French early nationwide idecabtagene vicleucel chimeric antigen receptor T-cell therapy experience in patients with relapsed/refractory multiple myeloma (FENIX): A real-world IFM study from the DESCAR-T registry.

Idecabtagene vicleucel (ide-cel), a chimeric antigen receptor T-cell therapy targeting B-cell maturation antigen (BCMA), received early access program (EAP) authorization in France in April 2021 for relapsed/refractory multiple myeloma (RRMM). We conducted a real-world registry-based multicentre observational study in 11 French hospitals to evaluate ide-cel outcomes. Data from 176 RRMM patients who underwent apheresis between June 2021 and November 2022 were collected from the French national DESCAR-T registry. Of these, 159 patients (90%) received ide-cel. Cytokine release syndrome occurred in 90% with 2% grade ≥3, and neurotoxicity occurred in 12% with 3% grade ≥3. Over the first 6 months, the best overall response and ≥complete response rates were 88% and 47% respectively. The median progression-free survival (PFS) from the ide-cel infusion was 12.5 months, the median overall survival (OS) was 20.8 months and the estimated OS rate at 12 months was 73.3%. Patients with extra-medullary disease (EMD) had impaired PFS (6.2 months vs. 14.8 months). On multivariable analysis, EMD and previous exposure to BCMA-targeted immunoconjugate or T-cell-redirecting GPRC5D bispecific antibody were associated with inferior PFS. Our study supports ide-cel's feasibility, safety and efficacy in real-life settings, emphasizing the importance of screening for EMD and considering prior treatments to optimize patient selection.

[TMPRSS2-Erg/AR-V7: Prognostic value of tests in urine and biopsy rince material in prostate cancer]. / TMPRSS2-Erg/AR-V7 : valeur diagnostique des tests urinaires et sur liquides biopsiques dans le cancer prostatique.

INTRODUCTION: Nowadays, diagnostic biomarker research is oriented on a genomic characterisation of prostate cancer (PCa). This study evaluated diagnostic values of TMPRSS2-Erg fusion transcripts expression (TE) and androgen receptor variant 7 (AR-V7) on urine (tU) and biopsic rince material (tLRB) samples. MATERIALS AND METHODS: TE and AR-V7 have been tested by RT-PCR and RT-qPCR on urine and biopsies' rince liquid on 372 patients referred for prostate biopsies. RESULTS: Two hundred thirty-three patients (62%) were diagnosed with PCa. tU.AR-V7 was positive for 15 healthy patients (28%) and 30 patients diagnosed with PCa (37%). tLRB.AR-V7 was positive for 66 patients (42%) diagnosed with PCa. Concerning TE for patients diagnosed with PCa, tU was positive for 59 patients (54%) and tLRB for 132 (55%). TE and TE/AR-V7 combination were significantly associated with PCa (P<0.001), as tLRB.AR-V7 (P<0.001). Sensitivity and specificity for TE/AR-V7 combination for PCa were respectively: tU.TE/AR-V7 67% and 70%, tLRB.TE/AR-V7 68.8% and 71%, and, tUtLRB.TE/AR-V7 83% and 60%. There was no benefit for AR-V7 and TE association versus TE alone when comparing AUC. CONCLUSION: AR-V7 is not specific of PCa because of detection on healthy patients. This study did not managed to show a sufficient diagnostic value for TE/AR-V7 combination on urine and biospic rince material tests. LEVEL OF EVIDENCE: 3.

Diagnostic accuracy of des-gamma-carboxy prothrombin for hepatocellular carcinoma in a French cohort using the Lumipulse® G600 analyzer.

The increasing incidence of hepatocellular carcinoma (HCC) in Western countries requests reliable tumour markers for preclinical diagnosis. We evaluated the diagnostic accuracy of des-gamma-carboxy prothrombin (DCP), in comparison with alpha-fetoprotein (AFP) in a French cohort using a new analyser. One hundred and sixty-two patients with virus-related cirrhosis (46 HCC patients and 116 controls) were recruited in this retrospective proof-of-concept study. DCP was measured on new Lumipulse® G600 analyzer and AFP on usual Cobas e602 analyzer in serum samples that were collected at the time of HCC diagnosis for HCC patients or during follow-up for controls. DCP and AFP levels were higher in HCC patients. The area under receiver operating characteristic curve was larger for DCP than for AFP (0.89 vs 0.77, P=.03). At the cut-off value of 128 mAU/mL, sensitivity and specificity for DCP were 74% and 92%. At the cut-off value of 20 µg/L, sensitivity and specificity for AFP were 63% and 82%. NRI>0 for the association of "AFP+DCP" were 101%, P<.0001, and 23%, P=.03, compared to "AFP" or "DCP" alone, respectively. We conclude that DCP outperformed AFP for the detection of HCC.

NUP98 is rearranged in 3.8% of pediatric AML forming a clinical and molecular homogenous group with a poor prognosis.

Pediatric acute myeloid leukemia (AML) is a rare disease whose prognosis is highly variable according to factors such as chromosomal abnormalities. Recurrent genomic rearrangements are detected in half of pediatric AML by karyotype. NUcleoPorin 98 (NUP98) gene is rearranged with 31 different fusion partner genes. These rearrangements are frequently undetected by conventional cytogenetics, as the NUP98 gene is located at the end of the chromosome 11 short arm (11p15). By screening a series of 574 pediatric AML, we detected a NUP98 rearrangement in 22 cases (3.8%), a frequency similar to CBFB-MYH11 fusion gene (4.0%). The most frequent NUP98 fusion gene partner is NSD1. These cases are homogeneous regarding their biological and clinical characteristics, and associated with bad prognosis only improved by bone marrow transplantation. We detailed the biological characteristics of these AML by exome sequencing which demonstrated few recurrent mutations (FLT3 ITD, WT1, CEBPA, NBPF14, BCR and ODF1). The analysis of the clonal structure in these cases suggests that the mutation order in the NUP98-rearranged pediatric AML begins with the NUP98 rearrangement leading to epigenetic dysregulations then followed by mutations of critical hematopoietic transcription factors and finally, activation of the FLT3 signaling pathway.

Increased risk of alteration of nutritional status in hospitalized elderly patients with advanced cancer.

Malnutrition is common in patients with advanced cancer and is associated with worse prognosis. The aim of this study was to follow-up the nutritional status of elderly patients with advanced cancer in comparison with that of younger ones, in the course of hospitalization. Eighty-eight (44 males and 44 females) patients with advanced cancer entered the study. Two groups were defined according to age : superior 70 y (n = 45) and < 70 y (n = 43). Nutritional status by means of anthropometric variables and daily intake were assessed on Day 0, Day 30 and Day 60. A blood sample was collected on Day 0 for determination of serum proteins. The two groups of patients did not differ in terms of anthropometry and biological variables on admission to our department ; only bicipital skinfold thickness and energy intake were lower in the elderly patients. After one month hospitalization, tricipital skinfold thickness and fat mass decreased in these patients. After two months, mid-arm circumference also decreased. Unlike the older group, the younger patients increased their daily energy and protein intakes. During hospitalization, older persons with advanced cancer cannot improve their energy intake and therefore, are at particular risk of aggravating their nutritional status.

Interrelations of immunological parameters, nutrition, and healthcare-associated infections: prospective study in elderly in-patients.

BACKGROUND & AIMS: Healthcare-associated infections [HAI] are common in elderly individuals and may be related to both nutritional deficiencies and immunosenescence. Here, we assessed whether overall malnutrition and/or specific nutrient deficiencies were associated with HAI via alterations in immune parameters. METHODS: Prospective observational cohort study in patients aged ≥ 70 years admitted to the geriatric rehabilitation unit of a teaching hospital in France between July 2006 and November 2008. Clinical and laboratory parameters reflecting nutritional status and immune function were collected at baseline. Flow cytometry was used to assess blood lymphocyte subsets including the naive CD4 T-cell count, naive and memory CD8 T-cell counts, effector CD8 T-cell count, and CD4/CD8 ratio. Patients were monitored for HAI for 3 months or until discharge from the geriatric unit or death. RESULTS: Of 252 consecutive in-patients aged ≥ 70 years [mean age, 85 ± 6.2 years], 181 [72%] met French National Authority for Health criteria for malnutrition and 97 [38%] experienced one or more HAI. Patients who subsequently experienced HAI had significantly lower baseline values for energy intake [odds ratio (OR), 0.76; 95% confidence interval (95%CI), 0.59-0.99], serum albumin [OR, 0.43; 95%CI, 0.32-0.58], serum zinc [OR, 0.77; 95%CI, 0.62-0.97], selenium [OR, 0.76; 95%CI, 0.61-0.95], and vitamin C [OR, 0.71; 95%CI, 0.54-0.93]. Associations linking these five variables to HAI were not significantly changed by adjusting for flow cytometry T-cell subset values. CONCLUSION: Our results suggest a direct effect of nutritional parameters on HAI rather than an indirect effect mediated by immune parameters.

Increased serum nitrate concentration in cardiac transplant patients. A marker for acute allograft cellular rejection.

The purpose of the present study was to investigate whether nitrate serum level, reflecting total body production of nitric oxide in vivo, could serve as a noninvasive marker for acute human cardiac rejection. Serum nitrate concentration was determined by an enzymatic method. During routine right ventricular endomyocardial biopsies in 59 recipients, 145 tissue samples were obtained. Two groups of biopsy specimen were considered on the basis of posttransplant delay: group 1, < or = 90 days (n=47; 12-90 days); and group 2, >90 days (n=98; 3-81 months). All patients had normal ventricular systolic function on the day of biopsy and none had evidence of infection. Rejection grade correlated closely with serum nitrate concentration (P<0.001). In both groups, nitrate serum concentrations differed significantly (P<0.001) among cases without rejection, those with mild ongoing rejection (grade 1A/1B), and those with focal or diffuse aggressive infiltrates (grade 2 or higher). A cutoff value of 20 micromol/L, was determined that was positively predictive for grade 2 or higher rejection in 62% cases of early episodes of rejection and in 68% cases of late rejection. Conversely, a serum nitrate level below 20 micromol/L was negatively predictive in 97% and 94% of early and late cases, respectively. We conclude that the acute rejection process of the human transplanted heart is accompanied by a significant increase in serum nitrate level, reflecting increased nitric oxide production during the immune response. Because of its high negative predictive value, irrespective of the posttransplantation delay, nitrate serum determination may have clinical utility in the noninvasive monitoring of the cardiac transplant patient and could also add important information to endomyocardial biopsy analysis for treatment decision making.

A macrophage-derived factor induced by alpha 1-acid glycoprotein that inhibits IL-1 comitogenic activity.

After exposure to a concanavalin A (Con A)-unreactive variant of alpha 1-acid glycoprotein (AGP), macrophages released an inhibitor of interleukin-1 (IL-1) proliferative activity in the thymocyte comitogenic assay. This effect was observed with AGP concentrations above 100 micrograms/ml in the macrophage supernatant and would appear to be mediated by the macrophages, since native AGP had no activity on thymocyte proliferation. Preliminary physicochemical characterization showed that the factor was partially resistant to heating, undialyzable, and eluted with an apparent molecular mass of 50-100 kDa when subjected to Sephacryl S-200 chromatography. Murine IL-1 and human (h) recombinant (r) IL-1 were affected by this factor to the same extent. IL-1 and IL-2 co-induced thymocyte proliferation, which is mitogen-independent, was also inhibited, whereas hrIL-2 activity was not suppressed when assayed in thymocytes with PHA at a submitogenic concentration or in CTLL cells. The factor did not interfere with TNF alpha or hrIL-6 activity when tested against their specific cell line. These data indicate that the inhibitor may act specifically against IL-1 activity and further elucidate the possible role of AGP in the modulation of IL-1 activity via the secretion of an inhibitor.

Reversible posterior leukoencephalopathy syndrome in hepatitis C virus-positive long-term hemodialysis patients.

Chronic hepatitis C virus (HCV) infection is quite prevalent in long-term hemodialysis (HD) patients. Patients who are candidates for renal transplantation might be treated, before grafting, with interferon-alpha (IFN-alpha). Among 39 HCV-positive long-term HD patients treated with IFN-alpha, we observed three cases of reversible posterior leukoencephalopathy syndrome (PLES). PLES included headaches in three patients, confusion in three patients, cortical blindness in two patients, visual hallucinations in one patient, seizures in three patients, and respiratory distress in one patient in a context of fluid overload and severe hypertension in all cases. The three patients were receiving IFN-alpha and recombinant erythropoietin therapies simultaneously for de novo anemia. Contrast-enhanced computed tomography scan or magnetic resonance imaging showed low-density areas in the occipital lobes (in three patients), frontal lobes (in one patient), and temporal lobes (in one patient). After withdrawal of IFN-alpha and recombinant erythropoietin therapies, hemodiafiltration, and symptomatic treatment of seizures and hypertension, PLES was reversible within 1 week in one patient, 10 days in one patient, and 2 months in the third patient. Our case reports show the occurrence of reversible PLES in HCV-positive long-term HD patients treated with IFN-alpha. Physicians caring for HCV-positive long-term HD patients treated with IFN-alpha need to be particularly cautious when these patients receive simultaneously recombinant erythropoietin and when IFN-alpha therapy induces a weight loss, which indicates a reduction in dry weight.

Short-term changes in energy metabolism after 1 month of a regular oral diet in severely malnourished cirrhotic patients.

Malnutrition in patients with liver cirrhosis is currently associated with abnormal fuel metabolism. The aim of this study was to evaluate changes in energy production and substrate oxidation rates in a group of 26 nonanorectic severely malnourished cirrhotic patients in stable clinical condition after 1 month of an oral diet. Child-Pugh score, nutritional status, energy expenditure, rates of nutrient oxidation, and plasma levels of intermediary metabolites in the postabsorptive phase were assessed before and after 1 month of oral nutrition. Upon entry onto the study, caloric and protein intakes were 40.1 +/- 2.0 kcal/kg and 1.44 +/- 0.8 g/kg, respectively. The Child-Pugh score did not change during the study, whereas nutritional status improved as shown by increased muscular midarm circumference, ([MMAC] P < .02), height-creatinine index (P < .05), triceps skinfold thickness ([TST] P < .01), and fat mass (P < .001). Inflammatory state improved during the study, as shown by the decrease of C-reactive protein ([CRP] P < .01) and orosomucoid (P < .001). The ratio of caloric intake to resting energy expenditure (REE) increased (1.53 +/- 0.06 v 1.66 +/- 0.07, P < .05), as well as the rate of glucose oxidation ([Gox] 73.6 +/- 9.9 v 128.1 +/- 10.3 mg/min, P < .001) and urine nitrogen excretion (6.69 +/- 0.47 v 7.96 +/- 0.48 g/d, P < .02). On the other hand, the rate of lipid oxidation (Lox) decreased (67.3 +/- 3.9 v 47.3 +/- 4.9 mg/min, P < .001) and was correlated with the decrease of free fatty acid (FFA) levels (P < .05).(ABSTRACT TRUNCATED AT 250 WORDS)

The thermogenic and metabolic effects of food in liver cirrhosis: consequences on the storage of nutrients and the hormonal counterregulatory response.

The thermogenic effect of food and the rates of oxidation and storage of nutrients were evaluated by indirect calorimetry in 10 cirrhotic patients and seven normal controls for a 6-hour period, after they had consumed a standard meal supplying 15 kcal/kg body weight with 15%, 30%, and 55% protein, fat, and carbohydrate calories, respectively. Although the thermogenic response to food was not significantly lower in patients than in controls (51.6 +/- 13.5 v 72.2 +/- 8.8 kcal/6 h), patients exhibited a delayed and blunted increment of energy expenditure after the meal intake (P less than .025). The greater part of the glucose load was oxidized in patients (70.2 +/- 3.9% v 50.4 +/- 3.9% in controls; P less than .01), suggesting a defective glucose storage as glycogen. This result could be related to insulin resistance, which was evidenced by a large increase in glucose and insulin levels after the meal intake in patients (P +/- .001). Conversely, lipid oxidation was sharply reduced and de novo lipogenesis occurred in patients, so that the rate of lipid storage was increased. The profiles of circulating levels of catecholamines, thyroid hormones (free thyroxine [FT4] and triiodothyronine [T3]), and glucagon were assayed during the test. Norepinephrine and glucagon levels remained higher in patients throughout the test (P less than .001), whereas thyroid hormones stayed in the same range in the two groups. After an initial increase, glucose levels decreased sharply, inducing an activation of counterregulatory hormones, glucagon, and notably, epinephrine, for which the increment was correlated with the decrease of glucose (r = -.917; P less than .001).(ABSTRACT TRUNCATED AT 250 WORDS)

Enzyme electrophoresis combined with serogrouping for improved differentiation of Clostridium difficile strains.

We used enzyme electrophoresis to study a set of epidemiologically related and unrelated isolates of Clostridium difficile. The 53 strains belonged to the most frequent serogroups (A1, C, G, H and K). Nine electrophoretic profiles were defined on the basis of five enzymes, and two were characteristic of a single strain. Each serogroup was resolved into two or three different enzyme patterns. By combining the two methods we were able to resolve the strains into 12 types. There was an excellent correlation between enzyme electrophoresis and serogrouping data. This method may be of use in investigating nosocomial transmission.

Analysis of nitrite and nitrate in biological fluids by capillary electrophoresis.

OBJECTIVES: We report a method for determining nitrite and nitrate in biological fluids by capillary electrophoresis. METHODS: A Waters capillary electrophoresis system was used with a filter for detection at 214 nm. After dilution with distilled water, the sample was loaded hydrostatically onto a 60 cm x 100 microm capillary and electrophoresed at 15 kV in 15 mmol/L sulfate buffer, pH 8.0, containing 2.5% electroosmotic flow modifier. RESULTS: The retention times for nitrite and nitrate were 3.9 +/- 0.8 and 4.0 +/- 0.8 min, respectively. The detection limit was 10 micromol/L for serum nitrate. The recovery was 93-115% for nitrite and 92-106% for nitrate. The within-day and between-day coefficients of variation were lower than 3.3% and 5.0%, respectively, for two pools with normal (28 micromol/L) and high (87 micromol/L) nitrate concentration. A comparison with the nitrate reductase method gave a correlation coefficient of 0.982. CONCLUSION: Capillary electrophoresis provides many advantages, namely low cost, small sample and buffer requirements, rapidity, which makes its use particularly suitable for clinical laboratories.

Serum and tissue nitrate levels in murine visceral leishmaniasis correlate with parasite load but not with host protection.

Nitrate levels were measured in serum and in organs from Lshs BALB/c and Lshr C3H/HeN mice during the acute phase (30 d) of infection by Leishmania donovani strain LV9. Serum nitrate levels increased rapidly in BALB/c mice from a baseline level (17 +/- 4 mumol/L) to a plateau (504 +/- 129 mumol/L) at 24 d and correlated with parasite loads in the liver (r = 0.817, P < 0.01) and in the spleen (r = 0.854, P < 0.001). Liver and spleen nitrate contents were enhanced 2.7-fold and 22.8-fold, respectively, with respect to uninfected controls (2692 +/- 249 vs. 992 +/- 231 nmol, P < 0.02 and 20 +/- 1 vs. 456 +/- 43 nmol, P < 0.02). In contrast, serum nitrate increased to a lesser extent in C3H/HeN mice, from 31 +/- 5 mumol/L to 86 +/- 5 mumol/L at 20 d. Liver nitrate content did not differ significantly between infected and control mice (1093 +/- 83 vs. 867 +/- 104 nmol), whereas the former had a higher spleen nitrate content (145 +/- 22 vs. 40 +/- 2 nmol, P < 0.02). Our findings indicate that production of NO by the susceptible BALB/c strain exceeded that of the resistant C3H/HeN strain during the acute stage of infection by L. donovani. Tissue NO overproduction in organs infected by L. donovani was related to the progression of parasitic disease and contributed to high nitrate serum levels. It would be very interesting to extend this investigation to human disease with the aim of evaluating serum nitrate as a marker of parasite load in the follow-up of patients suffering from visceral leishmaniasis.

Serum levels of insulin-like growth factor-1 in the three months following surgery for a hip fracture in elderly: relationship with nutritional status and inflammatory reaction.

BACKGROUND AND AIMS: Serum IGF-1 level declines with advancing age and is a reliable index of protein-energy undernutrition in elderly patients in a metabolically stable condition. We have examined the value of IGF-1 as an indicator of malnutrition in elderly patients during recovery within 1 month after surgery for a hip fracture and we have studied the relationship between changes in IGF-1 levels, nutritional status and inflammatory reaction during 2 month follow up. STUDY DESIGN: Forty elderly patients (mean age 84.0+/-1.9) were nutritionally assessed upon admission to our rehabilitation unit (D0) then monthly (D30-D60) by measurement of anthropometric and biological parameters. Two groups of patients were defined on the basis of mid-arm circumference (MAC) and tricipital skinfold thickness (TST) measurement at D0: group 1, undernourished (n=13) and group 2, normally nourished (n=27). Changes in anthropometric and biological parameters during the study were compared between these two groups of patients. RESULTS: IGF-1 level was significantly lower in group 1 (79.5+/-9.1 vs 108+/-8.6 ng/ml, P<0.05) while usual serum protein levels were in the same range in the two groups. Orosomucoid level significantly decreased during 2 month follow-up in group 2 (P<0.01), CRP level decreased but not significantly. TST and MAC decreased in group 2 (respectively P<0.02 and P<0.05) while anthropometric parameters tended to slightly increase in group 1 in relation with an increase in caloric intake (P<0.05). IGF-1 level increased significantly during the study in group 2 (P<0.05) and was significantly lower in patients with complications occurring between D0 and D30 in comparison with patients without complications (respectively P<0.05 at D0, P<0.02 at D30). IGF-1 level correlated with body mass index, MAC, TST, muscle midarm circumference, albumin and transthyretin levels. Changes in IGF-1 levels positively correlated with those in transthyretin levels and negatively with those in orosomucoid levels. CONCLUSION: IGF-1 level seems a reliable index of protein-energy under-nutrition in elderly patients in the recovery period after surgery for a hip fracture. This marker is influenced by the inflammatory reaction. Decline of inflammatory reaction, rather than change in nutritional status, is responsible for the variation in IGF-1 level during a 2 month follow-up.

Value of body mass index in the detection of severe malnutrition: influence of the pathology and changes in anthropometric parameters.

BACKGROUND & AIMS: We have estimated the prevalence of severe malnutrition in groups of patients hospitalized for different medical causes and assessed the sensitivity of BMI in the diagnosis of severe malnutrition. DESIGN: A prospective study enrolled 1052 patients: 396 patients with liver cirrhosis including 165 non-ascitic patients (NAP), 124 patients with mild ascites (MAP), 107 patients with tense ascites (TAP), 251 patients after cardiac surgery (SCP), 81 patients with cardiac diseases (MCP), 85 patients with stroke (SP), 36 patients with degenerative neurological diseases (DNP), 68 patients after surgery of a hip fracture (HFP), 91 patients with palliative care for cancer (CP) and 44 elderly patients with medical affections (EP). BMI, mid-arm muscular circumference (MAMC) and triceps skinfold thickness (TST) were measured within 48 h after admission. Patients with MAMC and TST below the 5th percentile of a reference population when aged < or = 74 or the 10th percentile when aged > or = 75 were defined as severely malnourished. Sensitivity of BMI < 20 to detect malnutrition was assessed. RESULTS: The prevalence of severe malnutrition was the highest in TAP (39.1%) HFP (25.6%) and MAP (24.3%) and the lowest in SCP (4%), SP (4.8%), DNP (5.7%) and MCP (7.4%) (P < 10(-4)). In multivariate analysis, low TST was associated with female gender (P < 10(-4)) mild and tense ascites (P = 0.038, P = 0.0004), low MAMC with male gender (P < 10(-4)), low BMI with female gender (P = 0.0082), hip fracture (P = 0.0407) and cancer (P = 0.0059). The sensitivity of BMI to detect severe malnutrition was the highest in HFP, CP and EP (100%, 80% and 100% respectively) and the lowest in TAP, MCP and SP (40%, 33.3% and 50% respectively). After exclusion of TAP, sensitivity of BMI to detect malnutrition correlated significantly with the coefficient of correlation between MAMC and TST observed in each group (r = 0.821, P = 0.0066). CONCLUSION: Ascitic cirrhotic patients and elderly patients after surgery of hip fracture had the highest prevalence of severe malnutrition. BMI had the highest sensitivity when both TST and MAMC were damaged to the same extent. BMI < 20 has a high sensitivity in the diagnosis of severe malnutrition in elderly and cancer patients but not in cirrhotic patients with tense ascites, cardiovascular and neurological patients.

Intestinal permeability in liver cirrhosis: relationship with severe septic complications.

OBJECTIVES: Patients with liver cirrhosis are at high risk of severe septic complications such as spontaneous bacterial peritonitis (SBP) and bacteraemia. The aims of this study were to assess intestinal permeability in patients with liver cirrhosis and to search for a relationship between an impaired intestinal permeability and the occurrence of severe septic complications. METHODS: Intestinal permeability was assessed in a group of 80 cirrhotic patients (Child A, n = 13; Child B, n = 26; Child C, n = 41) and 28 healthy control subjects. A severe septic complication (bacteraemia and/or SBP) occurred in 16 patients, within 10 days before (n = 8 cases) or after (n = 8 cases) the test was performed. Lactulose (LAC) 10 g was given orally together with mannitol (MAN) 5 g, and urinary excretion rates were determined. RESULTS: Urinary mannitol excretion (MAN%) was lower while the LAC/MAN ratio was higher in patients than in control subjects (P < 0.001); these abnormalities were more marked in Child C patients (Child C patients vs control subjects: MAN%, 8.20 +/- 0.79 vs 14.59 +/- 0.58, P < 0.001; LAC/MAN, 0.066 +/- 0.026 vs 0.017 +/- 0.001, P < 0.02). When compared with non-infected patients, septic patients had a lower MAN% and an increased LAC/ MAN ratio (5.45 +/- 1.12 vs 9.83 +/- 0.87, P < 0.02; 0.130 +/- 0.063 vs 0.029 +/- 0.005, P < 0.02). CONCLUSION: Although the main mechanism involved in the decrease in MAN% is likely a reduction in area of the intestinal absorptive surface, these results argue in favour of an increased intestinal permeability in liver cirrhosis, especially in patients with severe infectious complications. The impairment of intestinal function barrier may contribute to severe septic complications in these patients.

Postprandial de novo lipogenesis in alcoholic liver cirrhosis: relationship with fuel homeostasis and nutritional status.

The prevalence and nutritional consequences of postprandial de novo lipogenesis were evaluated in 24 stable alcoholic cirrhotic patients. Energy expenditure and the rates of nutrient oxidation were assessed by indirect calorimetry after an overnight fast and 2 h after a standard meal supplying 15 kcal/kg (63 kJ/kg) of body weight. Postprandially, net lipogenesis occurred in 16 patients (group L+) as shown by a respiratory quotient clearly above 1.00 (P < 0.01). The rate of lipid oxidation remained positive in 8 patients (group L-). The main mechanism involved in this metabolic pathway appeared to be a sharp postprandial hyperinsulinaemia. When compared to group L+, patient group L- showed an impaired thermic effect of food (P < 0.05), a lower rate of glucose oxidation (P < 0.05) and a mild hyperketonaemia (P < 0.05) at fasting levels. Muscular and fat masses were lower (respectively P < 0.05 and P = 0.05) and the severity of the disease as assessed by the Child-Pugh classification was more pronounced in this group (P < 0.02). The occurrence of postprandial lipogenesis in stable cirrhotic patients is related to better nutritional status. Such a metabolic pathway may explain the nutritional heterogeneity of cirrhotics and is likely to have an effect on the benefits of refeeding.

Serum leptin levels in alcoholic liver cirrhosis: relationship with gender, nutritional status, liver function and energy metabolism.

OBJECTIVE: To determine serum leptin levels in alcoholic liver cirrhosis and the relationship with gender, nutritional status, liver function, energy metabolism, inflammatory state and refeeding. SUBJECTS: Thirty-seven hospitalized alcoholic cirrhotic patients (M/F: 24/13), 27 hospitalized patients at risk of malnutrition but with normal liver function (M/F: 15/12) as control patients, and 31 healthy control subjects (M/F: 17/14) participated. DESIGN: Liver function was assessed from Child-Pugh classification; anthropometric parameters and resting energy expenditure (REE) were measured; caloric intake was evaluated over 5 days; and serum leptin and insulin were assayed. The same protocol was performed after 1 month refeeding in 22 patients. Healthy subjects were studied as controls for anthropometric parameters and serum leptin levels. RESULTS: Serum leptin levels were higher in male cirrhotic patients than in the other two male groups (P=0.0079) and in the same range in the female groups. They were higher in female than in male subjects in the three groups. In female cirrhotic patients, logarithmically transformed serum leptin levels correlated significantly with fat mass (P=0.0043), insulin levels (P=0.0072), REE (P=0.0133), bilirubin levels (P<0.0001), prothrombin time (P=0.0003) and Pugh score (P=0.0266) in simple regression analysis and with insulin levels (P=0.0137), but not with fat mass (P=0.0761), Pugh score (P=0.4472) and REE (P=0.4576) in multiple regression analysis. In the male cirrhotic and control patients, log (leptin) levels correlated with CRP (C reactive protein) (r=0.365, P=0.0223). Log (leptin) levels did not correlate with caloric intake in any of the groups. Leptin levels (P<0.05) and fat mass (P<0.02) increased with refeeding while liver function improved (P<0.01). CONCLUSION: There is a gender difference in regulation of serum leptin level in alcoholic liver cirrhosis. Insulin level is the best determinant of leptin level in female patients while inflammatory state related to alcoholic hepatitis seems to have a greater influence in male patients. Although leptin levels positively correlated with REE in female patients, there is no evidence that leptin reduces caloric intake and fat stores in these patients.

Beta 2-microglobulin in liver cirrhosis: study of a local synthesis in ascitic fluid.

Beta 2-microglobulin determinations in ascitic fluid (A) and serum (S) collected on the same day, were performed in 24 patients suffering from alcoholic liver cirrhosis. Ascitic beta 2-m concentration varied from 0.4 to 4.6 mg/l for patients with a normal renal function. Much higher values were found in patients with chronic renal failure. No correlation could be established between ascitic beta 2-m level and the clinical evolution of the cirrhosis. Comparative measurements of beta 2-m S/A ratio and albumin, transferrin, total protein S/A ratios suggests a local synthesis of beta 2-m in ascitic fluid. This is confirmed by an immuno-cytochemical technique which reveals the localisation of beta 2-m in the cytoplasm of peritoneal cells. The presence of beta 2-m in ascitic fluid seems to be related to an ultrafiltration across the peritoneal membrane as well as a local polyclonal activation of the immune system.