Centre Hospitalier Universitaire de Reims

BACKGROUND: Data are lacking on the efficacy and safety of a combination chemotherapy regimen consisting of oxaliplatin, irinotecan, fluorouracil, and leucovorin (FOLFIRINOX) as compared with gemcitabine as first-line therapy in patients with metastatic pancreatic cancer. METHODS: We randomly assigned 342 patients with an Eastern Cooperative Oncology Group performance status score of 0 or 1 (on a scale of 0 to 5, with higher scores indicating a greater severity of illness) to receive FOLFIRINOX (oxaliplatin, 85 mg per square meter of body-surface area; irinotecan, 180 mg per square meter; leucovorin, 400 mg per square meter; and fluorouracil, 400 mg per square meter given as a bolus followed by 2400 mg per square meter given as a 46-hour continuous infusion, every 2 weeks) or gemcitabine at a dose of 1000 mg per square meter weekly for 7 of 8 weeks and then weekly for 3 of 4 weeks. Six months of chemotherapy were recommended in both groups in patients who had a response. The primary end point was overall survival. RESULTS: The median overall survival was 11.1 months in the FOLFIRINOX group as compared with 6.8 months in the gemcitabine group (hazard ratio for death, 0.57; 95% confidence interval [CI], 0.45 to 0.73; P<0.001). Median progression-free survival was 6.4 months in the FOLFIRINOX group and 3.3 months in the gemcitabine group (hazard ratio for disease progression, 0.47; 95% CI, 0.37 to 0.59; P<0.001). The objective response rate was 31.6% in the FOLFIRINOX group versus 9.4% in the gemcitabine group (P<0.001). More adverse events were noted in the FOLFIRINOX group; 5.4% of patients in this group had febrile neutropenia. At 6 months, 31% of the patients in the FOLFIRINOX group had a definitive degradation of the quality of life versus 66% in the gemcitabine group (hazard ratio, 0.47; 95% CI, 0.30 to 0.70; P<0.001). CONCLUSIONS: As compared with gemcitabine, FOLFIRINOX was associated with a survival advantage and had increased toxicity. FOLFIRINOX is an option for the treatment of patients with metastatic pancreatic cancer and good performance status. (Funded by the French government and others; ClinicalTrials.gov number, NCT00112658.).

BACKGROUND: Among patients with metastatic pancreatic cancer, combination chemotherapy with fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) leads to longer overall survival than gemcitabine therapy. We compared the efficacy and safety of a modified FOLFIRINOX regimen with gemcitabine as adjuvant therapy in patients with resected pancreatic cancer. METHODS: We randomly assigned 493 patients with resected pancreatic ductal adenocarcinoma to receive a modified FOLFIRINOX regimen (oxaliplatin [85 mg per square meter of body-surface area], irinotecan [180 mg per square meter, reduced to 150 mg per square meter after a protocol-specified safety analysis], leucovorin [400 mg per square meter], and fluorouracil [2400 mg per square meter] every 2 weeks) or gemcitabine (1000 mg per square meter on days 1, 8, and 15 every 4 weeks) for 24 weeks. The primary end point was disease-free survival. Secondary end points included overall survival and safety. RESULTS: At a median follow-up of 33.6 months, the median disease-free survival was 21.6 months in the modified-FOLFIRINOX group and 12.8 months in the gemcitabine group (stratified hazard ratio for cancer-related event, second cancer, or death, 0.58; 95% confidence interval [CI], 0.46 to 0.73; P<0.001). The disease-free survival rate at 3 years was 39.7% in the modified-FOLFIRINOX group and 21.4% in the gemcitabine group. The median overall survival was 54.4 months in the modified-FOLFIRINOX group and 35.0 months in the gemcitabine group (stratified hazard ratio for death, 0.64; 95% CI, 0.48 to 0.86; P=0.003). The overall survival rate at 3 years was 63.4% in the modified-FOLFIRINOX group and 48.6% in the gemcitabine group. Adverse events of grade 3 or 4 occurred in 75.9% of the patients in the modified-FOLFIRINOX group and in 52.9% of those in the gemcitabine group. One patient in the gemcitabine group died from toxic effects (interstitial pneumonitis). CONCLUSIONS: Adjuvant therapy with a modified FOLFIRINOX regimen led to significantly longer survival than gemcitabine among patients with resected pancreatic cancer, at the expense of a higher incidence of toxic effects. (Funded by R&D Unicancer and others; ClinicalTrials.gov number, NCT01526135 ; EudraCT number, 2011-002026-52 .).

BACKGROUND: The BRAF inhibitors vemurafenib and dabrafenib have shown efficacy as monotherapies in patients with previously untreated metastatic melanoma with BRAF V600E or V600K mutations. Combining dabrafenib and the MEK inhibitor trametinib, as compared with dabrafenib alone, enhanced antitumor activity in this population of patients. METHODS: In this open-label, phase 3 trial, we randomly assigned 704 patients with metastatic melanoma with a BRAF V600 mutation to receive either a combination of dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) or vemurafenib (960 mg twice daily) orally as first-line therapy. The primary end point was overall survival. RESULTS: At the preplanned interim overall survival analysis, which was performed after 77% of the total number of expected events occurred, the overall survival rate at 12 months was 72% (95% confidence interval [CI], 67 to 77) in the combination-therapy group and 65% (95% CI, 59 to 70) in the vemurafenib group (hazard ratio for death in the combination-therapy group, 0.69; 95% CI, 0.53 to 0.89; P=0.005). The prespecified interim stopping boundary was crossed, and the study was stopped for efficacy in July 2014. Median progression-free survival was 11.4 months in the combination-therapy group and 7.3 months in the vemurafenib group (hazard ratio, 0.56; 95% CI, 0.46 to 0.69; P<0.001). The objective response rate was 64% in the combination-therapy group and 51% in the vemurafenib group (P<0.001). Rates of severe adverse events and study-drug discontinuations were similar in the two groups. Cutaneous squamous-cell carcinoma and keratoacanthoma occurred in 1% of patients in the combination-therapy group and 18% of those in the vemurafenib group. CONCLUSIONS: Dabrafenib plus trametinib, as compared with vemurafenib monotherapy, significantly improved overall survival in previously untreated patients with metastatic melanoma with BRAF V600E or V600K mutations, without increased overall toxicity. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT01597908.).

PURPOSE: After curative resection, the prognosis of gastroesophageal adenocarcinoma is poor. This phase III trial was designed to evaluate the benefit in overall survival (OS) of perioperative fluorouracil plus cisplatin in resectable gastroesophageal adenocarcinoma. PATIENTS AND METHODS: Overall, 224 patients with resectable adenocarcinoma of the lower esophagus, gastroesophageal junction (GEJ), or stomach were randomly assigned to either perioperative chemotherapy and surgery (CS group; n = 113) or surgery alone (S group; n = 111). Chemotherapy consisted of two or three preoperative cycles of intravenous cisplatin (100 mg/m(2)) on day 1, and a continuous intravenous infusion of fluorouracil (800 mg/m(2)/d) for 5 consecutive days (days 1 to 5) every 28 days and three or four postoperative cycles of the same regimen. The primary end point was OS. RESULTS: Compared with the S group, the CS group had a better OS (5-year rate 38% v 24%; hazard ratio [HR] for death: 0.69; 95% CI, 0.50 to 0.95; P = .02); and a better disease-free survival (5-year rate: 34% v 19%; HR, 0.65; 95% CI, 0.48 to 0.89; P = .003). In the multivariable analysis, the favorable prognostic factors for survival were perioperative chemotherapy (P = .01) and stomach tumor localization (P < .01). Perioperative chemotherapy significantly improved the curative resection rate (84% v 73%; P = .04). Grade 3 to 4 toxicity occurred in 38% of CS patients (mainly neutropenia) but postoperative morbidity was similar in the two groups. CONCLUSION: In patients with resectable adenocarcinoma of the lower esophagus, GEJ, or stomach, perioperative chemotherapy using fluorouracil plus cisplatin significantly increased the curative resection rate, disease-free survival, and OS.

BACKGROUND: Somatostatin analogues are commonly used to treat symptoms associated with hormone hypersecretion in neuroendocrine tumors; however, data on their antitumor effects are limited. METHODS: We conducted a randomized, double-blind, placebo-controlled, multinational study of the somatostatin analogue lanreotide in patients with advanced, well-differentiated or moderately differentiated, nonfunctioning, somatostatin receptor-positive neuroendocrine tumors of grade 1 or 2 (a tumor proliferation index [on staining for the Ki-67 antigen] of <10%) and documented disease-progression status. The tumors originated in the pancreas, midgut, or hindgut or were of unknown origin. Patients were randomly assigned to receive an extended-release aqueous-gel formulation of lanreotide (Autogel [known in the United States as Depot], Ipsen) at a dose of 120 mg (101 patients) or placebo (103 patients) once every 28 days for 96 weeks. The primary end point was progression-free survival, defined as the time to disease progression (according to the Response Evaluation Criteria in Solid Tumors, version 1.0) or death. Secondary end points included overall survival, quality of life (assessed with the European Organization for Research and Treatment of Cancer questionnaires QLQ-C30 and QLQ-GI.NET21), and safety. RESULTS: Most patients (96%) had no tumor progression in the 3 to 6 months before randomization, and 33% had hepatic tumor volumes greater than 25%. Lanreotide, as compared with placebo, was associated with significantly prolonged progression-free survival (median not reached vs. median of 18.0 months, P<0.001 by the stratified log-rank test; hazard ratio for progression or death, 0.47; 95% confidence interval [CI], 0.30 to 0.73). The estimated rates of progression-free survival at 24 months were 65.1% (95% CI, 54.0 to 74.1) in the lanreotide group and 33.0% (95% CI, 23.0 to 43.3) in the placebo group. The therapeutic effect in predefined subgroups was generally consistent with that in the overall population, with the exception of small subgroups in which confidence intervals were wide. There were no significant between-group differences in quality of life or overall survival. The most common treatment-related adverse event was diarrhea (in 26% of the patients in the lanreotide group and 9% of those in the placebo group). CONCLUSIONS: Lanreotide was associated with significantly prolonged progression-free survival among patients with metastatic enteropancreatic neuroendocrine tumors of grade 1 or 2 (Ki-67 <10%). (Funded by Ipsen; CLARINET ClinicalTrials.gov number, NCT00353496; EudraCT 2005-004904-35.).

PURPOSE: In 1992, preoperative radiotherapy was considered in France as the standard treatment for T3-4 rectal cancers. The present randomized trial compares preoperative radiotherapy with chemoradiotherapy. PATIENTS AND METHODS: Patients were eligible if they presented a resectable T3-4, Nx, M0 rectal adenocarcinoma accessible to digital rectal examination. Preoperative radiotherapy with 45 Gy in 25 fractions during 5 weeks was delivered. Concurrent chemotherapy with fluorouracil 350 mg/m2/d during 5 days, together with leucovorin, was administered during the first and fifth week in the experimental arm. Surgery was planned 3 to 10 weeks after the end of radiotherapy. All patients should receive adjuvant chemotherapy with the same fluorouracil/leucovorin regimen. The primary end point of the trial was overall survival. RESULTS: A total of 733 patients were eligible. Grade 3 or 4 acute toxicity was more frequent with chemoradiotherapy (14.6% v 2.7%; P < .05). There was no difference in sphincter preservation. Complete sterilization of the operative specimen was more frequent with chemoradiotherapy (11.4% v 3.6%; P < .05). The 5-year incidence of local recurrence was lower with chemoradiotherapy (8.1% v 16.5%; P < .05). Overall 5-year survival in the two groups did not differ. CONCLUSION: Preoperative chemoradiotherapy despite a moderate increase in acute toxicity and no impact on overall survival significantly improves local control and is recommended for T3-4, N0-2, M0 adenocarcinoma of the middle and distal rectum.

be considered in three groups: the more frequent gastrinomas and insulinomas considered independently and all the rare F-P-NETs (RFTs) considered together and as a separate category (Appendix 1 and table 1 ).Most P-NETs occur as sporadic tumors (non-inherited), although a variable proportion of the different F-P-NETs occurs as part of an inherited syndrome.MEN1 remains the most important inherited condition responsible for 20-30% of gastrinomas and <5% of insulinomas or RFTs [4-7] ; and uncommon causes of inherited P-NETs include von Hippel Lindau disease (VHL), von Recklinghausen's syndrome (neurofibromatosis 1) and tuberous sclerosis [4,5] .In each of the latter inherited

BACKGROUND: Cardiac injury and myocarditis have been described in adults with coronavirus disease 2019 (COVID-19). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children is typically minimally symptomatic. We report a series of febrile pediatric patients with acute heart failure potentially associated with SARS-CoV-2 infection and the multisystem inflammatory syndrome in children as defined by the US Centers for Disease Control and Prevention. METHODS: Over a 2-month period, contemporary with the SARS-CoV-2 pandemic in France and Switzerland, we retrospectively collected clinical, biological, therapeutic, and early outcomes data in children who were admitted to pediatric intensive care units in 14 centers for cardiogenic shock, left ventricular dysfunction, and severe inflammatory state. RESULTS: Thirty-five children were identified and included in the study. Median age at admission was 10 years (range, 2-16 years). Comorbidities were present in 28%, including asthma and overweight. Gastrointestinal symptoms were prominent. Left ventricular ejection fraction was <30% in one-third; 80% required inotropic support with 28% treated with extracorporeal membrane oxygenation. Inflammation markers were suggestive of cytokine storm (interleukin-6 median, 135 pg/mL) and macrophage activation (D-dimer median, 5284 ng/mL). Mean BNP (B-type natriuretic peptide) was elevated (5743 pg/mL). Thirty-one of 35 patients (88%) tested positive for SARS-CoV-2 infection by polymerase chain reaction of nasopharyngeal swab or serology. All patients received intravenous immunoglobulin, with adjunctive steroid therapy used in one-third. Left ventricular function was restored in the 25 of 35 of those discharged from the intensive care unit. No patient died, and all patients treated with extracorporeal membrane oxygenation were successfully weaned. CONCLUSIONS: Children may experience an acute cardiac decompensation caused by severe inflammatory state after SARS-CoV-2 infection (multisystem inflammatory syndrome in children). Treatment with immunoglobulin appears to be associated with recovery of left ventricular systolic function.

Several studies suggest that HPV testing is more sensitive than cytology in primary cervical screening. These studies had different designs and were reported in different ways. Individual patient data were collected for all European and North American studies in which cytology was routinely performed and HPV testing was included as an additional parallel test. More than 60,000 women were included. The sensitivity and specificity of HPV testing were compared with routine cytology, both overall and for ages <35, 35-49 and 50+. The age-specific prevalence of high risk HPV (hr-HPV) was also analysed. HPV testing was substantially more sensitive in detecting CIN2+ than cytology (96.1% vs. 53.0%) but less specific (90.7% vs. 96.3%). The sensitivity of HPV testing was similar in all studies carried out in different areas of Europe and North America, whereas the sensitivity of cytology was highly variable. HPV sensitivity was uniformly high at all ages, whereas the sensitivity of cytology was substantially better in women over the age of 50 than in younger women (79.3% vs. 59.6%). The specificity of both tests increased with age. Positivity rates for HPV testing in women without high-grade CIN were region dependent. These results support the use of HPV testing as the sole primary screening test, with cytology reserved for women who test HPV positive. Large demonstration projects are needed to fully evaluate this strategy.

OBJECTIVES: To update the 2012 ESGAR consensus guidelines on the acquisition, interpretation and reporting of magnetic resonance imaging (MRI) for clinical staging and restaging of rectal cancer. METHODS: Fourteen abdominal imaging experts from the European Society of Gastrointestinal and Abdominal Radiology (ESGAR) participated in a consensus meeting, organised according to an adaptation of the RAND-UCLA Appropriateness Method. Two independent (non-voting) Chairs facilitated the meeting. 246 items were scored (comprising 229 items from the previous 2012 consensus and 17 additional items) and classified as 'appropriate' or 'inappropriate' (defined by ≥ 80 % consensus) or uncertain (defined by < 80 % consensus). RESULTS: Consensus was reached for 226 (92 %) of items. From these recommendations regarding hardware, patient preparation, imaging sequences and acquisition, criteria for MR imaging evaluation and reporting structure were constructed. The main additions to the 2012 consensus include recommendations regarding use of diffusion-weighted imaging, criteria for nodal staging and a recommended structured report template. CONCLUSIONS: These updated expert consensus recommendations should be used as clinical guidelines for primary staging and restaging of rectal cancer using MRI. KEY POINTS: • These guidelines present recommendations for staging and reporting of rectal cancer. • The guidelines were constructed through consensus amongst 14 pelvic imaging experts. • Consensus was reached by the experts for 92 % of the 246 items discussed. • Practical guidelines for nodal staging are proposed. • A structured reporting template is presented.

BACKGROUND: Hidradenitis suppurativa is a painful, chronic inflammatory skin disease with few options for effective treatment. In a phase 2 trial, adalimumab, an antibody against tumor necrosis factor α, showed efficacy against hidradenitis suppurativa. METHODS: PIONEER I and II were similarly designed, phase 3 multicenter trials of adalimumab for hidradenitis suppurativa, with two double-blind, placebo-controlled periods. In period 1, patients were randomly assigned in a 1:1 ratio to 40 mg of adalimumab weekly or matching placebo for 12 weeks. In period 2, patients were reassigned to adalimumab at a weekly or every-other-week dose or to placebo for 24 weeks. The primary end point was a clinical response, defined as at least a 50% reduction from baseline in the abscess and inflammatory-nodule count, with no increase in abscess or draining-fistula counts, at week 12. RESULTS: We enrolled 307 patients in PIONEER I and 326 in PIONEER II. Clinical response rates at week 12 were significantly higher for the groups receiving adalimumab weekly than for the placebo groups: 41.8% versus 26.0% in PIONEER I (P=0.003) and 58.9% versus 27.6% in PIONEER II (P<0.001). Patients receiving adalimumab had significantly greater improvement than the placebo groups in rank-ordered secondary outcomes (lesions, pain, and the modified Sartorius score for disease severity) at week 12 in PIONEER II only. Serious adverse events in period 1 (excluding worsening of underlying disease) occurred in 1.3% of patients receiving adalimumab and 1.3% of those receiving placebo in PIONEER I and in 1.8% and 3.7% of patients, respectively, in PIONEER II. In period 2, the rates of serious adverse events were 4.6% or less in all the groups in both studies, with no significant between-group differences. CONCLUSIONS: Treatment with adalimumab (40 mg weekly), as compared with placebo, resulted in significantly higher clinical response rates in both trials at 12 weeks; rates of serious adverse events were similar in the study groups. (Funded by AbbVie; ClinicalTrials.gov numbers, NCT01468207 and NCT01468233 for PIONEER I and PIONEER II, respectively.).

IMPORTANCE: Up-to-date estimates of the health outcomes of preterm children are needed for assessing perinatal care, informing parents, making decisions about care, and providing evidence for clinical guidelines. OBJECTIVES: To determine survival and neonatal morbidity of infants born from 22 through 34 completed weeks' gestation in France in 2011 and compare these outcomes with a comparable cohort in 1997. DESIGN, SETTING, AND PARTICIPANTS: The EPIPAGE-2 study is a national, prospective, population-based cohort study conducted in all maternity and neonatal units in France in 2011. A total of 2205 births (stillbirths and live births) and terminations of pregnancy at 22 through 26 weeks' gestation, 3257 at 27 through 31 weeks, and 1234 at 32 through 34 weeks were studied. Cohort data were collected from January 1 through December 31, 1997, and from March 28 through December 31, 2011. Analyses for 1997 were run for the entire year and then separately for April to December; the rates for survival and morbidities did not differ. Data are therefore presented for the whole year in 1997 and the 8-month and 6-month periods in 2011. MAIN OUTCOMES AND MEASURES: Survival to discharge and survival without any of the following adverse outcomes: grade III or IV intraventricular hemorrhage, cystic periventricular leukomalacia, severe bronchopulmonary dysplasia, retinopathy of prematurity (stage 3 or higher), or necrotizing enterocolitis (stages 2-3). RESULTS: A total of 0.7% of infants born before 24 weeks' gestation survived to discharge: 31.2% of those born at 24 weeks, 59.1% at 25 weeks, and 75.3% at 26 weeks. Survival rates were 93.6% at 27 through 31 weeks and 98.9% at 32 through 34 weeks. Infants discharged home without severe neonatal morbidity represented 0% at 23 weeks, 11.6% at 24 weeks, 30.0% at 25 weeks, 47.5% at 26 weeks, 81.3% at 27 through 31 weeks, and 96.8% at 32 through 34 weeks. Compared with 1997, the proportion of infants surviving without severe morbidity in 2011 increased by 14.4% (P < .001) at 25 through 29 weeks and 6% (P < .001) at 30 through 31 weeks but did not change appreciably for those born at less than 25 weeks. The rates of antenatal corticosteroid use, induced preterm deliveries, cesarean deliveries, and surfactant use increased significantly in all gestational-age groups, except at 22 through 23 weeks. CONCLUSIONS AND RELEVANCE: The substantial improvement in survival in France for newborns born at 25 through 31 weeks' gestation was accompanied by an important reduction in severe morbidity, but survival remained rare before 25 weeks. Although improvement in survival at extremely low gestational age may be possible, its effect on long-term outcomes requires further studies. The long-term results of the EPIPAGE-2 study will be informative in this regard.

BACKGROUND: Patients with primary biliary cholangitis who have an inadequate response to therapy with ursodeoxycholic acid are at high risk for disease progression. Fibrates, which are agonists of peroxisome proliferator-activated receptors, in combination with ursodeoxycholic acid, have shown potential benefit in patients with this condition. METHODS: In this 24-month, double-blind, placebo-controlled, phase 3 trial, we randomly assigned 100 patients who had had an inadequate response to ursodeoxycholic acid according to the Paris 2 criteria to receive bezafibrate at a daily dose of 400 mg (50 patients), or placebo (50 patients), in addition to continued treatment with ursodeoxycholic acid. The primary outcome was a complete biochemical response, which was defined as normal levels of total bilirubin, alkaline phosphatase, aminotransferases, and albumin, as well as a normal prothrombin index (a derived measure of prothrombin time), at 24 months. RESULTS: The primary outcome occurred in 31% of the patients assigned to bezafibrate and in 0% assigned to placebo (difference, 31 percentage points; 95% confidence interval, 10 to 50; P<0.001). Normal levels of alkaline phosphatase were observed in 67% of the patients in the bezafibrate group and in 2% in the placebo group. Results regarding changes in pruritus, fatigue, and noninvasive measures of liver fibrosis, including liver stiffness and Enhanced Liver Fibrosis score, were consistent with the results of the primary outcome. Two patients in each group had complications from end-stage liver disease. The creatinine level increased 5% from baseline in the bezafibrate group and decreased 3% in the placebo group. Myalgia occurred in 20% of the patients in the bezafibrate group and in 10% in the placebo group. CONCLUSIONS: Among patients with primary biliary cholangitis who had had an inadequate response to ursodeoxycholic acid alone, treatment with bezafibrate in addition to ursodeoxycholic acid resulted in a rate of complete biochemical response that was significantly higher than the rate with placebo and ursodeoxycholic acid therapy. (Funded by Programme Hospitalier de Recherche Clinique and Arrow Génériques; BEZURSO ClinicalTrials.gov number, NCT01654731 .).

OBJECTIVE: To obtain large scale and generalisable data on the long term predictive value of cytology and human papillomavirus (HPV) testing for development of cervical intraepithelial neoplasia grade 3 or cancer (CIN3+). DESIGN: Multinational cohort study with joint database analysis. SETTING: Seven primary HPV screening studies in six European countries. PARTICIPANTS: 24,295 women attending cervical screening enrolled into HPV screening trials who had at least one cervical cytology or histopathology examination during follow-up. MAIN OUTCOME MEASURE: Long term cumulative incidence of CIN3+. RESULTS: The cumulative incidence rate of CIN3+ after six years was considerably lower among women negative for HPV at baseline (0.27%, 95% confidence interval 0.12% to 0.45%) than among women with negative results on cytology (0.97%, 0.53% to 1.34%)). By comparison, the cumulative incidence rate for women with negative cytology results at the most commonly recommended screening interval in Europe (three years) was 0.51% (0.23% to 0.77%). The cumulative incidence rate among women with negative cytology results who were positive for HPV increased continuously over time, reaching 10% at six years, whereas the rate among women with positive cytology results who were negative for HPV remained below 3%. CONCLUSIONS: A consistently low six year cumulative incidence rate of CIN3+ among women negative for HPV suggests that cervical screening strategies in which women are screened for HPV every six years are safe and effective.

Gastrinomas are neuroendocrine neoplasms, usually located in the duodenum or pancreas, that secrete gastrin and cause a clinical syndrome known as Zollinger-Ellison syndrome (ZES).ZES is characterized by gastric acid hypersecretion resulting in severe peptic disease (peptic ulcer disease (PUD), gastroesophageal reflux disease (GERD)) [8-10] .In this section, ZES due to both duodenal and pancreatic gastrinomas will be covered together because clinically they are similar [8,10] .Specific points related to gastrinomas associated with the genetic syndrome of Multiple Endocrine Neoplasia type 1 (MEN1) (25% of cases) will also be mentioned [11,12] .Insulinomas are neuroendocrine neoplasms located in the pancreas that secrete insulin, which causes a distinct syndrome characterized by symptoms due to hypoglyce-

PURPOSE: Complete resection of liver metastases of colorectal origin is the only potentially curative treatment. In order to decrease recurrences, the use of adjuvant systemic chemotherapy after liver resection is controversial because no randomized study demonstrated its benefit. PATIENTS AND METHODS: In a multicenter trial, we randomly assigned 173 patients with completely resected (R0) hepatic metastases from colorectal cancer to surgery alone and observation (87 patients) or to surgery followed by 6 months of systemic adjuvant chemotherapy with a fluorouracil and folinic acid monthly regimen (86 patients). The main outcome criterion was disease-free survival. Secondary outcome measures were overall survival and treatment-related toxicity. RESULTS: The intention-to-treat analysis was based on 171 patients, after a median follow-up of 87 months (SE = 5.8). The 5-year disease-free survival rate, after adjustment for major prognostic factors, was 33.5% for patients in the chemotherapy group and 26.7% for patients in the control group (Cox multivariate analysis: odds ratio for recurrence or death = 0.66; 95% CI, 0.46 to 0.96; P = .028). With regard to secondary outcome measures, a trend towards increased overall survival was observed but did not reach statistical significance (5-year overall survival: chemotherapy group, 51.1% v control group, 41.1%; odds ratio for death, 0.73; 95% CI, 0.48 to 1.10; P = .13). CONCLUSION: Despite a suboptimal regimen, which was the standard at the beginning of the study, adjuvant intravenous systemic chemotherapy provided a significant disease-free survival benefit for patients with resected liver metastases from colorectal cancer.

Objective To describe clinical and radiologic features associated with myelin oligodendrocyte glycoprotein antibodies (MOG-Ab) in a large French nationwide adult cohort, to assess baseline prognostic features of MOG-Ab-associated diseases after a first acute demyelinating syndrome, and to evaluate the clinical value of MOG-Ab longitudinal analysis. Methods Clinical data were obtained from 197 MOG-Ab-positive patients ≥18 years of age. Complete imaging data were available in 108, and 54 serum samples were eligible for longitudinal evaluation. For survival analysis comparison, 169 aquaporin-4 antibody (AQP4-Ab)-positive patients from the NOMADMUS database were included. Results Median age at onset was 36.46 (range 18.0–76.8) years, and patients were predominantly white (92.9%) with male:female ratio, 1.1. Clinical phenotype at onset included optic neuritis or myelitis in 90.86%, isolated brainstem or encephalopathy syndromes in 6.6%, and a combination of syndromes in 2.5%. Distinctive brain MRI findings in MOG-Ab-positive patients were thalamic and pontine lesions. Cortical and leptomeningeal lesions were found in 16.3% and 6.1%, respectively. The probability of reaching a first relapse after 2 and 5 years was 44.8% and 61.8%, respectively. MOG-Ab-positive patients were at lower risk at presentation of further clinical relapse (hazard ratio [HR] 0.45, 95% confidence interval [CI] 0.26–0.79) compared to AQP4-Ab-positive individuals. MOG-Ab-positive individuals had a lower risk of reaching Disability Status Scale score of 3.0 (HR 0.46, 95% CI 0.22–0.94) and visual acuity of 20/100 (HR 0.23, 95% CI 0.07–0.72). Finally, MOG-Ab titers were higher at relapse than in remission (p = 0.009). Conclusion In adults, MOG-Ab-associated disease extends beyond clinical and radiologic abnormalities in the optic nerve and spinal cord. Despite the relapsing course, the overall visual and motor outcome is better compared with AQP4-Ab-positive patients.

Chromosomal rearrangements of the human MLL (mixed lineage leukemia) gene are associated with high-risk infant, pediatric, adult and therapy-induced acute leukemias. We used long-distance inverse-polymerase chain reaction to characterize the chromosomal rearrangement of individual acute leukemia patients. We present data of the molecular characterization of 1590 MLL-rearranged biopsy samples obtained from acute leukemia patients. The precise localization of genomic breakpoints within the MLL gene and the involved translocation partner genes (TPGs) were determined and novel TPGs identified. All patients were classified according to their gender (852 females and 745 males), age at diagnosis (558 infant, 416 pediatric and 616 adult leukemia patients) and other clinical criteria. Combined data of our study and recently published data revealed a total of 121 different MLL rearrangements, of which 79 TPGs are now characterized at the molecular level. However, only seven rearrangements seem to be predominantly associated with illegitimate recombinations of the MLL gene (≈ 90%): AFF1/AF4, MLLT3/AF9, MLLT1/ENL, MLLT10/AF10, ELL, partial tandem duplications (MLL PTDs) and MLLT4/AF6, respectively. The MLL breakpoint distributions for all clinical relevant subtypes (gender, disease type, age at diagnosis, reciprocal, complex and therapy-induced translocations) are presented. Finally, we present the extending network of reciprocal MLL fusions deriving from complex rearrangements.

BACKGROUND: Multiplex digital PCR (dPCR) enables noninvasive and sensitive detection of circulating tumor DNA with performance unachievable by current molecular-detection approaches. Furthermore, picodroplet dPCR facilitates simultaneous screening for multiple mutations from the same sample. METHODS: We investigated the utility of multiplex dPCR to screen for the 7 most common mutations in codons 12 and 13 of the KRAS (Kirsten rat sarcoma viral oncogene homolog) oncogene from plasma samples of patients with metastatic colorectal cancer. Fifty plasma samples were tested from patients for whom the primary tumor biopsy tissue DNA had been characterized by quantitative PCR. RESULTS: Tumor characterization revealed that 19 patient tumors had KRAS mutations. Multiplex dPCR analysis of the plasma DNA prepared from these samples identified 14 samples that matched the mutation identified in the tumor, 1 sample contained a different KRAS mutation, and 4 samples had no detectable mutation. Among the tumor samples that were wild type for KRAS, 2 KRAS mutations were identified in the corresponding plasma samples. Duplex dPCR (i.e., wild-type and single-mutation assay) was also used to analyze plasma samples from patients with KRAS-mutated tumors and 5 samples expected to contain the BRAF (v-raf murine sarcoma viral oncogene homolog B) V600E mutation. The results for the duplex analysis matched those for the multiplex analysis for KRAS-mutated samples and, owing to its higher sensitivity, enabled detection of 2 additional samples with low levels of KRAS-mutated DNA. All 5 samples with BRAF mutations were detected. CONCLUSIONS: This work demonstrates the clinical utility of multiplex dPCR to screen for multiple mutations simultaneously with a sensitivity sufficient to detect mutations in circulating DNA obtained by noninvasive blood collection.

Objective We developed a validated index for assessing histological disease activity in UC and established its responsiveness. Methods Two hundred biopsies were scored. The outcome was the Global Visual Evaluation (GVE). Eight histological features were tested. The Nancy index was developed by multiple linear regression and bootstrap process to create an index that best matched the GVE. Goodness of fit was assessed by the adjusted R squared (adjusted R 2 ). The second step was the validation of the index: 100 biopsies were scored for the Nancy index by three pathologists from different centres. Inter-reader reliability was evaluated for each reader. The relationship between the change of the Nancy index and the Geboes index was assessed to assess the responsiveness. Results After backward selection with bootstrap validation, 3/8 items were selected: ulceration (adjusted R 2 =0.55), acute inflammatory infiltrate (adjusted R 2 =0.88) and chronic inflammatory infiltrate (adjusted R 2 =0.79). The Nancy index is defined by a 5-level classification ranging from grade 0 (absence of significant histological disease activity) to grade 4 (severely active disease). The intraclass correlation coefficient (ICC) for the intrareader reliability was 0.88 (95% CI 0.82 to 0.92) and the index had good inter-reader reliability (ICC=0.86 (0.81 to 0.99)). The correlation between the Nancy index and the Geboes score or the GVE was very good. The index had a good responsiveness with a high correlation between changes in the Geboes score and changes in the Nancy index (0.910 (0.813 to 0.955)). Conclusions A three descriptor histological index has been validated for use in clinical practice and clinical trials.