Recurrence After Surgery for Primary Hyperparathyroidism in 517 Patients With Multiple Endocrine Neoplasia Type 1: An Association Francophone de Chirurgie Endocrinienne and Groupe d'étude des Tumeurs Endocrines study.

OBJECTIVE: To assess recurrence according to the type of surgery for primary hyperparathyroidism (pHPT) in multiple endocrine neoplasia type 1 ( MEN1 ) patients and to identify the risk factors for recurrence after the initial surgery. BACKGROUND: In MEN1 patients, pHPT is multiglandular, and the optimal extent of initial parathyroid resection influences the risk of recurrence. METHODS: MEN1 patients who underwent initial surgery for pHPT between 1990 and 2019 were included. Persistence and recurrence rates after less than subtotal parathyroidectomy (LTSP) and subtotal parathyroidectomy (STP) were analyzed. Patients with total parathyroidectomy with reimplantation were excluded. RESULTS: Five hundred seventeen patients underwent their first surgery for pHPT: 178 had LTSP (34.4%) and 339 STP (65.6%). The recurrence rate was significantly higher after LTSP (68.5%) than STP (45%) ( P < 0.001). The median time to recurrence after pHPT surgery was significantly shorter after LTSP than after STP: 4.25 (1.2-7.1) versus 7.2 (3.9-10.1) years ( P < 0.001). A mutation in exon 10 was an independent risk factor of recurrence after STP (odds ratio = 2.19; 95% CI: 1.31; 3.69; P = 0.003). The 5 and 10-year recurrent pHPT probabilities were significantly higher in patients after LTSP with a mutation in exon 10 (37% and 79% vs 30% and 61%; P = 0.016). CONCLUSIONS: Persistence, recurrence of pHPT, and reoperation rate are significantly lower after STP than LTSP in MEN1 patients. Genotype seems to be associated with the recurrence of pHPT. A mutation in exon 10 is an independent risk factor for recurrence after STP, and LTSP may not be recommended when exon 10 is mutated.

Pneumococcal pneumonia and endotoxemia: An experimental and clinical reappraisal.

BACKGROUND: Circulating endotoxins could result from bacterial digestive translocation during sepsis, thus contributing to uncontrolled systemic inflammation, leading in turn to organ dysfunction. We addressed this issue in the setting of severe pneumococcal pneumonia. METHODS: Endotoxemia was measured in a clinically relevant rabbit model of ventilated pneumococcal pneumonia and in 110 patients with bacteraemic pneumonia, using a patented mass spectrometry (LC-MS/MS) method for detection of 3-OH fatty acids (C10, C12, C14, C16 and C18), which are molecules bound to the lipid A motif of LPS. RESULTS: Whereas higher levels of systemic inflammation and organ dysfunctions were found, there was no significant difference in lipopolysaccharide concentrations when infected rabbits were compared to non-infected ones, or when patients were compared to healthy volunteers. CONCLUSIONS: Seemingly, endotoxins do not drive the overwhelming inflammation associated with severe forms of pneumococcal pneumonia.

Recipient age influences survival after liver transplant: Results of the French national cohort 2007-2017.

BACKGROUND: In recent years, age at liver transplantation (LT) has markedly increased. In the context of organ shortage, we investigated the impact of recipient age on post-transplantation mortality. METHODS: All adult patients who received a first LT between 2007 and 2017 were included in this cross-sectional study. Recipients' characteristics at the time of listing, donor and surgery data, post-operative complications and follow-up of vital status were retrieved from the national transplantation database. The impact of age on 5-year overall mortality post-LT was estimated using a flexible multivariable parametric model which was also used to estimate the association between age and 10-year net survival, accounting for expected age- and sex-related mortality. RESULTS: Among the 7610 patients, 21.4% were aged 60-65 years, and 15.7% over 65. With increasing age, comorbidities increased but severity of liver disease decreased. Older recipient age was associated with decreased observed survival at 5 years after LT (p < .001), with a significant effect particularly during the first 2 years. The linear increase in the risk of death associated with age does not allow any definition of an age's threshold for LT (p = .832). Other covariates associated with an increased risk of 5-year death were dialysis and mechanical ventilation at transplant, transfusion during LT, hepatocellular carcinoma and donor age. Ten-year flexible net survival analysis confirmed these results. CONCLUSION: Although there was a selection process for older recipients, increasing age at LT was associated with an increased risk of death, particularly in the first years after LT.

CMV Infection and Lymphopenia: Warning Markers of Pneumocystis Pneumonia in Kidney Transplant Recipients.

Pneumocystis pneumonia (PcP) remains life-threatening in kidney transplant recipients (KTR). Our study investigated risk factors one-year before PcP. We conducted a monocentric, case-control study including all KTR at the Dijon University Hospital (France) with a diagnosis of PcP between 2005 and 2022 (cases), and matched control KTR with no history of PcP (3 controls/case). Among all 1,135 KTR, 57 cases (5%) and 169 matched-controls were included. PcP was associated with 18% mortality. Compared to controls, cases were older, with a higher immunological risk, and CMV infection was more frequent in the year preceding the occurrence of PcP (23% vs. 4%; p < 0.001). As early as 1 year before PcP, lymphocyte counts were lower and serum creatinine levels were higher in cases, but immunosuppressive regimens were not significantly different. Multivariable analysis identified lymphocyte count, serum creatinine level, being treated by immunosuppressive therapy other than anti-rejection drugs, and CMV infection in the year preceding the time PcP as independently associated with the occurrence of PcP. PcP was associated with an increased risk of subsequent chronic rejection (27% vs. 3%; p = 0.001) and return to dialysis (20% vs. 3%; p = 0.002). The occurrence of CMV infection and a low lymphocyte count could redefine the indications for continuation or reinitiation of anti-Pneumocystis prophylaxis.

Eliciting men's preferences for decision-making relative to treatments of localized prostate cancer with a good or moderate prognosis.

PURPOSE: In diseases where there is no real consensus regarding treatment modalities, promoting shared decision-making can contribute to improving safety and quality of care. This is the case in low- or intermediate-risk localized prostate cancer (PC) treatment. The aim of this study was to investigate the preferences guiding men's decisions regarding the characteristics of the treatment strategies for PC to help physicians adopt a more patient-centered approach. METHODS: This prospective multicenter study used a discrete choice experiment (DCE). The attributes and the modalities were identified from a qualitative study and a literature review. Relative preferences were estimated using a logistic regression model. Interaction terms (demographic, clinical and socio-economic characteristics) were added to the model to assess heterogeneity in preferences. RESULTS: 652 men were enrolled in the study and completed a questionnaire with 12 pairs of hypothetical therapeutic alternatives between which they had to choose. Men's choices were significantly negatively influenced by the risk of impotence and urinary incontinence, death, and the length and frequency of care. They preferred treatments with a rescue possibility in case of deterioration or recurrence and the use of innovative technology. Surprisingly, the possibility of undergoing prostate ablation negatively influenced their choice. The results also highlighted differences in trade-offs according to socio-economic level. CONCLUSION: This study confirmed the importance of considering patients' preferences in the decision-making process. It appears essential to better understand these preferences to allow physicians to improve communication and promote case-by-case decision-making.

Differential effect on mortality of the timing of initiation of renal replacement therapy according to the criteria used to diagnose acute kidney injury: an IDEAL-ICU substudy.

BACKGROUND: This substudy of the randomized IDEAL-ICU trial assessed whether the timing of renal replacement therapy (RRT) initiation has a differential effect on 90-day mortality, according to the criteria used to diagnose acute kidney injury (AKI), in patients with early-stage septic shock. METHODS: Three groups were considered according to the criterion defining AKI: creatinine elevation only (group 1), reduced urinary output only (group 2), creatinine elevation plus reduced urinary output (group 3). Primary outcome was 90-day all-cause death. Secondary endpoints were RRT-free days, RRT dependence and renal function at discharge. We assessed the interaction between RRT strategy (early vs. delayed) and group, and the association between RRT strategy and mortality in each group by logistic regression. RESULTS: Of 488 patients enrolled, 205 (42%) patients were in group 1, 174 (35%) in group 2, and 100 (20%) in group 3. The effect of RRT initiation strategy on 90-day mortality across groups showed significant heterogeneity (adjusted interaction p = 0.021). Mortality was 58% vs. 42% for early vs. late RRT initiation, respectively, in group 1 (p = 0.028); 57% vs. 67%, respectively, in group 2 (p = 0.18); and 58% vs. 55%, respectively, in group 3 (p = 0.79). There was no significant difference in secondary outcomes. CONCLUSION: The timing of RRT initiation has a differential impact on outcome according to AKI diagnostic criteria. In patients with elevated creatinine only, early RRT initiation was associated with significantly increased mortality. In patients with reduced urine output only, late RRT initiation was associated with a nonsignificant, 10% absolute increase in mortality.

Early detection of anastomotic leak with C-reactive protein increases the chances of anastomotic salvage.

AIM: Anastomotic leak results in increased morbidity and affects functional and oncological outcomes after colectomy. Measurement of C-reactive protein (CRP) allows early detection of anastomotic leaks. The aim of this study was to evaluate the benefit to the patient of earlier diagnosis and management of anastomotic leaks, namely avoiding takedown of the anastomosis. METHOD: Patients with an anastomotic fistula after elective colorectal surgery from 2010 to 2020 were included. Three periods were defined according to progressive adherence to the CRP protocol in our department. A comparison was made between the periods 'before' (2010-2013) and 'after' (2016-2020) in terms of morbidity, mortality, anastomotic salvage, days spent in hospital within the first postoperative month, timely adjuvant chemotherapy and anastomotic stenosis. RESULTS: Out of 2655 elective colorectal operations, 171 patients presented with an anastomotic leak and 123 patients were included in the study. In univariate analysis, patients in the 'after' group had fewer severe complications (Clavien-Dindo Grade III to IV, 66.7% vs. 56.9; p = 0.017); the difference did not reach significance regarding timely postoperative chemotherapy (p = 0.058) and anastomotic stenosis (p = 0.682). In both, univariate and multivariate analysis, the 'after' period increased the chances of preserving the anastomosis (OR = 2.37 [1.08-5.17]) and increased the number of days out of hospital (p = 0.0002). CONCLUSION: A CRP-based protocol for the screening of anastomotic leaks after colorectal surgery was related to increased anastomotic conservation, a decreased impact and severity of the leak and a shorter length of hospital stay.

Life expectancy and likelihood of surgery in multiple endocrine neoplasia type 1: AFCE and GTE cohort study.

BACKGROUND: The overall natural history, risk of death and surgical burden of patients with multiple endocrine neoplasia type 1 (MEN1) is not well known. METHODS: Patients with MEN1 from a nationwide cohort were included. The survival of patients with MEN1 was compared with that of the general population using simulated controls. The cumulative probabilities of MEN1-specific operations and postoperative mortality were assessed, and surgical sequences were analysed using sunburst charts and Venn diagrams. RESULTS: A total of 1386 patients with MEN1 were included. Life expectancy was significantly reduced in patients with MEN1 compared with simulated controls from the general population, with a lifetime difference of 15 years. Mutations affecting the JunD interaction domain had a significant negative impact on survival. Survival for patients with MEN1 compared with the general population improved over time. The probability of experiencing at least one specific MEN1 operation was above 95 per cent after 75 years, and most patients had surgery at least twice during their lifetime. Time to a 50 per cent risk of MEN1 surgery was 30.5 years for patients born after 1960, compared with 47.9 years for those born before 1960. Sex and mutations affecting the JunD interacting domain had no impact on time to first surgery. There was considerable heterogeneity in surgical sequences, with no specific clinical pathway. CONCLUSION: Life expectancy was significantly lower among patients with MEN1 compared with the general population, and further decreased in patients with mutations affecting the JunD interacting domain. Almost all patients underwent at least one MEN1-specific operation during their lifetime, but there was no standardized sequence of surgery.

Does underlying infertility in natural conception modify the epigenetic control of imprinted genes and transposable elements in newborns?

RESEARCH QUESTION: Does the epigenetic control of imprinted genes and transposable elements at birth differ according to time to conception in natural conception and after intrauterine insemination (IUI)? DESIGN: A total of 144 singletons were included in four groups: 50 natural pregnancies obtained within 6 months after stopping contraception (group 1); 34 natural pregnancies with infertility period between 6 and 12 months (group 2); 36 pregnancies with an infertility period of more than 12 months (group 3) and 24 pregnancies obtained after IUI (group 4). RESULTS: The placental DNA methylation levels of H19/IGF2 and KCNQ1OT1 were lower in groups 2, 3 and 4 than in group 1 (P = 0.025 in the overall comparison). The DNA methylation rate for LINE-1 was higher in placentas from group 2 than in group 1 (P = 0.022). In cord blood, DNA methylation levels were not significantly different between groups except for H19/IGF2 for which the DNA methylation levels were higher in group 2 than in group 1 (H19/IGF2-seq1 and seq2: P = 0.023 and P = 0.002, respectively). In placenta tissue, compared with group 1, relative expression for SNRPN and for LINE-1 was significantly higher in group 2 (P = 0.002 and P < 0.001, respectively). The relative expression of KCNQ1 in placenta was lower in group 4 than in group 1 (P = 0.013). In cord blood, compared with group 1, the relative expression for H19 was significantly higher in group 3 (P = 0.026), and the relative expression of LINE-1 was higher in groups 2 and 3 and in group 4 (P < 0.001). CONCLUSIONS: Infertility itself, and not only ART techniques, could contribute to potential epigenetic risks for children.

Analysis and quantification of female and male contributions to the first stages of embryonic kinetics: study from a time-lapse system.

PURPOSE: The few studies that examined the effect of male and/or female features on early embryo development, notably using the time-lapse system (TL), reported conflicting results. This can be explained by the small number of studies using an adapted model. METHODS: We used two original designs to study the female and male effects on embryo development: (1) based on embryos from donor oocytes (TL-DO), and (2) from donor sperm (TL-DS). Firstly, we analyzed the female and male similarities using an ad hoc intraclass correlation coefficient (ICC), then we completed the analysis with a multivariable model to assess the association between both male and female factors, and early embryo kinetics. A total of 572 mature oocytes (TL-DO: 293; TL-DS: 279), fertilized by intracytoplasmic sperm injection (ICSI) and incubated in a TL (Embryoscope®) were included from March 2013 to April 2019; 429 fertilized oocytes (TL-DO: 212; TL-DS: 217) were assessed. The timings of the first 48 h have been analyzed. RESULTS: The similarities in the timings thought to be related to the female component were significant: (ICC in both DO-DS designs respectively: tPB2: 9-18%; tPNa: 16-21%; tPNf: 40-26%; t2: 38-24%; t3: 15-20%; t4: 21-32%). Comparatively, those related to male were lower. Surprisingly after multivariable analyses, no intrinsic female factors were clearly identified. However, in TL-DO design, oligozoospermia was associated with a tendency to longer timings, notably for tPB2 (p = 0.026). CONCLUSION: This study quantifies the role of the oocyte in the first embryo cleavages, but without identified specific female factors. However, it also highlights that sperm may have an early embryonic effect.

Prévention au premier trimestre de la grossesse : perspective des professionnels.

INTRODUCTION: The environment and living conditions of parents during the "first 1000 days" period influence the short- and long-term health trajectories of children. Professionals following pregnancies play an important role in advising future parents to adopt health-promoting behaviors. It appeared necessary to describe the prevention messages transmitted by professionals early in pregnancy. OBJECTIVES: To identify the prevention messages systematically delivered during the first trimester of pregnancy and determine the degree of priority that professionals (midwives, obstetricians, general practitioners) of Bourgogne-Franche-Comté give to them. RESULTS: Prevention messages on infectious risk were addressed by 96.5% of respondents, and those on risk behaviors and addictions by 93.7%. Dietary balance and sports activities (78.5%), as well as risks in the daily life (47.1%) were less delivered. The messages that professionals declared to be delivered systematically to pregnant women during the first trimester were generally those that they considered to be priorities. There were some differences depending on the professional. Regarding information media, the majority of respondents did not use any. They agreed on the importance of a paper-based information medium and wished to be able to rely on a digital medium (62.6%). CONCLUSION: The co-construction of support that meets the needs of both women and professionals and that is validated by health authorities would contribute to better consideration and promotion of health-promoting behaviors by parents, by promoting empowerment of women and couples from the beginning of pregnancy.

Timing of Renal-Replacement Therapy in Patients with Acute Kidney Injury and Sepsis.

BACKGROUND: Acute kidney injury is the most frequent complication in patients with septic shock and is an independent risk factor for death. Although renal-replacement therapy is the standard of care for severe acute kidney injury, the ideal time for initiation remains controversial. METHODS: In a multicenter, randomized, controlled trial, we assigned patients with early-stage septic shock who had severe acute kidney injury at the failure stage of the risk, injury, failure, loss, and end-stage kidney disease (RIFLE) classification system but without life-threatening complications related to acute kidney injury to receive renal-replacement therapy either within 12 hours after documentation of failure-stage acute kidney injury (early strategy) or after a delay of 48 hours if renal recovery had not occurred (delayed strategy). The failure stage of the RIFLE classification system is characterized by a serum creatinine level 3 times the baseline level (or ≥4 mg per deciliter with a rapid increase of ≥0.5 mg per deciliter), urine output less than 0.3 ml per kilogram of body weight per hour for 24 hours or longer, or anuria for at least 12 hours. The primary outcome was death at 90 days. RESULTS: The trial was stopped early for futility after the second planned interim analysis. A total of 488 patients underwent randomization; there were no significant between-group differences in the characteristics at baseline. Among the 477 patients for whom follow-up data at 90 days were available, 58% of the patients in the early-strategy group (138 of 239 patients) and 54% in the delayed-strategy group (128 of 238 patients) had died (P=0.38). In the delayed-strategy group, 38% (93 patients) did not receive renal-replacement therapy. Criteria for emergency renal-replacement therapy were met in 17% of the patients in the delayed-strategy group (41 patients). CONCLUSIONS: Among patients with septic shock who had severe acute kidney injury, there was no significant difference in overall mortality at 90 days between patients who were assigned to an early strategy for the initiation of renal-replacement therapy and those who were assigned to a delayed strategy. (Funded by the French Ministry of Health; IDEAL-ICU ClinicalTrials.gov number, NCT01682590 .).

Are adipokines the missing link between obesity, immune response, and outcomes in severe COVID-19?

INTRODUCTION: Obesity is commonly reported in COVID-19 patients and is associated with poorer outcomes. It is suggested that leptin could be the missing link between obesity and severe COVID-19. Our study aimed to unravel the link between adipokines, COVID-19 status, immune response, and outcomes in severe pneumonia. METHODS: In this prospective observational single-center study, 63 immunocompetent patients with severe pneumonia (36 non-COVID-19 and 27 COVID-19) were enrolled, most required intensive care. Clinical and biological characteristics (glucose metabolism, plasma adipokines, and cytokine concentrations) and outcomes were compared. RESULTS: At similar baseline severity, COVID-19 patients required mechanical ventilation for significantly longer than non-COVID-19 patients (p = 0.0049). Plasma concentrations of leptin and adiponectin were respectively positively and negatively correlated with BMI and glucose metabolism (glycemia and insulinemia), but not significantly different between the two groups. Leptin levels were negatively correlated with IL-1ß and IL-6, but the adipokines were not correlated with most other inflammatory mediators, baseline severity (SOFA score), or the duration of mechanical ventilation. CONCLUSION: Adipokine levels were correlated with BMI but not with most inflammatory mediators, severity, or outcomes in severe pneumonia, regardless of the origin. The link between obesity, dysregulated immune response, and life-threatening COVID-19 requires further investigation. CLINICAL TRIAL: ClinicalTrials.gov: NCT03505281.

Impact of time-varying cumulative bevacizumab exposures on survival: re-analysis of data from randomized clinical trial in patients with metastatic colo-rectal cancer.

BACKGROUND: As cancer treatment, biotherapies can be as effective as chemotherapy while reducing the risk of secondary effects, so that they can be taken over longer periods than conventional chemotherapy. Thus, some trials aimed at assessing the benefit of maintaining biotherapies during chemotherapy-free intervals (CFI). For example, the recent PRODIGE9 trial assessed the effect of maintaining bevacizumab during CFI in metastatic colorectal cancer (mCRC) patients. However, its analysis was hindered by a small difference of exposure to the treatment between the randomized groups and by a large proportion of early drop outs, leading to a potentially unbalanced distribution of confounding factors among the trial completers. To address these limitations, we re-analyzed the PRODIGE9 data to assess the effects of different exposure metrics on all-cause mortality of patients with mCRC using methods originally developed for observational studies. METHODS: To account for the actual patterns of drug use by individual patients and for possible cumulative effects, we used five alternative time-varying exposure metrics: (i) cumulative dose, (ii) quantiles of the cumulative dose, (iii) standardized cumulative dose, (iv) Theoretical Blood Concentration (TBC), and (v) Weighted Cumulative Exposure (WCE). The last two metrics account for the timing of drug use. Treatment effects were estimated using adjusted Hazard Ratio from multivariable Cox proportional hazards models. RESULTS: After excluding 112 patients who died during the induction period, we analyzed data on 382 patients, among whom 320 (83.8%) died. All time-varying exposures improved substantially the model's fit to data, relative to using only the time-invariant randomization group. All exposures indicated a protective effect for higher cumulative bevacizumab doses. The best-fitting WCE and TBC models accounted for both the cumulative effects and the different impact of doses taken at different times. CONCLUSIONS: All time-varying analyses, regardless of the exposure metric used, consistently suggested protective effects of higher cumulative bevacizumab doses. However, the results may partly reflect the presence of a confusion bias. Complementing the main ITT analysis of maintenance trials with an analysis of potential cumulative effects of treatment actually taken can provide new insights, but the results must be interpreted with caution because they do not benefit from the randomization. TRIAL REGISTRATION: clinicaltrials.gov, NCT00952029 . Registered 8 August 2009.

Pancreatoduodenectomy for Neuroendocrine Tumors in Patients with Multiple Endocrine Neoplasia Type 1: An AFCE (Association Francophone de Chirurgie Endocrinienne) and GTE (Groupe d'étude des Tumeurs Endocrines) Study.

AIM: To assess postoperative complications and control of hormone secretions following pancreatoduodenectomy (PD) performed on multiple endocrine neoplasia type 1 (MEN1) patients with duodenopancreatic neuroendocrine tumors (DP-NETs). BACKGROUND: The use of PD to treat MEN1 remains controversial, and evaluating the right place of PD in MEN1 disease makes sense. METHODS: Thirty-one MEN1 patients from the Groupe d'étude des Tumeurs Endocrines MEN1 cohort who underwent PD for DP-NETs between 1971 and 2013 were included. Early and late postoperative complications, secretory control and overall survival were analyzed. RESULTS: Indication for surgery was: Zollinger-Ellison syndrome (n = 18; 58%), nonfunctioning tumor (n = 9; 29%), insulinoma (n = 2; 7%), VIPoma (n = 1; 3%) and glucagonoma (n = 1; 3%). Mean follow-up was 141 months (range 0-433). Pancreatic fistulas occurred in 5 patients (16.1%), distant metastases in 6 (mean onset of 43 months; range 13-110 months), postoperative diabetes mellitus in 7 (22%), and pancreatic exocrine insufficiency in 6 (19%). Five-year overall survival was 93.3% [CI 75.8-98.3] and ten-year overall survival was 89.1% [CI 69.6-96.4]. After a mean follow-up of 151 months (range 0-433), the biochemical cure rate for MEN-1 related gastrinomas was 61%. CONCLUSION: In MEN1 patients, pancreatoduodenectomy can be used to control hormone secretions (gastrin, glucagon, VIP) and to remove large NETs. PD was found to control gastrin secretions in about 60% of cases.

EPIDEMIOLOGY OF VITREOMACULAR INTERFACE ABNORMALITIES USING MACULAR SPECTRAL-DOMAIN OPTICAL COHERENCE TOMOGRAPHY IN AN ELDERLY POPULATION (THE MONTRACHET STUDY).

PURPOSE: The aim of this study was to investigate the prevalence of vitreomacular interface abnormalities (VMIAs) and to identify associated factors in an elderly population in Europe. METHODS: The MONTRACHET (Maculopathy Optic Nerve nuTRition neurovAsCular and HEarT diseases) Study is a population-based study, conducted in subjects older than 75 years. Vitreomacular adhesions, vitreomacular tractions, macular holes, epiretinal membranes, and macular cysts were assessed on spectral-domain optical coherence tomography examinations. The prevalence of VMIAs was estimated. We studied the association of demographic and clinical factors with VMIAs. RESULTS: The mean age of the participants was 82.3 (SD, 3.8) years, and 37.3% were men. The prevalence rates of VMIAs were vitreomacular adhesions (17.7%), vitreomacular tractions (1.4%), lamellar macular holes (1.0%), full-thickness macular holes (0.2%), macular pseudoholes (0.4%), epiretinal membranes (38.9%), and macular cysts (5.8%). In multivariate analysis, vitreomacular adhesions were positively associated with male sex (P < 0.001) and negatively associated with older age (P < 0.001) and cataract extraction (P < 0.001). Epiretinal membranes were positively associated with older age (P < 0.001) and cataract extraction (P < 0.001). CONCLUSION: The prevalence of VMIAs based on spectral-domain optical coherence tomography analysis was high in subjects older than 75 years.

Metastatic Potential and Survival of Duodenal and Pancreatic Tumors in Multiple Endocrine Neoplasia Type 1: A GTE and AFCE Cohort Study (Groupe d'étude des Tumeurs Endocrines and Association Francophone de Chirurgie Endocrinienne).

OBJECTIVE: To assess the distant metastatic potential of duodeno-pancreatic neuroendocrine tumors (DP-NETs) in patients with MEN1, according to functional status and size. SUMMARY BACKGROUND DATA: DP-NETs, with their numerous lesions and endocrine secretion-related symptoms, continue to be a medical challenge; unfortunately they can become aggressive tumors associated with distant metastasis, shortening survival. The survival of patients with large nonfunctional DP-NETs is known to be poor, but the overall contribution of DP-NETs to metastatic spread is poorly known. METHODS: The study population included patients with DP-NETs diagnosed after 1990 and followed in the MEN1 cohort of the Groupe d'étude des Tumeurs Endocrines (GTE). A multistate Markov piecewise constant intensities model was applied to separate the effects of prognostic factors on 1) metastasis, and 2) metastasis-free death or 3) death after appearance of metastases. RESULTS: Among the 603 patients included, 39 had metastasis at diagnosis of DP-NET, 50 developed metastases during follow-up, and 69 died. The Markov model showed that Zollinger-Ellison-related tumors (regardless of tumor size and thymic tumor pejorative impact), large tumors over 2 cm, and age over 40 years were independently associated with an increased risk of metastases. Men, patients over 40 years old and patients with tumors larger than 2 cm, also had an increased risk of death once metastasis appeared. CONCLUSIONS: DP-NETs of 2 cm in size or more, regardless of the associated secretion, should be removed to prevent metastasis and increase survival. Surgery for gastrinoma remains debatable.

The dysregulated innate immune response in severe COVID-19 pneumonia that could drive poorer outcome.

BACKGROUND: Although immune modulation is a promising therapeutic avenue in coronavirus disease 2019 (COVID-19), the most relevant targets remain to be found. COVID-19 has peculiar characteristics and outcomes, suggesting a unique immunopathogenesis. METHODS: Thirty-six immunocompetent non-COVID-19 and 27 COVID-19 patients with severe pneumonia were prospectively enrolled in a single center, most requiring intensive care. Clinical and biological characteristics (including T cell phenotype and function and plasma concentrations of 30 cytokines) and outcomes were compared. RESULTS: At similar baseline respiratory severity, COVID-19 patients required mechanical ventilation for significantly longer than non-COVID-19 patients (15 [7-22] vs. 4 (0-15) days; p = 0.0049). COVID-19 patients had lower levels of most classical inflammatory cytokines (G-CSF, CCL20, IL-1ß, IL-2, IL-6, IL-8, IL-15, TNF-α, TGF-ß), but higher plasma concentrations of CXCL10, GM-CSF and CCL5, compared to non-COVID-19 patients. COVID-19 patients displayed similar T-cell exhaustion to non-COVID-19 patients, but with a more unbalanced inflammatory/anti-inflammatory cytokine response (IL-6/IL-10 and TNF-α/IL-10 ratios). Principal component analysis identified two main patterns, with a clear distinction between non-COVID-19 and COVID-19 patients. Multivariate regression analysis confirmed that GM-CSF, CXCL10 and IL-10 levels were independently associated with the duration of mechanical ventilation. CONCLUSION: We identified a unique cytokine response, with higher plasma GM-CSF and CXCL10 in COVID-19 patients that were independently associated with the longer duration of mechanical ventilation. These cytokines could represent the dysregulated immune response in severe COVID-19, as well as promising therapeutic targets. ClinicalTrials.gov: NCT03505281.

CXCL10 could drive longer duration of mechanical ventilation during COVID-19 ARDS.

BACKGROUND: COVID-19-related ARDS has unique features when compared with ARDS from other origins, suggesting a distinctive inflammatory pathogenesis. Data regarding the host response within the lung are sparse. The objective is to compare alveolar and systemic inflammation response patterns, mitochondrial alarmin release, and outcomes according to ARDS etiology (i.e., COVID-19 vs. non-COVID-19). METHODS: Bronchoalveolar lavage fluid and plasma were obtained from 7 control, 7 non-COVID-19 ARDS, and 14 COVID-19 ARDS patients. Clinical data, plasma, and epithelial lining fluid (ELF) concentrations of 45 inflammatory mediators and cell-free mitochondrial DNA were measured and compared. RESULTS: COVID-19 ARDS patients required mechanical ventilation (MV) for significantly longer, even after adjustment for potential confounders. There was a trend toward higher concentrations of plasma CCL5, CXCL2, CXCL10, CD40 ligand, IL-10, and GM-CSF, and ELF concentrations of CXCL1, CXCL10, granzyme B, TRAIL, and EGF in the COVID-19 ARDS group compared with the non-COVID-19 ARDS group. Plasma and ELF CXCL10 concentrations were independently associated with the number of ventilator-free days, without correlation between ELF CXCL-10 and viral load. Mitochondrial DNA plasma and ELF concentrations were elevated in all ARDS patients, with no differences between the two groups. ELF concentrations of mitochondrial DNA were correlated with alveolar cell counts, as well as IL-8 and IL-1ß concentrations. CONCLUSION: CXCL10 could be one key mediator involved in the dysregulated immune response. It should be evaluated as a candidate biomarker that may predict the duration of MV in COVID-19 ARDS patients. Targeting the CXCL10-CXCR3 axis could also be considered as a new therapeutic approach. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03955887.

Impact of Cytomegalovirus Infection on the Outcome of Patients With Cirrhosis: A Preliminary Study.

GOALS: The aims of this study were to evaluate whether cytomegalovirus (CMV) infection is associated with hepatocellular carcinoma (HCC) and liver-related mortality in cirrhotic patients. BACKGROUND: In cirrhotic patients, the determinants of HCC and liver-related death are imperfectly known. CMV infection, by its prooncogenic and proinflammatory properties, may favor both the development of HCC and deleterious systemic inflammation. STUDY: In the 1178 patients included between June 2008 and December 2012 in the CIrrhose et Risque de Carcinome Hépatocellulaire dans le grand-Est (CIRCE) study, a French multicenter case-control study designed to identify risk factors of HCC among cirrhotic patients, we identified 432 patients with interpretable CMV serological status at baseline. They included 159 cases with HCC and 273 controls. We measured factors associated with HCC at baseline and subsequent HCC in controls, and predictors of overall and liver-related death in the whole study population. RESULTS: During a median follow-up of 31 months, 25 cases of HCC developed in controls, and 209 deaths (163 liver-related) were recorded. There were 247 (57.2%) CMV-seropositive patients. CMV seropositivity was not associated with more frequent HCC at baseline or during follow-up, but among CMV-positive patients with HCC, the proportion of multinodular, infiltrative, or metastatic tumors at diagnosis was higher (73.8% vs. 57.3%; P=0.029), inducing higher mortality (74% vs. 52% at 3 years; P=0.004). By Cox-regression adjusted for age, gender, Model for End-stage Liver Disease (MELD) score, HCC at baseline, and diabetes, CMV seropositivity independently predicted all-cause (hazard ratio=1.45; 95% confidence interval, 1.08-1.94; P=0.013) and liver-related mortality (hazard ratio=1.56; 95% confidence interval, 1.04-2.30; P=0.031). CONCLUSIONS: In this preliminary study, CMV-seropositive cirrhotic patients were at higher risk of liver-related death caused by more aggressive HCCs or severe cirrhosis complications. These findings warrant confirmation.