Determinants of ventricular arrhythmias in sickle cell anemia: toward better prevention of sudden cardiac death.

Sudden death is 1 of the leading causes of death in adults with sickle cell anemia (SCA) but its etiology remains mostly unknown. Ventricular arrhythmia (VA) carries an increased risk of sudden death; however, its prevalence and determinants in SCA are poorly studied. This study aimed to identify the prevalence and predictors of VA in patients with SCA. From 2019 to 2022, 100 patients with SCA were referred to the physiology department to specifically analyze cardiac function and prospectively included in the DREPACOEUR registry. They underwent a 24-hour electrocardiogram monitoring (24h-Holter), transthoracic echocardiography, and laboratory tests on the same day. The primary end point was the occurrence of VA, defined as sustained or nonsustained ventricular tachycardia (VT), >500 premature ventricular contractions (PVCs) on 24h-Holter, or a recent history of VT ablation. The mean patient age was 46 ± 13 years, and 48% of the patients were male. Overall, VA was observed in 22 (22%) patients. Male sex (81% vs 34%; P = .02), impaired global longitudinal strain (GLS): -16% ± 1.9% vs -18.3% ± 2.7%; P = .02), and decreased platelet count (226 ± 96 giga per liter [G/L] vs 316 ± 130 G/L) were independently associated with VA. GLS correlated with PVC load every 24 hours (r = 0.39; P < .001) and a cutoff of -17.5% could predict VA with a sensitivity of 82% and a specificity of 63%. VAs are common in patients with SCA, especially in men. This pilot study uncovered GLS as a valuable parameter for improving rhythmic risk stratification.

Phase II study evaluating the association of gemcitabine, trastuzumab and erlotinib as first-line treatment in patients with metastatic pancreatic adenocarcinoma (GATE 1).

In a previous phase II study (THERAPY), cetuximab and trastuzumab combination, as second-line after progression with gemcitabine, showed disease stabilization in 27% of 33 patients with pancreatic carcinoma. In the present phase II multicenter study, we assessed the efficacy and tolerance of gemcitabine, trastuzumab plus erlotinib as first-line treatment of metastatic pancreatic cancer. The primary endpoint was disease control rate (DCR, RECIST v.1); secondary endpoints were progression-free (PFS), overall (OS) survival and toxicity (NCI-CTCAE v3.0). Ancillary study addressed the predictive value of both EGFR/HER2 expression and KRAS mutational status. Sixty-three patients from four centers were included (62 evaluable for toxicity, 59 for efficacy), median age was 62 years (35-77), 59.7% men. The median treatment duration was 16.1 weeks (2.1-61). Eleven patients (19%) reported a partial tumor response, and 33 (56%) disease stabilization. DCR was 74.6% (95%CI: 61.8-85.0; 44/59 patients). After a median follow-up of 23.3 months (0.6-23.6), median PFS was 3.5 months (95%CI: 2.4-3.8) and median OS 7.9 months (95%CI: 5.1-10.2). PFS was significantly longer in patients with grade ≥ 2 cutaneous toxicities vs patients with grade 0-1 toxicities (HR = 0.55, 95%CI: 0.33-0.92, P = .020). Expression of EGFR and HER2 was correlated with PFS and OS in multivariate analysis; HER2 expression was correlated with the tumor response. Main severe toxicities were neutropenia (32%), cutaneous rash (37%) and thrombosis/embolisms (35.5%). This triplet combination is effective in terms of disease control, PFS and OS, and acceptable for safety. A larger study to investigate this combination compared to the standard regimen should be discussed.

Tivantinib for second-line treatment of MET-high, advanced hepatocellular carcinoma (METIV-HCC): a final analysis of a phase 3, randomised, placebo-controlled study.

BACKGROUND: Tivantinib (ARQ 197), a selective, oral MET inhibitor, improved overall survival and progression-free survival compared with placebo in a randomised phase 2 study in patients with high MET expression (MET-high) hepatocellular carcinoma previously treated with sorafenib. The aim of this phase 3 study was to confirm the results of the phase 2 trial. METHODS: We did a phase 3, randomised, double-blind, placebo-controlled study in 90 centres in Australia, the Americas, Europe, and New Zealand. Eligible patients were 18 years or older and had unresectable, histologically confirmed, hepatocellular carcinoma, an Eastern Cooperative Oncology Group performance status of 0-1, high MET expression (MET-high; staining intensity score ≥2 in ≥50% of tumour cells), Child-Pugh A cirrhosis, and radiographically-confirmed disease progression after receiving sorafenib-containing systemic therapy. We randomly assigned patients (2:1) in block sizes of three using a computer-generated randomisation sequence to receive oral tivantinib (120 mg twice daily) or placebo (twice daily); patients were stratified by vascular invasion, extrahepatic spread, and α-fetoprotein concentrations (≤200 ng/mL or >200 ng/mL). The primary endpoint was overall survival in the intention-to-treat population. Efficacy analyses were by intention to treat and safety analyses were done in all patients who received any amount of study drug. This study is registered with ClinicalTrials.gov, number NCT01755767. FINDINGS: Between Dec 27, 2012, and Dec 10, 2015, 340 patients were randomly assigned to receive tivantinib (n=226) or placebo (n=114). At a median follow-up of 18·1 months (IQR 14·1-23·1), median overall survival was 8·4 months (95% CI 6·8-10·0) in the tivantinib group and 9·1 months (7·3-10·4) in the placebo group (hazard ratio 0·97; 95% CI 0·75-1·25; p=0·81). Grade 3 or worse treatment-emergent adverse events occurred in 125 (56%) of 225 patients in the tivantinib group and in 63 (55%) of 114 patients in the placebo group, with the most common being ascites (16 [7%] patients]), anaemia (11 [5%] patients), abdominal pain (nine [4%] patients), and neutropenia (nine [4%] patients) in the tivantinib group. 50 (22%) of 226 patients in the tivantinib group and 18 (16%) of 114 patients in the placebo group died within 30 days of the last dose of study medication, and general deterioration (eight [4%] patients) and hepatic failure (four [2%] patients) were the most common causes of death in the tivantinib group. Three (1%) of 225 patients in the tivantinib group died from a treatment-related adverse event (one sepsis, one anaemia and acute renal failure, and one acute coronary syndrome). INTERPRETATION: Tivantinib did not improve overall survival compared with placebo in patients with MET-high advanced hepatocellular carcinoma previously treated with sorafenib. Although this METIV-HCC trial was negative, the study shows the feasibility of doing integral tissue biomarker studies in patients with advanced hepatocellular carcinoma. Additional randomised studies are needed to establish whether MET inhibition could be a potential therapy for some subsets of patients with advanced hepatocellular carcinoma. FUNDING: ArQule Inc and Daiichi Sankyo (Daiichi Sankyo Group).

How we perceive our own hands: Effects of attention, aging, and sex.

This study investigates whether both the perception of somesthetic sensations arising spontaneously on the hand and their modulation by attention are subject to change with advancing age and sex. Participants aged between 50 and 68 (N = 24), and younger (19-27; N = 24), with an equal sex ratio in each group, described the spontaneous sensations they felt on one of their hands. Two 10-s tests were carried out with participants either seeing their tested hand (gaze towards the visible hand) or not (contralateral gaze, hidden hand). Within the age range covered by our participants, aging had an effect on the spatial distribution of sensations, insofar as the older participants reported feeling more sensations in their palm whereas the younger participants had more sensitive fingers. Age also influenced the number, nature, intensity, and duration of sensations in interaction with gaze and/or sex. The most frequent pattern was a benefit of ipsilateral relative to contralateral gazing in young women. Attentional modulation was seldom observed in men and was absent among older participants.

Transient neonatal liver disease after maternal antenatal intravenous Ig infusions in gestational alloimmune liver disease associated with neonatal haemochromatosis.

OBJECTIVES: Neonatal haemochromatosis is a rare gestational disease that results in severe foetal liver disease with extrahepatic iron overload, sparing the reticuloendothelial system. Recurrence can be prevented with intravenous immunoglobulin (IVIG) infusions during pregnancy, supporting an alloimmune aetiology. The aim of the study was to assess the effect of antenatal treatment with IVIG infusion on the outcome of pregnancies in women with a history of documented neonatal haemochromatosis likely owing to gestational alloimmune disease and to analyse IVIG tolerance. METHODS: From 2004 to 2012, 8 pregnant women were treated with IVIG at 1 g/kg body weight weekly from 18 weeks' gestation until birth in a prospective multicentre study. RESULTS: All 8 neonates born to the treated women survived. Five developed mild neonatal liver disease with hepatomegaly (n = 1), hyperechogenic liver (n = 2), abnormal liver function tests (n = 1), raised serum ferritin (n = 3) and α-fetoprotein (n = 5) levels, or mild iron overload on liver magnetic resonance imaging (n = 1). Ferritin and α-fetoprotein levels normalised before 14 days and 2 months, respectively. A per-mother-basis analysis comparing outcomes of treated (n = 8) and untreated (n = 9) gestations showed a significant improvement in the survival of neonates with gestational IVIG therapy (survival 8/8 vs 0/9, P < 0.001). Adverse effects of IVIG infusion occurred in 5 mothers leading to discontinuation of treatment in 1 case. Preterm neonates born before 37 weeks' gestation had a decreased risk of neonatal liver disease (P = 0.04). CONCLUSIONS: Antenatal treatment with IVIG infusion in women at risk for gestational alloimmune disease recurrence improves the outcome of pregnancies despite mild signs of transient neonatal liver disease.

Evaluation of immunoturbidimetric albumin reagent from Diagam on c502/Cobas8000® analyzer: comparison with immunonephelometry and colorimetric methods.

BACKGROUND: Until now, specific proteins have traditionally been analyzed by immunonephelometry requiring spe- cific equipment. Due to laboratory consolidation, turbidimetry is commonly used for the determination of specific proteins. Biochemistry analyzers have a wide range of turbidimetric assays available to a single workstation, which makes them particularly efficient. For our laboratory consolidation, we installed two distinct Cobas8000® modular analyzer series. However, the turbidimetric albumin from Roche did not give satisfactory results in re- gard to the traceability to the reference measurement material. METHODS: Analytical assays of turbidimetric albumin from Diagam (Liège, Belgique) on c502/Cobas8000®, includ- ing imprecision studies, accuracy using the ERM®-DA470k/IFCC, and correlation with nephelometry and colo- rimetry, were performed. RESULTS: Total precision for the immunoturbidimetric assays was consistently better than 2.3% CV and linear throughout the dynamic range of the assays. Correlation of serum albumin by turbidimetry is in good agreement with nephelometry. The mean ± SD of the reference material ERM-DA470k was 37.6 ± 0.25 g/L, with a bias of 1.07%. CONCLUSIONS: Turbidimetric albumin from Diagam meets the requirements of accuracy and precision for optimal clinical use and could be an alternative without the associated cost of a dedicated instrument in the context of lab- oratory consolidation.

Influence of COVID-19 on Stress at Work During the First Wave of the Pandemic Among Emergency Health Care Workers.

OBJECTIVES: For more than 2 years, coronavirus disease (COVID-19) has forced worldwide health care systems to adapt their daily practice. These adaptations add to the already stressful demands of providing timely medical care in an overcrowded health care system. Specifically, the COVID-19 pandemic added stress to an already overwhelmed emergency and critical care health care workers (HCWs) on the front lines during the first wave of the pandemic.This study assessed comparative subjective and objective stress among frontline HCWs using a visual analog scale and biometric data, specifically heart rate variability (HRV). METHODS: This is a prospective, observational study using surveys and heart rate monitoring among HCWs who work in 3 frontline health care units (emergency department, mobile intensive care unit, and intensive care unit) in the University Hospital of Clermont-Ferrand, France. Two sessions were performed: 1 during the first wave of the pandemic (April 10 to May 10, 2020) and 1 after the first wave of the pandemic (June 10 to July 15, 2020).The primary outcome is the difference in stress levels between the 2 time points. Secondary objectives were the impact of overcrowding, sociodemographics, and other variables on stress levels. We also assessed the correlation between subjective and objective stress levels. RESULTS: Among 199 HCWs, 98 participated in biometric monitoring, 84 had biometric and survey data, and 12 with only biometric data. Subjective stress was higher during the second time point compared to the first (4.39 ± 2.11 vs 3.16 ± 2.34, P = 0.23). There were higher objective stress levels with a decrease in HRV between the first and the second time points. Furthermore, we found higher patient volumes as a source of stress during the second time point. We did not find any significant correlation between subjective and objective stress levels. CONCLUSION: HCWs had higher stress levels between the 2 waves of the pandemic. Overcrowding in the emergency department is associated with higher stress levels. We did not find any correlation between subjective and objective stress among intensive care and emergency HCWs during the first wave of the pandemic.

Stereotactic MR-Guided Radiotherapy for Liver Metastases: First Results of the Montpellier Prospective Registry Study.

Liver stereotactic body radiotherapy (SBRT) is a local treatment that provides good local control and low toxicity. We present the first clinical results from our prospective registry of stereotactic MR-guided radiotherapy (MRgRT) for liver metastases. All patients treated for liver metastases were included in this prospective registry study. Stereotactic MRgRT indication was confirmed by multidisciplinary specialized tumor boards. The primary endpoints were acute and late toxicities. The secondary endpoints were survival outcomes (local control, overall survival (OS), disease-free survival, intrahepatic relapse-free survival). Twenty-six consecutive patients were treated for thirty-one liver metastases between October 2019 and April 2022. The median prescribed dose was 50 Gy (40-60) in 5 fractions. No severe acute MRgRT-related toxicity was noted. Acute and late gastrointestinal and liver toxicities were low and mostly unrelated to MRgRT. Only 5 lesions (16.1%) required daily adaptation because of the proximity of organs at risk (OAR). With a median follow-up time of 17.3 months since MRgRT completion, the median OS, 1-year OS and 2-year OS rates were 21.7 months, 83.1% (95% CI: 55.3-94.4%) and 41.6% (95% CI: 13.5-68.1%), respectively, from MRgRT completion. The local control at 6 months, 1 year and 2 years was 90.9% (95% CI: 68.3-97.7%). To our knowledge, we report the largest series of stereotactic MRgRT for liver metastases. The treatment was well-tolerated and achieved a high LC rate. Distant relapse remains a challenge in this population.

Interacting effects of vision and attention in perceiving spontaneous sensations arising on the hands.

Visual input and attention enhance tactile perception. But do they influence the perception of spontaneous sensations (SPS) arising in the absence of any external stimulus? We have investigated this by requiring subject to focus attention on each hand while orienting overtly toward it (convergent focusing) or away (divergent focusing) and to subsequently describe the properties of the SPS they felt. Subjects performed this task under free viewing conditions or while blindfolded. Enhanced perception of SPS was found under convergent focusing and also under free viewing conditions. However, the effects of focusing were different whether visual input was available or not. When visual input was available, SPS were enhanced in the fingers but suppressed in the palm, suggesting that enhancement and suppression operated to refine perception of SPS. When visual input was unavailable, only enhancement was observed, even in areas of the hand where suppressing effects were found under free viewing conditions. These interacting effects between vision and attention were observed exclusively in the left hand. A control experiment failed to evidence whether looking at different parts of the hand modulates SPS. We suggest that vision facilitates perception and, when interacting with attention, it enables better perception by promoting suppression of SPS arising in areas of lower sensitivity that may interfere with processing in more sensitive zones. The results are discussed with respect to mechanisms lateralized in the right cerebral hemisphere, and a role of SPS in the maintenance of a conscious image of the body is suggested.

Plasma hPG80 (Circulating Progastrin) as a Novel Prognostic Biomarker for Hepatocellular Carcinoma.

Alpha-fetoprotein (AFP) is the most widely used biomarker for hepatocellular carcinoma (HCC) prognosis. However, AFP is not useful in establishing a prognosis for patients with a tumor in the early stages. hPG80 (circulating progastrin) is a tumor promoting peptide present in the blood of patients with various cancers, including HCC. In this study, we evaluated the prognostic value of plasma hPG80 in patients with HCC, alone or in combination with AFP. A total of 168 HCC patients were tested prospectively for hPG80 and analyzed retrospectively. The prognostic impact of hPG80 and AFP levels on patient survival was assessed using Kaplan-Meier curves and log-rank tests. hPG80 was detected in 84% of HCC patients. There was no correlation between hPG80 and AFP levels in the training and validation cohorts. Both cohorts showed higher sensitivity of hPG80 compared to AFP, especially at early stages. Patients with high hPG80 (hPG80+) levels (optimal cutoff value 4.5 pM) had significantly lower median overall survival (OS) compared to patients with low hPG80 (hPG80-) levels (12.4 months versus not reached respectively, p < 0.0001). Further stratification by combining hPG80 and AFP levels (cutoff 100 ng/mL) improved prognosis in particular for those patients with low AFP level (hPG80-/AFP+ and hPG80-/AFP-, 13.4 months versus not reached respectively, p < 0.0001 and hPG80+/AFP+ and hPG80+/AFP-, 5.7 versus 26 months respectively, p < 0.0001). This was corroborated when analyses were performed using the BCLC staging especially at early stages. Our findings show that hPG80 could serve as a new prognostic biomarker in HCC. Used in combination with AFP, it improves the stratification of the patients in good and poor prognosis, especially for those patients with negative AFP and early-stage HCC.

Survival after Multimodal Treatment Including Surgery for Metastatic Esophageal Cancer: A Systematic Review.

(1) Background: The management of metastatic esophageal cancer is more often limited to palliative chemotherapy. Limited data are available regarding the role of surgery that remains controversial. The aim of this systematic review is to assess the survival outcome of surgically treated metastatic esophageal cancer patients. (2) Methods: The present systematic review is designed using the PRISMA guidelines and has been registered with PROSPERO (CRD42019140306). Two reviewers independently searched and identified studies dealing with surgery for stage IV esophageal cancer in the Medline and Google Scholar databases between January 2008 and December 2019. (3) Results: Seven retrospective nonrandomized studies, totaling 1756 patients with stage IV esophageal cancer who underwent curative surgery, were included. Our analysis demonstrates a three-year overall survival rate of 23% (CI 95% 17-31) among patients undergoing surgery. Because only two comparative studies were identified, data compilation and relative risk evaluation through meta-analysis were not possible. (4) Conclusions: Multimodality treatment, including surgery in curative intent, seems associated with a significant chance of three-year overall survival. A prospective evaluation of this approach and validation of adequate selection criteria are needed.

Stereotactic MR-Guided Radiotherapy for Pancreatic Tumors: Dosimetric Benefit of Adaptation and First Clinical Results in a Prospective Registry Study.

Introduction: Stereotactic MR-guided adaptive radiotherapy (SMART) is an attractive modality of radiotherapy for pancreatic tumors. The objectives of this prospective registry study were to report the dosimetric benefits of daily adaptation of SMART and the first clinical results in pancreatic tumors. Materials and Methods: All patients treated in our center with SMART for a pancreatic tumor were included. Patients were planned for five daily-adapted fractions on consecutive days. Endpoints were acute toxicities, late toxicities, impact of adaptive treatment on target volume coverage and organs at risk (OAR) sparing, local control (LC) rate, distant metastasis-free survival (DMFS), and overall survival (OS). Results: Thirty consecutive patients were included between October 2019 and April 2021. The median dose prescription was 50 Gy. No patient presented grade > 2 acute toxicities. The most frequent grade 1-2 toxicities were asthenia (40%), abdominal pain (40%), and nausea (43%). Daily adaptation significantly improved planning target volume (PTV) and gross tumor volume (GTV) coverage and OAR sparing. With a median follow-up of 9.7 months, the median OS, 6-month OS, and 1-year OS were 14.1 months, 89% (95% CI: 70%-96%), and 75% (95% CI: 51%-88%), respectively, from SMART completion. LC at 6 months and 1 year was respectively 97% (95% CI: 79-99.5%) and 86% (95% CI: 61%-95%). There were no grade > 2 late toxicities. With a median follow-up of 10.64 months, locally advanced pancreatic cancer (LAPC) and borderline resectable pancreatic cancer (BRPC) patients (22 patients) had a median OS, 6-month OS, and 1-year OS from SMART completion of 14.1 months, 76% (95% CI: 51%-89%), and 70% (95% CI: 45%-85%), respectively. Nine patients underwent surgical resection (42.1% of patients with initial LAPC and 33.3% of patients with BRPC), with negative margins (R0). Resected patients had a significantly better OS as compared to unresected patients (p = 0.0219, hazard ratio (HR) = 5.78 (95% CI: 1.29-25.9)). Conclusion: SMART for pancreatic tumors is feasible without limiting toxicities. Daily adaptation demonstrated a benefit for tumor coverage and OAR sparing. The severity of observed acute and late toxicities was low. OS and LC rates were promising. SMART achieved a high secondary resection rate in LAPC patients. Surgery after SMART seemed to be feasible and might increase OS in these patients.

Socio-demographic and lifestyle factors associated with overweight in a representative sample of 11-15 year olds in France: results from the WHO-Collaborative Health Behaviour in School-aged Children (HBSC) cross-sectional study.

BACKGROUND: The prevalence of overweight in children and adolescents is high and overweight is associated with poor health outcomes over short- and long-term. Lifestyle factors can interact to influence overweight. Comprehensive studies linking overweight concomitantly with several demographic and potentially-modifiable lifestyle factors and health-risk behaviours are limited in adolescents--an age-group characterized by changes in lifestyle behaviours and high prevalence of overweight. Thus, the objective of the current study was to examine the association of overweight with several socio-demographic and lifestyle variables simultaneously in a representative sample of adolescents. METHODS: A nationally representative sample of 11-15 year-olds (n = 7154) in France participated as part of the WHO-Collaborative Health Behaviour in School-aged Children (HBSC) study. Students reported data on their age, height, weight, socio-demographic variables, lifestyle factors including nutrition practices, physical activity at two levels of intensity (moderate and vigorous), sedentary behaviours, as well as smoking and alcohol consumption patterns using standardized HBSC protocols. Overweight (including obesity) was defined using the IOTF reference. The multivariate association of overweight with several socio-demographic and lifestyle factors was examined with logistic regression models. RESULTS: The adjusted odds ratios for the association with overweight were: 1.80 (95% CI: 1.37-2.36) for low family affluence; 0.73 (0.60-0.88) for eating breakfast daily; 0.69 (0.56-0.84) for moderate to vigorous physical activity (MVPA); and 0.71 (0.59-0.86) for vigorous physical activity (VPA). Significant interactions between age and gender as well as television (TV) viewing and gender were noted: for boys, overweight was not associated with age or TV viewing; in contrast, for girls overweight correlated negatively with age and positively with TV viewing. Fruit and vegetable intake, computer and video-games use, smoking and alcohol consumption were not associated with overweight. CONCLUSIONS: In multivariate model, family affluence, breakfast consumption and moderate to vigorous as well as vigorous physical activity were negatively associated with overweight. These findings extend previous research to a setting where multiple risk and protective factors were simultaneously examined and highlight the importance of multi-faceted approaches promoting physical activity and healthy food choices such as breakfast consumption for overweight prevention in adolescents.

Multimodal treatment including surgery for esophageal adenocarcinoma with liver oligo-metastases: a pathological complete response but early brain metastasis.

Survival of patients with stage IV esophageal adenocarcinoma is exceedingly poor, with less than 5% surviving 5 years. Current National Comprehensive Cancer Network guidelines recommend only palliative and supportive measures for patients with metastatic esophageal cancer. Treatment for stage IV disease is chemotherapy in selected patients, while the role of radiation therapy and surgical resection remain controversial. We report herein a young patient with esophageal adenocarcinoma and synchronous liver metastasis who underwent induction chemotherapy with encouraging downstaging, then two-field esophageal resection with left liver lobectomy. Despite a complete response of esophageal and residual liver lesions, early progression with isolated brain metastasis occurred 2 months after discharge. Our case highlights that despite progress in perioperative chemotherapy, the role of surgery remains uncertain for patients with esophageal cancer and synchronous M1 disease who exhibit excellent response to neoadjuvant treatment.

Outcome after pancreatectomy for neuroendocrine neoplams according to the WHO 2017 grading system: A retrospective multicentric analysis of 138 consecutive patients.

AIM: The aim of this study was to evaluate the new World Health Organization (WHO) 2017 grading system and the others clinicopathological factors in pancreatic neuroendocrine tumor (panNET) operated patients. METHODS: Histological staging was based on the WHO 2017 grading system. Outcome after surgery and predictors of overall survival (OS) and disease free survival (DFS) were evaluated. RESULTS: A total of 138 patients underwent surgical resection with a severe morbidity and mortality rates of 14.5% and 0.7% respectively. Five years OS differed according to WHO 2017: 95% among 58 patients with NETG1, 82% in 68 patients with NETG2, 35% in 7 patients with NETG3 and 0% in 5 patients with NECG3 (P<0.0001). Independent predictors of worse OS were age>60 y.o (P=0.014), synchronous metastasis (P=0.005) and WHO 2017 with significant differences between NETG1 versus NETG2 (P=0.005), NETG3 (P<0.001) and NECG3 (P<0.001). Independent predictors of worse DFS were symptomatic NET (P=0.038), pN+ status (P=0.027) and WHO 2017 with significant differences between NETG1 versus NETG3 (P=0.014) and NECG3 (P=0.009). CONCLUSION: The WHO 2017 grading system is a useful tool for patient prognosis after panNET resection and the tailoring of therapeutic strategy. Surgery could provide good results in NETG3 patients.

Machine Learning-Assisted Evaluation of Circulating DNA Quantitative Analysis for Cancer Screening.

While the utility of circulating cell-free DNA (cfDNA) in cancer screening and early detection have recently been investigated by testing genetic and epigenetic alterations, here, an original approach by examining cfDNA quantitative and structural features is developed. First, the potential of cfDNA quantitative and structural parameters is independently demonstrated in cell culture, murine, and human plasma models. Subsequently, these variables are evaluated in a large retrospective cohort of 289 healthy individuals and 983 patients with various cancer types; after age resampling, this evaluation is done independently and the variables are combined using a machine learning approach. Implementation of a decision tree prediction model for the detection and classification of healthy and cancer patients shows unprecedented performance for 0, I, and II colorectal cancer stages (specificity, 0.89 and sensitivity, 0.72). Consequently, the methodological proof of concept of using both quantitative and structural biomarkers, and classification with a machine learning method are highlighted, as an efficient strategy for cancer screening. It is foreseen that the classification rate may even be improved by the addition of such biomarkers to fragmentomics, methylation, or the detection of genetic alterations. The optimization of such a multianalyte strategy with this machine learning method is therefore warranted.

The oncogenic and druggable hPG80 (Progastrin) is overexpressed in multiple cancers and detected in the blood of patients.

BACKGROUND: In colorectal cancer, hPG80 (progastrin) is released from tumor cells, promotes cancer stem cells (CSC) self-renewal and is detected in the blood of patients. Because the gene GAST that encodes hPG80 is a target gene of oncogenic pathways that are activated in many tumor types, we hypothesized that hPG80 could be expressed by tumors from various origins other than colorectal cancers, be a drug target and be detectable in the blood of these patients. METHODS: hPG80 expression was monitored by fluorescent immunohistochemistry and mRNA expression in tumors from various origins. Cancer cell lines were used in sphere forming assay to analyze CSC self-renewal. Blood samples were obtained from 1546 patients with 11 different cancer origins and from two retrospective kinetic studies in patients with peritoneal carcinomatosis or hepatocellular carcinomas. These patients were regularly sampled during treatments and assayed for hPG80. FINDINGS: We showed that hPG80 was present in the 11 tumor types tested. In cell lines originating from these tumor types, hPG80 neutralization decreased significantly CSC self-renewal by 28 to 54%. hPG80 was detected in the blood of patients at significantly higher concentration than in healthy blood donors (median hPG80: 4.88 pM versus 1.05 pM; p < 0.0001) and shown to be correlated to GAST mRNA levels in the matched tumor (i.e., lung cancers, Spearman r = 0.8; p = 0.0023). Furthermore, we showed a strong association between longitudinal hPG80 concentration changes and anti-cancer treatment efficacy in two independent retrospective studies. In the peritoneal carcinomatosis cohort, median hPG80 from inclusion to the post-operative period decreased from 5.36 to 3.00 pM (p < 0.0001, n = 62) and in the hepatocellular carcinoma cohort, median hPG80 from inclusion to remission decreased from 11.54 pM to 1.99 pM (p < 0.0001, n = 63). INTERPRETATION: Because oncogenic hPG80 is expressed in tumor cells from different origins and because circulating hPG80 in the blood is related to the burden/activity of the tumor, it is a promising cancer target for therapy and for disease monitoring. FUNDINGS: ECS-Progastrin.

Quantitative evaluation of liver metastases density on computed tomography: A new tool to evaluate early response to bevacizumab-containing chemotherapy.

BACKGROUND: Response Evaluation Criteria in Solid Tumors (RECIST) are used to assess tumour shrinkage after cytotoxic chemotherapy, but may be inadequate for efficacy evaluation of anti-angiogenic therapies. AIMS: This study aimed to identify novel radiologic tumour response criteria based on early changes in tumour size and density, observed on computed tomography (CT), in patients with colorectal liver metastases (CRLM) treated with bevacizumab-containing chemotherapy. METHODS: CT of 71 and 68 CRLM patients treated with bevacizumab and non-bevacizumab-based regimens, respectively, were retrospectively reviewed. Tumour size, tumour density, and tumour-to-liver density (TTLD) ratio were determined at baseline and at first restaging. We tested their correlation with progression-free (PFS) and overall survival (OS) using the log-rank test. RESULTS: In the bevacizumab group, neither RECIST response nor tumour density variation was correlated with PFS or OS. In contrast, PFS and OS were significantly longer in patients with tumour size reduction ≥15% (RECIST-15%) and/or decrease in TTLD ratio not exceeding -10% (TTLD-10%) than in patients who did not reach any of those criteria, in univariate and multivariate analysis. Only size-response criteria predicted clinical outcome in the non-bevacizumab group. CONCLUSIONS: This study highlights new quantitative CT criteria that may early predict the efficacy of bevacizumab in CRLM patients.

Factors associated with overweight in preschool-age children in southwestern France.

BACKGROUND: Pediatric overweight and obesity are becoming an epidemic worldwide, which indicates the need for formulating preventive programs and policies during a child's early years. OBJECTIVE: We identified factors associated with overweight in young children in southwestern France. DESIGN: Children [n = 1780; x (+/-SD) age: 3.9 +/- 0.4 y] were recruited in kindergarten. Medical information on the parents, grandparents, and child as well as the child's 3-d dietary intake, participation in organized sports, and television-viewing habits were ascertained, and anthropometric measurements of the child were taken. RESULTS: The prevalence of overweight was 9.1% when using body mass index >or= 90th percentile of French reference curves as a cutoff. In a multivariate logistic regression, overweight at 4 y was associated with female sex, having an overweight mother, and having >or=1 diabetic grandparent; odds ratios (ORs; 95% CIs) for these variables were 1.9 (1.2, 3.0), 2.2 (1.0, 4.7), and 2.6 (1.6, 4.1), respectively. Being small or large for gestational age was not associated with the risk of overweight at 4 y, whereas this risk was increased for children who were overweight at 9 or 24 mo: ORs (95% CIs) were 4.0 (2.4, 6.9) and 11.7 (6.1, 22.2), respectively. Nutrient intakes did not differ significantly with weight status in girls; however, overweight boys had significantly greater energy and lipid intakes than did their nonoverweight counterparts. Overweight was positively associated with television viewing (>1 h/d) in both sexes and with participation in organized sports in girls only. CONCLUSIONS: A family history of overweight or diabetes, overweight in the first 2 y of life, and television viewing are associated with overweight at 4 y. These factors should be considered in developing programs for the prevention of overweight in early childhood.

My heart is in my hands: the interoceptive nature of the spontaneous sensations felt on the hands.

Somatic sensations may arise in the total absence of external stimuli, i.e., spontaneous sensations (SPSs). Because the background of body sensations has been mentioned as a possible contributor to interoceptive functions, such as the perception of the self and the conscious awareness of one's own body, a possible link between SPSs and interoception has been advocated. Yet, no study has provided direct evidence on such a relationship. The aim of the present study was to establish a link between SPSs and interoception. On the basis of the literature, the accuracy of heartbeat perception was taken as an index of general interoception across different bodily modalities. It was found that individuals with good heartbeat perception experienced more numerous and more intense SPSs. Furthermore, taken along with other individual characteristics, heartbeat perception accuracy predicted the perceived intensity of SPSs, their spatial extent, their variety, as well as confidence in their spatial characteristics. However, we also provide evidence that good vs. poor heartbeat perception is not just a matter of degree. We conclude that interoception definitely contributes to the perception of SPSs.