Alain Beauchet

The Ratio of Metastatic to Examined Lymph Nodes Is a Powerful Independent Prognostic Factor in Rectal Cancer

Objective:The aim of the study was to evaluate the prognostic value of the ratio of metastatic to examined lymph nodes (LNR) in patients with rectal cancer. Summary Background Data:Lymph nodes ratio (LNR) has been shown to have prognostic value in patients with colon cancer. The impact of LNR on disease-free and overall survival in patients with rectal cancer is unknown. Patients and Methods:From 1998 to 2004, 307 patients underwent rectal resection for adenocarcinoma. The relationships between overall and disease-free survival at 3 years and 15 variables, including the presence or absence of metastatic lymph nodes, the total number of lymph nodes examined, and LNR, were analyzed by multivariate analysis. Patients were then assigned to 4 groups based on LNR: LNR = 0 (N0 patients), LNR = 0.01 to 0.07, LNR >0.07 to 0.2, LNR >0.2. Results:The mean number of lymph nodes examined was 22 ± 12. In the multivariate analysis, LNR was a significant prognostic factor for both disease-free (P = 0.006) and overall survival (P = 0.0003), whereas the presence or absence of metastatic lymph nodes was not. LNR remained a significant prognostic factor in the 59 patients in whom fewer than 12 lymph nodes were examined (P = 0.0058). According to LNR values, disease-free and overall survival decreased significantly with increasing LNR (P < 0.001). Conclusions:LNR is the most significant prognostic factor for both overall and disease-free survival in patients with rectal cancer, even in patients with fewer than 12 lymph nodes examined.

Accuracy of Magnetic Resonance Imaging in Rectal Cancer Depends on Location of the Tumor

PURPOSEThis study was designed to evaluate prospectively magnetic resonance imaging for the prediction of the circumferential resection margin in rectal cancer to identify in which patient magnetic resonance imaging could accurately assess the circumferential resection margin before surgery and in which patients it could not.METHODSDuring a 17-month period, a preoperative magnetic resonance imaging for the assessment of circumferential resection margin was obtained prospectively in 38 patients with mid or low rectal cancer. The agreement of magnetic resonance imaging and pathologic examination for assessment of circumferential resection margin was analyzed.RESULTSOverall, magnetic resonance imaging agreed with histologic examination of the circumferential resection margin assessment in 28 patients (73 percent; κ = 0.47). In all cases of disagreement between magnetic resonance imaging and pathology, magnetic resonance imaging overestimated the circumferential resection margin involvement. For the 11 patients with mid rectal cancer, circumferential resection margin was well predicted by magnetic resonance imaging in all cases (κ = 1). For 27 patients with low rectal tumor, overall agreement between magnetic resonance imaging and histologic assessment was 63 percent (κ = 0.35). Agreement was 22 percent (κ = 0.03) for the 9 patients with low anterior and 83 percent (κ = 0.67) for the 18 patients with low posterior rectal tumor. Univariate analysis revealed that only low and anterior rectal tumor was risk factor of overestimation of the circumferential resection margin by magnetic resonance imaging.CONCLUSIONSAlthough magnetic resonance imaging remains the best imaging tool for the preoperative assessment of the circumferential resection margin in patients with rectal cancer, it can overestimate the circumferential resection margin involvement in low and anterior tumor with the risk of overtreating the patients.

Diffuse Pulmonary Arteriovenous Malformations in Hereditary Hemorrhagic Telangiectasia: Long-term Results of Embolization According to the Extent of Lung Involvement

OBJECTIVESnTo review the safety of embolization in patients affected with hereditary hemorrhagic telangiectasia (HHT) presenting with diffuse pulmonary arteriovenous malformations (PAVMs). To correlate the initial presentation and long-term results of embolization according to the distribution of PAVMs.nnnMATERIALS AND METHODSnAll consecutively treated patients were divided into three groups, according to the involvement of every subsegmental pulmonary artery (group 1), segmental artery (group 2), or both (group 3) of at least one lobe. Age, sex, initial clinical presentation, and Pao(2) were recorded before embolization. Per and postprocedural complications were carefully recorded. Clinical outcome and imaging follow-up were obtained at 6 months and annually thereafter.nnnRESULTSnThirty-nine patients (31 women, 8 men; mean age, 35 years), all of them with bilateral lung involvement, were treated. Group 1 consisted of 8, group 2 of 17, and group 3 of 14 patients. Dyspnea was present in 35 of the patients (90%) and cyanosis in 17 patients (44%). Preembolization Pao(2) was different between groups 1 (52.6 +/- 11.6 mm Hg) and 3 (70.7 +/- 14.1 mm Hg). Neurologic events were more frequently reported before treatment in group 1 (62.5%) than in group 2 (35%) or in group 3 (43%). Eighty percent of patients reported improvement in their dyspnea after embolization. Pao(2) levels improved more in group 2 than in groups 1 and 3. Eight ischemic or infectious complications occurred in 4 patients (10%) due to reperfusion of embolized PAVMs or enlargement of non-embolized PAVMs. Complete and partial treatment success was reported using CT scanning in 59% and 38% of cases, respectively.nnnCONCLUSIONnDyspnea and paradoxical embolism are frequently encountered in HHT patients with diffuse PAVMs. Prevention of complications and improvement of dyspnea can be achieved after successful embolization in most patients. Better improvement of Pao(2) can be achieved in group 2.

Detection of BRAF p.V600E Mutations in Melanoma by Immunohistochemistry Has a Good Interobserver Reproducibility.

CONTEXTnAssessment of BRAF p.V600E mutational status has become necessary for treatment of patients with metastatic melanoma. Detection of p.V600E mutation by immunohistochemistry was recently reported in several tumor types.nnnOBJECTIVEnTo evaluate the interobserver reproducibility of BRAF p.V600E detection by immunohistochemistry in melanoma.nnnDESIGNnImmunohistochemistry with VE1 antibody was performed on metastatic melanomas of 67 patients. Staining interpretation was performed on digital image virtual slides of tissue microarrays. The p.V600E status was determined by 7 pathologists from 3 European laboratories, blinded for other interpretations and for molecular biology results.nnnRESULTSnMelanomas had p.V600E (n = 30), p.V600K (n = 4), p.K601E (n = 1), p.600-601delinsE (n = 1), or no p.V600 mutations (n = 31). Staining of p.V600E within mutated cells was cytoplasmic and diffuse, and for each case the staining on the 3 tissue microarray cores was similar. In 53 cases (79.1%) the 7 pathologists had perfect concordance. Agreement of interobserver reproducibility was almost perfect (κ = 0.81 [0.77-0.85]). Only 2 false-positive responses (0.9%) were obtained. The specificities reported were 100% for 5 pathologists (two of whom previously trained for p.V600E interpretation), and 97% for 2 untrained pathologists.nnnCONCLUSIONSnDetection of BRAF p.V600E mutation by immunohistochemistry in melanomas has an excellent interobserver reproducibility. Our results suggest that immunohistochemistry could be used as a first step for detection of BRAF p.V600E mutation, to identify patients with melanoma as candidates for BRAF inhibitors.

Multidrug resistance proteins in gastrointestinal stromal tumors: site-dependent expression and initial response to imatinib.

Gastrointestinal stromal tumors (GIST) are the most frequent mesenchymal tumors of the digestive tract and respond poorly to chemotherapy. A tyrosine kinase inhibitor treatment, imatinib mesylate, was recently shown to have antitumor effects in metastatic patients. However, this drug is a substrate for multidrug resistance (MDR) proteins. Therefore, we investigated the expression of ABCB1 (P-glycoprotein), ABCC1 (MRP1), and ABCG2 (BCRP) by Western blotting in 21 GISTs and 3 leiomyosarcomas. All the GISTs were positive for either ABCB1 (86% of cases) or ABCC1 expression (62%), but negative for ABCG2. ABCB1 was expressed in all gastric GISTs, but in only 67% of nongastric GISTs. By contrast, ABCC1 expression was more common in nongastric tumors (78% versus 42%). The levels of these MDR proteins in gastric GISTs were higher for ABCB1 (P = 0.007) and lower for ABCC1 (P = 0.004) compared with nongastric GISTs. We found no correlation between MDR protein expression and the risk assessment. None of the six patients treated with imatinib was resistant, although all were positive for at least one MDR protein. These results confirm that gastric and nongastric GISTs have different biological characteristics and suggest that MDR proteins do not impair the initial response of the tumor to imatinib.

Prognosis and predictive value of KIT exon 11 deletion in GISTs

Background:KIT exon 11 mutations are observed in 60% of gastrointestinal stromal tumours (GIST). Exon 11 codes for residues Tyr568 and Tyr570, which play a major role in signal transduction and degradation of KIT. Our aim was to compare the outcome of patients with deletion of both Tyr568–570 (delTyr) and the most frequent deletion delWK557–558 (delWK).Methods:Pathology and clinical characteristics of 68 patients with delTyr (n=26) or delWK (n=42) were reviewed and compared.Results:GISTs with delTyr were more frequently extragastric than those with delWK (69 vs 26%, P<0.0005). After curative surgery, median relapse-free survival were 10.8 and 11.1 months for patients with delTyr (n=14) and delWK (n=29), respectively (P=0.92). All patients treated with imatinib for a non-resectable or metastatic GIST had an objective response (n=15) or a stable disease (n=21) as best response, regardless of mutation. Median progression-free survival with imatinib were 21.9 and 18.9 months for patients with GIST with delTyr (n=14) and delWK (n=22), respectively (P=0.43).Conclusion:In this large retrospective series, the type of KIT exon 11 mutation was correlated with the origin of GIST, but not with prognosis or response to imatinib.

Frequent EGFR Positivity and Overexpression in High-Grade Areas of Human MPNSTs.

Malignant peripheral nerve sheath tumours (MPNSTs) are highly malignant and resistant. Transformation might implicate up regulation of epidermal growth factor receptor (EGFR). Fifty-two MPNST samples were studied for EGFR, Ki-67, p53, and survivin expression by immunohistochemistry and for EGFR amplification by in situ hybridization. Results were correlated with clinical data. EGFR RNA was also quantified by RT-PCR in 20 other MPNSTs and 14 dermal neurofibromas. Half of the patients had a neurofibromatosis type 1 (NF1). EGFR expression, detected in 86% of MPNSTs, was more frequent in NF1 specimens and closely associated with high-grade and p53-positive areas. MPNSTs expressed more EGFR transcripts than neurofibromas. No amplification of EGFR locus was observed. NF1 status was the only prognostic factor in multivariate analysis, with median survivals of 18 and 43 months for patients with or without NF1. Finally, EGFR might become a new target for MPNSTs treatment, especially in NF1-associated MPNSTs.

Value and determinants of the mean systemic filling pressure in critically ill patients

Mean systemic filling pressure (Pmsf) is a major determinant of venous return. Its value is unknown in critically ill patients (ICU). Our objectives were to report Pmsf in critically ill patients and to look for its clinical determinants, if any. We performed a prospective study in 202 patients who died in the ICU with a central venous and/or arterial catheter. One minute after the heart stopped beating, intravascular pressures were recorded in the supine position after ventilator disconnection. Parameters at admission, during the ICU stay, and at the time of death were prospectively collected. One-minute Pmsf was 12.8 ± 5.6 mmHg. It did not differ according to gender, severity score, diagnosis at admission, fluid balance, need for and duration of mechanical ventilation, or length of stay. Nor was there any difference according to suspected cause of death, classified as shock (cardiogenic, septic, and hemorrhagic) and nonshock, although a large variability of values was observed. The presence of norepinephrine at the time of death (102 patients) was associated with a higher 1-min Pmsf (14 ± 6 vs. 11.4 ± 4.5 mmHg), whereas the decision to forgo life-sustaining therapy (34 patients) was associated with a lower 1-min Pmsf (10.9 ± 3.8 vs. 13.1 ± 5.3 mmHg). In a multiple-regression analysis, norepinephrine (β = 2.67, P = 0.0004) and age (β = -0.061, P = 0.022) were associated with 1-min Pmsf. One-minute Pmsf appeared highly variable without any difference according to the kind of shock and fluid balance, but was higher with norepinephrine.

Hemodynamic effects of medical antishock trousers during mechanical ventilation.

PurposeTo compare the hemodynamic effects of medical antishock trousers (MAST) inflation in mechanically ventilated patients with normal and poor left ventricular function.MethodsTwelve patients requiring respiratory support were divided into two groups according to baseline transesophageal echocardiography (TEE) measurements: normal left ventricular dimensions and fractional area of contraction (FAC=61 ± 5%) (n=7) and dilated cardiomyopathy with reduced FAC (21 ± 1%) (n=5). All patients were studied when two successive levels of load (mild load by inflation of the leg compartment of MAST at 50 cmH2O and high load by adding the abdominal compartment of MAST inflated at 30 cmH2O) were applied. Global left ventricular systolic function was assessed on the TEE transgastric short-axis view. End-systolic wall stress (ESWS) was used as an indicator of left ventricular afterload.ResultsTotal respiratory, lung and chest wall compliances were reduced by 48%, 51% and 27% respectively at the high load level (P < 0.05). Whereas no hemodynamic changes occurred at mild load, the high load level produced an increase in left ventricular afterload as evidenced by concomitant increases in diastolic arterial blood pressure (66 ± 6 to 79 ± 6 mmHg,P < 0.05) and ESWS (69 ± 12 to 74 ± 12 Kdyn·cm−2·m−2,P < 0.05). In patients with dilated cardiomyopathy, this increase in afterload impaired the left ventricular systolic function and end-systolic area increased (19.0 ± 2.5 to 21.4 ± 2.9 cm2·m−2,P < 0.05) while FAC decreased (22 ± 2 to 16 ± 2%,P < 0.05). Left ventricular end-diastolic area remained unchanged during the study in both groups.ConclusionMAST inflation impairs respiratory mechanics and global left ventricular systolic function in cardiac patients without changes in left ventricular preload.RésuméObjectifComparer les effets circulatoires du pantalon antichoc (PAC) chez des patients ventilés à fonction ventriculaire gauche (VG) normale et altérée.MéthodesDouze patients ventilés ont été répartis en deux groupes selon les données de l’échocardiographie transesophagienne (ETO): dimensions VG et fraction de raccourcissement de surface (FRS) normales (n = 7) ou myocardiopathie dilatée (FRS = 21 ± 1%) (n = 5). Deux niveaux de charge ont été appliqués: charge légère obtenue en gonflant les membres inférieurs du PAC à 50 mmHg et charge élevée en ajoutant le compartiment abdominal gonflé à 30 mmHg. La performance globale VG a été mesurée par ETO et le calcu de la contrainte télésystolique (CSVG) utilisé pour l’appréciation de la postcharge.RésultatsLes compliances respiratoire totale, pulmonaire et pariétale sont abaissées pour le niveau de charge élevé. Si le niveau de charge légère n’a pas entraîné de modifications hémodynamiques, la charge élevée a provoqué une augmentation de la post charge VG objectivée par l’augmentation de la pression artérielle diastolique (66 ± 6 à 79 ± 6 mmHg,P < 0,05) et de la CSVG (69 ± 12 à 74 ± 12 Kdyn·cm−2·m−2,P < 0,05). Chez les patients dilatés, cette élévation de postcharge s’est accompagnée d’une détérioration de la performance VG: augmentation de la surface télésystolique VG (19,0 ± 2,5 à 21,4 ± 2,9 cm−2·m−2,P < 0,05) et diminution de la FRS (22 ± 2 à 16 ± 2 %,P < 0,05). Les dimensions diastoliques VG n’ont pas varié au cours de l’étude.ConclusionLe PAC altère la mécanique respiratoire et génère une élévation de postcharge VG qui détériore la fonction systolique globale chez les patients cardiaques sans modifier la précharge VG.

Radiofrequency ablation for colorectal cancer liver metastases initially greater than 25 mm but downsized by neo-adjuvant chemotherapy is associated with increased rate of local tumor progression

BACKGROUNDnRadiofrequency ablation (RFA) is a valid treatment for liver metastases from colorectal cancer (CRLM) smaller than 25xa0mm and unsuitable for surgical resection. Tumor size is predictive for local tumor progression (LTP). The aim of this study was to evaluate whether RFA is indicated for lesions >25xa0mm at presentation but <25xa0mm after chemotherapy.nnnMETHODnPatients who underwent RFA for CRLM after chemotherapy (January 2004-December 2012) were reviewed. Metastases were classified according to their size. Group 1: ≤25xa0mm before and after chemotherapy. Group 2A: >25xa0mm before but ≤25xa0mm after chemotherapy. Group 2B: >25xa0mm before and after chemotherapy.nnnRESULTSn133 CRLM were ablated in 83 patients (median follow-up 56 months). At 1-year, the LTP rate was higher in group 2A than in group 1 (32% vs. 16%, pxa0≤xa00.001). The highest rate of 1-year LTP was 64% in group 2B. Time to LTP (TLTP) was shorter in group 2A than in group 1 (HR: 2.89; 95% CI [1.04-8.01]; pxa0=xa00.004). Following multivariate analysis, the group type was the only predictive factor for TLTP (pxa0<xa00.001).nnnCONCLUSIONSnRFA is not the optimal treatment for CRLMxa0>xa025xa0mm at presentation.