risque de complications de la tumeur primitive sous chimiotherapie, la morbidite de la colectomie prophylactique en situation metastasique et l’impact de la strategie sur la survie.

Prediction of response to anticancer treatment as simple as the resolution of ordinary differential equations

The introduction of differential equations in medicine is due to the Swiss physician mathematician, Daniel Bernoulli (1700–1782), who calculated the survival gain of the population by the generalisation of smallpox virus inoculation.1 Many models in systems biology are described as systems of ordinary differential equations, which consist of establishing series of mathematical relationships that describe the sequential changes in components of the systems over time.2 Programmed cell death, apoptosis, can be activated through two different pathways: the death receptor or extrinsic pathway, engaged by members of the tumour necrosis factor (TNF) receptor family on the cell surface; and the Bcl-2-regulated mitochondrial (B-cell lymphoma 2) or intrinsic pathway. The intrinsic pathway starts with BH3-only protein induction or post-translational activation, which results in inactivation of some BCL-2 family members. This relieves inhibition of BAX(BCL2-associated X protein) and BAK (BCL2-antagonist/killer 1) activation, which in turn promotes apoptosis through induction of permeabilisation of the outer mitochondrial membrane and subsequent release of apoptogenic molecules, such as cytochrome c and DIABLO (IAP-binding mitochondrial protein). Cytochrome c binds to APAF1 (apoptotic peptidase …