Daniel Benchimol

K-Ras Mutations and Treatment Outcome in Colorectal Cancer Patients Receiving Exclusive Fluoropyrimidine Therapy

Purpose: K-Ras mutations predict resistance to anti–epidermal growth factor receptor (EGFR) monoclonal antibodies. Because combinations of anti-EGFR with 5-fluorouracil (5-FU)-based chemotherapy are promising treatments, we analyzed the effect of K-Ras mutations in patients having received exclusive 5-FU therapy. Experimental Design: This study was conducted on 93 stage IV colorectal cancer patients with unresectable measurable liver metastasis receiving 5-FU-leucovorin (56 men and 37 women; 77 cancer deaths). Liver metastases (n = 93) along with primary tumors (n = 48) were analyzed for K-Ras mutations (codons 12 and 13), p53 mutations (exons 4-9), p53 polymorphism (codon 72), thymidylate synthase (TS) polymorphism (28-bp repeats including G>C mutation), methylenetetrahydrofolate reductase polymorphism (677C>T, 1298A>C), thymidylate synthase (TS) activity, dihydropyrimidine dehydrogenase activity, folylpolyglutamate synthase activity, and p53 protein expression. Results: Thirty-six of 93 (38.7%) metastases were K-Ras mutated (30 at codon 12 and 6 at codon 13). Mutated primary tumors (16 of 48) matched perfectly with mutated metastases. The additional analyzed tumor markers were not different between K-Ras mutated and wild-type tumors. The objective response rate was 37%: 44.4% in K-Ras mutated versus 32.1% in wild-type K-Ras metastasis (P = 0.27). Low TS activity in metastasis was the only significant predictor of tumor response (P = 0.047). K-Ras status did not influence specific survival. Conclusions: The present data indicate a perfect concordance of K-Ras mutations between primary and liver metastasis and suggest that any predictive and/or prognostic value of K-Ras mutations in treatments combining anti-EGFR monoclonal antibodies with 5-FU should be exclusively linked to the anti-EGFR agent.

KRAS and BRAF Mutational Status in Primary Colorectal Tumors and Related Metastatic Sites: Biological and Clinical Implications

BackgroundKRAS and BRAF mutations in primary colorectal tumors (PT) are predictive of nonresponse to anti–epidermal growth factor receptor (EGFR) antibodies in patients with metastatic colorectal cancer (mCRC). The question of primary resistance to anti-EGFR treatment as a result of the presence of KRAS or BRAF mutations only in metastases has been raised but not resolved.MethodsWe analyzed the mutational status of KRAS and BRAF in 64 new patients with mCRC and performed a systematic review of published data from 285 patients.ResultsA total of 285 and 95 matched PT/metastases were available for the analysis of the KRAS and the BRAF status, respectively. An identical mutational pattern of KRAS in PT and the matching metastases were reported in all the cases but 14 (5%). In six cases (2%), KRAS was mutated in the PT and wild type in the metastatic site, whereas in eight cases (3%), KRAS was wild type in the PT and mutated in the metastatic site. An identical mutational pattern of BRAF in PT and the matching metastases was reported in all but two cases (3%). In one case (1.5%), BRAF was mutated in the PT and wild type in the metastatic site, whereas in one case (1.5%), BRAF was wild type in the PT and mutated in the metastatic site.ConclusionsThe acquisition by metastases of a KRAS or a BRAF mutation that was not present in the PT is a rare event, occurring in 5% of cases of mCRC. This is not a frequent mechanism of primary resistance to anti-EGFR treatments in mCRC.

Technique for the Repair of Diaphragmatic Eventration

In contrast to the large thoracotomy incisions required by standard surgical techniques for repair of diaphragmatic eventration, the procedure we developed can be performed by video-assisted thoracoscopy, thus offering patients the advantages of a minimally invasive operation. Using two superposed series of transverse back-and-forth continuous sutures, the diaphragm is invaginated, then stretched. The first suture line holds the diaphragm down and maintains the excess within the abdomen; the second suture line places the desired tension on the diaphragmatic dome. Successful repair of 3 cases by this technique is described.

Cetuximab shows activity in colorectal cancer patients with tumors for which FISH analysis does not detect an increase in EGFR gene copy number.

BackgroundEGFR (epidermal growth factor receptor) gene gain assessed by FISH (fluorescence in situ hybridization) has been shown to be predictive of response to EGFR-targeted therapies in patients with non–small cell lung cancer. The aim or our study was to relate the EGFR gene copy number to therapeutic results in patients with metastatic colorectal cancer (CRC) treated with a cetuximab-containing regimen.MethodsForty-seven patients with metastatic CRC treated with a cetuximab-containing regimen between August 2004 and September 2006 were included in our study. EGFR status was assessed by immunohistochemistry (IHC) and by FISH on fixed paraffin-embedded sections of tumor specimens.ResultsBy IHC (n = 47), 39 patients (83%) had EGFR-positive tumors. EGFR gene copy gain was detected in 8 (19.5%) of 41 tumors. Neither EGFR expression assessed by IHC nor EGFR gene copy gain assessed by FISH were statistically significantly correlated with objective response rate, disease control rate, progression-free survival, and overall survival. Of the 33 patients whose tumors were FISH negative, 8 patients (24.2%) had a partial response, and 10 (30.3%) had stable disease.ConclusionsEGFR FISH analysis does not seem to be a sufficiently robust test for selecting candidate CRC patients for cetuximab therapy.

Role of Radiotherapy With Surgery for T3 and Resectable T4 Rectal Cancer: Evidence From Randomized Trials

PurposeThe main treatment for resectable rectal cancer T2–T4 N0–N2 M0 is surgery. The benefit of preoperative or postoperative radiation therapy can be analyzed in terms of improvement of local control, sphincter preservation, and survival weighted against increased toxicity.MethodsOnly randomized trials can provide strong evidence of a positive cost-benefit ratio of such combined approach. The most recent trials were reviewed.ResultsThree randomized trials, including the latest German CAO-ARO trial, have demonstrated the superiority of preoperative radiotherapy with or without chemotherapy (vs. postoperative) in terms of local control and toxicity. The Ducth TME trial showed that even with modern standard surgery, preoperative radiotherapy improved local control. Preoperative irradiation using a high dose in a small volume and a long interval before surgery may improve sphincter preservation (Lyon trials). Concurrent chemoradiation (FFCD 9203, EORTC 22921, did not significantly improve sphincter preservation or survival but significantly reduced the local recurrence rate.ConclusionsIn 2005 examination of randomized trials provides evidence for the benefit of preoperative chemoradiation in improving local control and probably sphincter preservation in rectal cancer. Randomized trials should be designed to further demonstrate improved sphincter preservation and to increase survival using adjuvant medical treatments.

Can we increase the chance of sphincter saving surgery in rectal cancer with neoadjuvant treatments: Lessons from a systematic review of recent randomized trials

PURPOSE A common hypothesis is that neo-adjuvant treatment in rectal cancer, is able to increase sphincter saving surgery. This review studies data relevant to this question. STUDY SELECTION A total of 17 randomized trials were analysed. RESULTS Since 1976, the rate of sphincter saving surgery increased from 20% to 75%. In none of the 17 trials it was possible to demonstrate a significant benefit of the neo-adjuvant regimens on the rate of sphincter saving surgery. There was a reduction in the risk of 5-year local recurrence partly due to these neo-adjuvant treatments. These neo-adjuvant regimens had no significant impact on the overall 5-year survival. CONCLUSIONS None of the neo-adjuvant treatments tested was able to demonstrate an increase in the rate of sphincter saving surgery. The improvement in conservative surgery is mainly due to technical changes in surgery. Organ preservation after complete clinical response appears as an interesting hypothesis to test.

Contact X-ray Therapy for Rectal Cancer: Experience in Centre Antoine-Lacassagne, Nice, 2002–2006

PURPOSE To report the results of using contact X-ray (CXR), which has been used in the Centre-Lacassagne since 2002 for rectal cancer. METHODS AND MATERIALS A total of 44 patients were treated between 2002 and 2006 using four distinct clinical approaches. Patients with Stage T1N0 tumors were treated with transanal local excision (TLE) and adjuvant CXR (45 Gy in three fractions) (n = 7). The 11 inoperable (or who had refused surgery) patients with Stage T2-T3 disease were treated with CXR plus external beam radiotherapy (EBRT). Those with Stage T3N0-N2 tumors were treated with preoperative CXR plus EBRT (with or without concurrent chemotherapy) followed by surgery (n = 21). Finally, the patients with Stage T2 disease were treated with CXR plus EBRT followed by TLE (n = 5). RESULTS The median follow-up was 25 months. In the 7 patients who underwent TLE first, no local failure was observed, and their anorectal function was good. Of the 11 inoperable patients who underwent CXR plus EBRT alone, 10 achieved local control. In the third group (preoperative CXR plus EBRT), anterior resection was performed in 16 of 21 patients. Complete sterilization of the operative specimen was seen in 4 cases (19%). No local recurrence occurred. Finally, of the 5 patients treated with CXR plus EBRT followed by TLE, a complete or near complete clinical response was observed in all. TLE with a R0 resection margin was performed in all cases. The rectum was preserved with good function in all 5 patients. CONCLUSION These early results have confirmed that CXR combined with surgery (or alone with EBRT) can play a major role in the conservative and curative treatment of rectal cancer.

NFIB rearrangement in superficial, retroperitoneal, and colonic lipomas with aberrations involving chromosome band 9p22

Lipomas are frequently characterized by rearrangements resulting in the fusion of the HMGA2 gene (12q14.3) with a variety of partners. Chromosome band 9p22 rearrangements occur in about 1% of lipomas. We report here the molecular cytogenetic analysis of five cases of lipoma with a 9p22 aberration, including the first cytogenetic analysis of a colonic lipoma. Three out of the five cases showed a rearrangement of NFIB at 9p22.3. The NFIB rearrangement involved a fusion with HMGA2 in two cases. We have identified an in‐frame fusion of the first three exons of HMGA2 with exon 6 of MSRB3 (12q14.3) and exons 8 and 9 of NFIB by using 3′RACE‐PCR in a case of superficial lipoma. In a case of retroperitoneal lipoma we found a fusion of HMGA2 with NFIB by fluorescence in situ hybridization analysis. The colonic lipoma was characterized by a t(9;16;19)(p22;q21;q13) with a rearrangement of NFIB and no rearrangement of HMGA2. NFIB belongs to the nuclear factor I transcription family. It has been previously shown to be fused with HMGA2 in one case of lipoma and to be a recurrent partner of HMGA2 in pleormorphic adenoma of salivary glands. We here demonstrate that NFIB can also be rearranged independently from HMGA2, indicating a potentially important role in lipoma pathobiology. Our findings suggest that the rearrangement of NFIB might be associated with deep‐seated lipomas, such as retroperitoneal or gastro‐intestinal lipomas.

Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy for the treatment of endometrial cancer with peritoneal carcinomatosis

OBJECTIVE To investigate the benefit of cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) for the treatment of endometrial peritoneal carcinomatosis. STUDY DESIGN Preoperative, intraoperative and postoperative data were collected prospectively for 13 patients treated in our University hospital. RESULTS Of the thirteen patients treated, one patient was lost to follow up. Three patients died within the first twelve months of treatment, and two patients died at respectively 12.4 and 19.4 months after the HIPEC procedure. Seven patients are alive, four of them without recurrence, between 1.5 and 124.8 months after surgery. The Peritoneal Cancer Index (PCI) and the Completeness of Cytoreduction-Score (CC-S) are prognostic factors for survival after HIPEC treatment for peritoneal carcinomatosis of endometrial origin. CONCLUSIONS The significant survival time in selected patients should lead to a study of the management of peritoneal carcinomatosis of endometrial origin in a larger number of cases, and justifies a clinical trial on a larger scale.

The place of simulation in the surgical resident curriculum. The pedagogic program of the Nice Medical School Simulation Center.

INTRODUCTION Surgical training relies on medical school lectures, practical training in patient care and in the operating room including instruction in anatomy and experimental surgery. Training with different techniques of simulators can complete this. Simulator-based training, widely used in North America, can be applied to several aspects of surgical training without any risk for patients: technical skills in both open and laparoscopic surgery, the notion of teamwork and the multidisciplinary management of acute medicosurgical situations. METHOD We present the curriculum developed in the Simulation Center of the Medical School of Nice Sophia-Antipolis. All residents in training at the Medical School participate in this curriculum. RESULTS Each medical student is required to pursue theoretical training (familiarization with the operating room check-list), training in patient management using a high fidelity mannequin for various medical and surgical scenarios and training in technical gestures in open and laparoscopic surgery over a 2-year period, followed by an examination to validate all technical aptitudes. This curriculum has been approved and accredited by the prestigious American College of Surgeons, making this the first of its kind in France. CONCLUSION As such, it should be considered as a model and, in accordance to the wishes of the French Surgical Academy, the first step toward the creation of true schools of surgery.