Esophageal cancer - French intergroup clinical practice guidelines for diagnosis, treatments and follow-up (TNCD, SNFGE, FFCD, GERCOR, UNICANCER, SFCD, SFED, SFRO, ACHBT, SFP, RENAPE, SNFCP, AFEF, SFR).

INTRODUCTION: This document is a summary of the French intergroup guidelines regarding the management of esophageal cancer (EC) published in July 2022, available on the website of the French Society of Gastroenterology (SNFGE) (www.tncd.org). METHODS: This collaborative work was conducted under the auspices of several French medical and surgical societies involved in the management of EC. Recommendations were graded in three categories (A, B and C), according to the level of evidence found in the literature until April 2022. RESULTS: EC diagnosis and staging evaluation are mainly based on patient's general condition assessment, endoscopy plus biopsies, TAP CT-scan and 18F FDG-PET. Surgery alone is recommended for early-stage EC, while locally advanced disease (N+ and/or T3-4) is treated with perioperative chemotherapy (FLOT) or preoperative chemoradiation (CROSS regimen) followed by immunotherapy for adenocarcinoma. Preoperative chemoradiation (CROSS regimen) followed by immunotherapy or definitive chemoradiation with the possibility of organ preservation are the two options for squamous cell carcinoma. Salvage surgery is recommended for incomplete response or recurrence after definitive chemoradiation and should be performed in an expert center. Treatment for metastatic disease is based on systemic therapy including chemotherapy, immunotherapy or combined targeted therapy according to biomarkers testing such as HER2 status, MMR status and PD-L1 expression. CONCLUSION: These guidelines are intended to provide a personalised therapeutic strategy for daily clinical practice and are subject to ongoing optimization. Each individual case should be discussed by a multidisciplinary team.

Carrier suppression system to measure phase noise of acoustic resonators with low motional resistance.

A carrier suppression system is implemented in order to measure the phase noise of acoustic resonators that have a low motional resistance. A special adapters' system using transformers is proposed to improve the loaded quality factor of the resonators. With this developed device and described protocol, the inherent noise of resonators can be obtained without the usual electronical oscillator conditioning that could take part in the results. The loaded quality factor is improved from about 10% to 60% of the intrinsic quality factor. As an example, the system is used to study Langatate crystal resonators vibrating at 10 MHz. Langatate crystals can be an alternative to substitute for the quartz crystal resonators for frequency and time applications. Their coupling coefficient and the product quality factor-frequency are normally higher than those in quartz crystal resonators. For ultrastable resonators, the motional resistance obtained with Langatate crystals is about five times lower than that for the quartz crystal; it can reach typically few ohms. These resonators have been characterized in terms of impedance, Q-factors, turnover temperature, amplitude-frequency effect, and phase noise. The short-term stability of these resonators is given in terms of Allan standard deviation. The influence of the driving power is presented.

2.44-GHz Surface Acoustic Wave Resonator Phase Noise Measured by Carrier Suppression Technique.

The phase noise of surface acoustic wave resonators is explored by a passive measurement system based on the carrier suppression technique. The measurements are focused on 2.44-GHz quartz crystal resonators. These resonators are characterized in terms of motional parameters. The power dissipated through the resonators is around [Formula: see text]. The second-order frequency-temperature coefficient of the resonators has been measured to be around -0.038 ppm/°C2 that corresponds to a classical ST cut. The resonator conditioning is presented. The measured noise exhibits a 1/ f frequency fluctuation behavior. The short-term stability (flicker floor) is given in terms of Allan standard deviation. The order of magnitude is around 2×10-10 . Additional measurements are given for resonators at 433 and 915 MHz in order to compare them. The results are presented according to the intrinsic quality factor of the resonators and compared to the previous works done in the past by T. Parker. These additional data provide valuable information on the dependence of the flicker noise levels on resonator frequency.

FOLFOX4 versus sequential dose-dense FOLFOX7 followed by FOLFIRI in patients with resectable metastatic colorectal cancer (MIROX): a pragmatic approach to chemotherapy timing with perioperative or postoperative chemotherapy from an open-label, randomized phase III trial.

BACKGROUND: Perioperative FOLFOX4 (oxaliplatin plus 5-fluorouracil/leucovorin) chemotherapy is the current standard in patients with resectable metastases from colorectal cancer (CRC). We aimed to determine whether a sequential chemotherapy with dose-dense oxaliplatin (FOLFOX7) and irinotecan (FOLFIRI; irinotecan plus 5-fluorouracil/leucovorin) is superior to FOLFOX4. The chemotherapy timing was not imposed, and was perioperative or postoperative. PATIENTS AND METHODS: In this open-label, phase III trial, patients with resectable or resected metastases were randomly assigned either to 12 cycles of FOLFOX4 (oxaliplatin 85 mg/m(2)) or 6 cycles of FOLFOX7 (oxaliplatin 130 mg/m(2)) followed by 6 cycles of FOLFIRI (irinotecan 180 mg/m(2)). Randomization was done centrally, with stratification by chemotherapy timing, type of local treatment (surgery versus radiofrequency ablation with/without surgery), and Fong's prognostic score. The primary end point was 2-year disease-free survival (DFS). RESULTS: A total of 284 patients were randomized, 142 in each treatment group. Chemotherapy was perioperative in 168 (59.2%) patients and postoperative in 116 (40.8%) patients. Perioperative chemotherapy was preferentially proposed for synchronous metastases, whereas postoperative chemotherapy was more frequently used for metachronous metastases. Two-year DFS was 48.5% in the FOLFOX4 group and 50.0% in the FOLFOX7-FOLFIRI group. In the multivariable analysis, more than one metastasis [hazard ratio (HR) = 2.15] and synchronous metastases (HR = 1.63) were independent prognostic factors for shorter DFS. Five-year overall survival (OS) rate was 69.5% with FOLFOX4 versus 66.6% with FOLFOX7-FOLFIRI. CONCLUSIONS: FOLFOX7-FOLFIRI is not superior to FOLFOX4 in patients with resectable metastatic CRC. Five-year OS rates observed in both groups are the highest ever reported in this setting, possibly reflecting the pragmatic approach to chemotherapy timing. CLINICAL TRIALS NUMBER: NCT00268398.

Experience from start-ups of the first ANITA Mox plants.

ANITA™ Mox is a new one-stage deammonification Moving-Bed Biofilm Reactor (MBBR) developed for partial nitrification to nitrite and autotrophic N-removal from N-rich effluents. This deammonification process offers many advantages such as dramatically reduced oxygen requirements, no chemical oxygen demand requirement, lower sludge production, no pre-treatment or requirement of chemicals and thereby being an energy and cost efficient nitrogen removal process. An innovative seeding strategy, the 'BioFarm concept', has been developed in order to decrease the start-up time of new ANITA Mox installations. New ANITA Mox installations are started with typically 3-15% of the added carriers being from the 'BioFarm', with already established anammox biofilm, the rest being new carriers. The first ANITA Mox plant, started up in 2010 at Sjölunda wastewater treatment plant (WWTP) in Malmö, Sweden, proved this seeding concept, reaching an ammonium removal rate of 1.2 kgN/m³ d and approximately 90% ammonia removal within 4 months from start-up. This first ANITA Mox plant is also the BioFarm used for forthcoming installations. Typical features of this first installation were low energy consumption, 1.5 kW/NH4-N-removed, low N2O emissions, <1% of the reduced nitrogen and a very stable and robust process towards variations in loads and process conditions. The second ANITA Mox plant, started up at Sundets WWTP in Växjö, Sweden, reached full capacity with more than 90% ammonia removal within 2 months from start-up. By applying a nitrogen loading strategy to the reactor that matches the capacity of the seeding carriers, more than 80% nitrogen removal could be obtained throughout the start-up period.

Transcription factor gene MNX1 is a novel cause of permanent neonatal diabetes in a consanguineous family.

AIM: Permanent neonatal diabetes mellitus (PNDM) is a rare monogenic form of non-autoimmune diabetes. Genetic defects have been identified in∼60% of cases, with mutations in ABCC8, KCNJ11 and INS being the most frequent causes of PNDM. Recognition of genetic subtypes strongly impacts on both patients' care and family counseling. This study aimed to identify the genetic aetiology of PNDM in a diabetic girl born of consanguineous parents. METHODS: DNA samples from both the proband and her non-diabetic parents were analyzed for homozygosity mapping, using Illumina Infinium 660K SNP microarrays, focusing on the runs of homozygosity (ROHs) detected only in the patient. Standard Sanger sequencing of candidate genes (MNX1 and GATA6) present in the ROHs was subsequently performed, as well as expression analyses on human embryonic and adult pancreatic islet samples. RESULTS: A putative causal homozygous mutation in the transcription factor gene MNX1 (c.816C>A/p.Phe272Leu) was identified in the PNDM patient, who was clinically diagnosed as a typical case of PNDM with no developmental pancreatic defects or other clinical features. The probable deleterious mutation was located within the MNX1 homeodomain helix 2 that is highly conserved between species. In human embryonic pancreatic islet samples, it has been shown that MNX1 expression is significantly enriched in pancreatic epithelium compared with mesenchyme, suggesting a role for MNX1 in human pancreatic beta-cell development. CONCLUSION: This study found a new putative cause of PNDM in a consanguineous family. Replication in other cohorts would help to clarify the clinical spectrum of MNX1 mutations in PNDM patients.

Contribution of 24 obesity-associated genetic variants to insulin resistance, pancreatic beta-cell function and type 2 diabetes risk in the French population.

CONTEXT: Obesity is the major determinant of type 2 diabetes (T2D), presumably through its effect on insulin resistance. Genome-wide association studies reported many single-nucleotide polymorphisms (SNPs) that increase obesity risk and body mass index (BMI), but their impact on T2D-related traits and risk is unclear. OBJECTIVE: We aimed at analyzing the effect of 24 obesity risk alleles, separately and in combination, on variation of both insulin resistance and ß-cell dysfunction, and on T2D risk. DESIGN: We genotyped 24 obesity-associated SNPs and calculated an obesity genotype score (sum of the obesity risk alleles per individual). We analyzed the contribution of each SNP and this score to the variation of four metabolic indices: homeostasis model assessment of insulin resistance (HOMA-IR), homeostasis model assessment of the pancreatic ß-cell function (HOMA-B), insulin sensitivity index (ISI) and insulinogenic index (II) (in up to 8050 nondiabetic French individuals) and to T2D risk (in 2077 T2D cases and 3085 controls). RESULTS: We found a highly significant effect of the obesity genotype score on increased insulin resistance adjusted for age and gender (ß=0.02; P-value=7.16 × 10(-9) for HOMA-IR). Individually, we identified nominal or significant association between increased insulin resistance and risk alleles in FAIM2, FTO, GNPDA2, MC4R, NPC1, PTER and SH2B1. Most signals, including the obesity genotype score and FTO SNP, were also associated with increased ß-cell function (ß=0.01; P-value=1.05 × 10(-6) and ß=0.04; P-value=3.45 × 10(-4), respectively). In our T2D case-control study, only the obesity genotype score and the well-known FTO locus significantly contributed to T2D risk (OR=1.03; P-value=9.99 × 10(-3) and OR=1.15; P-value=9.46 × 10(-4), respectively). Adjustment for BMI abolished all significant associations. CONCLUSIONS: Genetic predisposition to obesity contributes to increased insulin resistance and to its compensation through increased ß-cell function, and weakly increases the T2D risk. These associations are mediated by BMI.

Reassessment of the putative role of BLK-p.A71T loss-of-function mutation in MODY and type 2 diabetes.

AIMS/HYPOTHESIS: MODY is believed to be caused by at least 13 different genes. Five rare mutations at the BLK locus, including only one non-synonymous p.A71T variant, were reported to segregate with diabetes in three MODY families. The p.A71T mutation was shown to abolish the enhancing effect of BLK on insulin content and secretion from pancreatic beta cell lines. Here, we reassessed the contribution of BLK to MODY and tested the effect of BLK-p.A71T on type 2 diabetes risk and variations in related traits. METHODS: BLK was sequenced in 64 unelucidated MODY samples. The BLK-p.A71T variant was genotyped in a French type 2 diabetes case-control study including 4,901 cases and 4,280 controls, and in the DESIR (Data from an Epidemiological Study on the Insulin Resistance Syndrome) and SUVIMAX (Supplementation en Vitamines et Mineraux Antioxydants) population-based cohorts (n = 6,905). The variant effects were assessed by logistic and linear regression models. RESULTS: No rare non-synonymous BLK mutations were found in the MODY patients. The BLK p.A71T mutation was present in 52 normoglycaemic individuals, making it very unlikely that this loss-of-function mutation causes highly penetrant MODY. We found a nominal association between this variant and increased type 2 diabetes risk, with an enrichment of the mutation in the obese diabetic patients, although no significant association with BMI was identified. CONCLUSIONS/INTERPRETATION: No mutation in BLK was found in our MODY cohort. From our findings, the BLK-p.A71T mutation may weakly influence type 2 diabetes risk in the context of obesity; however, this will require further validation.

Differential coexpression analysis of obesity-associated networks in human subcutaneous adipose tissue.

OBJECTIVE: To use a unique obesity-discordant sib-pair study design to combine differential expression analysis, expression quantitative trait loci (eQTLs) mapping and a coexpression regulatory network approach in subcutaneous human adipose tissue to identify genes relevant to the obese state. STUDY DESIGN: Genome-wide transcript expression in subcutaneous human adipose tissue was measured using Affymetrix U133 Plus 2.0 microarrays (Affymetrix, Santa Clara, CA, USA), and genome-wide genotyping data was obtained using an Applied Biosystems (Applied Biosystems; Life Technologies, Carlsbad, CA, USA) SNPlex linkage panel. SUBJECTS: A total of 154 Swedish families ascertained through an obese proband (body mass index (BMI) >30 kg m(-2)) with a discordant sibling (BMI>10 kg m(-2) less than proband). RESULTS: Approximately one-third of the transcripts were differentially expressed between lean and obese siblings. The cellular adhesion molecules (CAMs) KEGG grouping contained the largest number of differentially expressed genes under cis-acting genetic control. By using a novel approach to contrast CAMs coexpression networks between lean and obese siblings, a subset of differentially regulated genes was identified, with the previously GWAS obesity-associated neuronal growth regulator 1 (NEGR1) as a central hub. Independent analysis using mouse data demonstrated that this finding of NEGR1 is conserved across species. CONCLUSION: Our data suggest that in addition to its reported role in the brain, NEGR1 is also expressed in subcutaneous adipose tissue and acts as a central 'hub' in an obesity-related transcript network.

Endoscopic submucosal dissection in a European setting. A multi-institutional report of a technique in development.

BACKGROUND AND STUDY AIMS: Endoscopic submucosal dissection (ESD) is a technique for "en bloc" resection of superficial tumors of the gastrointestinal tract. In France, experience with this technique is still limited. We wanted to assess the development of ESD in France, with special attention to short term outcomes. PATIENTS AND METHODS: Members of the Société Française d'Endoscopie Digestive (SFED) who declared performing ESD reported their cases prospectively on a voluntary basis. Demographic, clinical, and technical data, and the results of immediate complications were collected. Case reports were completed prospectively by each investigator before pooled analysis. RESULTS: A total of 188 consecutive case reports were collected from 16 centers. The median case mix per center was 6 patients (range 1-43). The lesion sites treated by ESD were the stomach (n = 75), esophagus (n = 27), duodenum (n = 1), cecum (n = 2), right colon (n = 3), transverse colon (n = 5), sigmoid (n = 3), and rectum (n = 72). The median size of the lesions was 26 mm (range 2-150 mm). En bloc resection was achieved in 77.1% of cases, with complete R0 resection in 72.9%. Histopathology results showed high grade dysplasia or superficial cancer in 71.2%. The median duration of ESD was 105 minutes (range 20-450 minutes). The short term morbidity was 29.2% including 34 cases of perforation (18.1%), and 21 hemorrhages (11.2%) during the 24 hours following ESD, 89% of which were managed conservatively or endoscopically. CONCLUSION: In this early experience, the feasibility of ESD appeared to be good but R0 resection and complication rates did not match those reported by Japanese authors and must be improved by an extended practice.

Effect of ENPP1/PC-1-K121Q and PPARgamma-Pro12Ala polymorphisms on the genetic susceptibility to T2D in the Tunisian population.

Diabetes mellitus is the most common chronic metabolic disease. The raising diabetes epidemic is unfolding as an interaction between several environmental factors and a genetic predisposition. The aim of the current study was to evaluate the role of the PPARgamma-Pro12Ala and ENPP1-K121Q polymorphisms on type 2 diabetes (T2D) risk in a case-control study in the Tunisian population. To assess for any association of ENPP1-K121Q and PPARgamma-Pro12Ala polymorphisms with T2D risk, we analysed the genotypic and allelic distributions of each variant in the studied cohort. Our results support that the genetic variation at ENPP1-K121Q predisposes to T2D in the Tunisian population after adjustment on gender, age and BMI status (OR=1.55, 95%CI [1.11-2.16], p=0.007). Conversely, the PPARgamma-Pro12Ala variant seems not to have a significant effect on T2D risk in our Tunisian cohort. However, the minor A-allele would convey protection against overweight in the Tunisian population. In fact, the over weighted subjects showed a significantly lower frequency of A-allele than lean controls (OR=0.49, 95%CI [0.25-0.97], p=0.02). In conclusion, our findings support the hypothesis that ENPP1-121Q is involved in the genetic susceptibility of T2D in the Tunisian population, while the PPARgamma-12Ala allele may confer protection against overweight.

Diagnosis and treatment of biliary obstruction caused by portal cavernoma.

While hemorrhagic complications of portal cavernoma are frequent, compression of the bile ducts by portal cavernoma is uncommon and treatment is still a matter for debate. We report here six new cases in order to describe: (a) the clinical, biological, and morphological features of this condition, and (b) the long-term results of a combined endoscopic and surgical treatment. The median age of patients at the time of diagnosis was 36.5 years. The circumstances of diagnosis were acute cholangitis (n=3), asymptomatic biological cholestasis (n=1), pruritus, jaundice and asthenia (n=1) and jaundice alone (n=1). Portal cavernoma and bile duct dilatation were confirmed by abdominal ultrasonography with pulsed color doppler and endoscopic retrograde cholangiography (ERC). Gallstones were found in four patients. Following stenting of the bile duct, there was a good outcome in two patients. In four patients, after failure of prolonged endoscopic treatment, second-line surgical portal-systemic shunting allowed removal of the biliary stent, and no recurrence of disease. In conclusion, biliary involvement in portal cavernoma is now a well-recognized entity, and our results suggest that combined endoscopic and surgical treatment could be required.

Rapid SNP allele frequency determination in genomic DNA pools by pyrosequencing.

Individual genotyping of single nucleotide polymorphisms (SNPs) remains expensive, especially for linkage disequilibrium mapping strategies involving high-throughput SNP genotyping. On one hand, current methods may suit scientific and laboratory needs in regard to accuracy, reproducibility/robustness, and large-scale application. On the other hand, a cheaper and less time-consuming alternative to individual genotyping is the use of SNP allelefrequencies determined in DNA pools. We have developed an accurate and reproducible protocol for allele frequency determination using Pyrosequencing technology in large genomic DNA pools (374 individuals). The measured correlation (R2) in large DNA pools was 0.980. In the context of disease-associated SNPs studies, we compared the allele frequencies between the disease (e.g., type 2 diabetes and obesity) and control groups detected by either individual genotyping or Pyrosequencing of DNA pools. In large pools, the variation between the two methods was 1.5 +/- 0.9%. It may be concluded that the allele frequency determination protocol could reliably detect over 4% differences between populations. The method is economical in regard to amounts of DNA, PCR, and primer extension reagents required. Furthermore, it allows the rapid determination of allelefrequency differences in case/control groups for association studies and susceptibility gene discovery in complex diseases.

[Curative treatment of non-metastatic esophageal cancer: concomitant chemoradiotherapy and high-dose-rate endoluminal curietherapy boost]. / Traitement à visée curative du cancer de l'oesophage non métastatique: chimio-radiothérapie concomitante et surdosage par curiethérapie endoluminale à haut débit de dose.

OBJECTIVES: The aim of this study was to evaluate the feasibility, toxicity, and efficacy of a curative combination of chemo-radiotherapy with high-dose-rate brachytherapy (HDRB) in patients with non metastatic esophageal cancer. PATIENTS AND METHODS: Fifty-two patients with esophageal carcinoma were treated with > 50 Gy external irradiation, concomitant chemotherapy (5FU-CDDP) followed by HDRB delivering 12.5 Gy (6-20) as a boost. Twelve patients were stage I, 20 stage IIa, 5 stage IIb, and 13 stage III, 1 Tis, 1 stage N unknown. Surgery was not indicated for medical reasons. RESULTS: The response rate was 96%, with complete response rate 85%. The 1-, 3-, 5-year overall survival rates were 78%, 33%, and 22% respectively. A local failure occurred in 32%, and distant metastasis in 16%. Severe (grade 3, 4) acute toxicity occurred in 6 cases, severe late toxicity in 2 cases and there was 1 toxic death. Tumoral length > or = 5 cm and stage IIa, IIb and III versus stage 1 indicated poor prognosis. CONCLUSION: This regimen is feasible and well tolerated. The 5-year overall survival is 22%, but the local failure rate is still very high. These results are encouraging and will be prospectively evaluated with currently ongoing randomized trial.

A genome-wide scan for human obesity genes reveals a major susceptibility locus on chromosome 10.

Obesity, a common multifactorial disorder, is a major risk factor for type 2 diabetes, hypertension and coronary heart disease (CHD). According to the definition of the World Health Organization (WHO), approximately 6-10% of the population in Westernized countries are considered obese. Epidemiological studies have shown that 30-70% of the variation in body weight may be attributable to genetic factors. To date, two genome-wide scans using different obesity-related quantitative traits have provided candidate regions for obesity. We have undertaken a genome-wide scan in affected sibpairs to identify chromosomal regions linked to obesity in a collection of French families. Model-free multipoint linkage analyses revealed evidence for linkage to a region on chromosome 10p (MLS=4.85). Two further loci on chromosomes 5cen-q and 2p showed suggestive evidence for linkage of serum leptin levels in a genome-wide context. The peak on chromosome 2 coincided with the region containing the gene (POMC) encoding pro-opiomelanocortin, a locus previously linked to leptin levels and fat mass in a Mexican-American population and shown to be mutated in obese humans. Our results suggest that there is a major gene on chromosome 10p implicated in the development of human obesity, and the existence of two further loci influencing leptin levels.