A systematic review and meta-analysis evaluating the impact of antibiotic use on the clinical outcomes of cancer patients treated with immune checkpoint inhibitors.

Background: Immune checkpoint inhibitors (ICIs) have considerably improved patient outcomes in various cancer types, but their efficacy remains poorly predictable among patients. The intestinal microbiome, whose balance and composition can be significantly altered by antibiotic use, has recently emerged as a factor that may modulate ICI efficacy. The objective of this systematic review and meta-analysis is to investigate the impact of antibiotics on the clinical outcomes of cancer patients treated with ICIs. Methods: PubMed and major oncology conference proceedings were systematically searched to identify all studies reporting associations between antibiotic use and at least one of the following endpoints: Overall Survival (OS), Progression-Free Survival (PFS), Objective Response Rate (ORR) and Progressive Disease (PD) Rate. Pooled Hazard Ratios (HRs) for OS and PFS, and pooled Odds Ratios (ORs) for ORR and PD were calculated. Subgroup analyses on survival outcomes were also performed to investigate the potential differential effect of antibiotics according to cancer types and antibiotic exposure time windows. Results: 107 articles reporting data for 123 independent cohorts were included, representing a total of 41,663 patients among whom 11,785 (28%) received antibiotics around ICI initiation. The pooled HRs for OS and PFS were respectively of 1.61 [95% Confidence Interval (CI) 1.48-1.76] and 1.45 [95% CI 1.32-1.60], confirming that antibiotic use was significantly associated with shorter survival. This negative association was observed consistently across all cancer types for OS and depending on the cancer type for PFS. The loss of survival was particularly strong when antibiotics were received shortly before or after ICI initiation. The pooled ORs for ORR and PD were respectively of 0.59 [95% CI 0.47-0.76] and 1.86 [95% CI 1.41-2.46], suggesting that antibiotic use was significantly associated with worse treatment-related outcomes. Conclusion: As it is not ethically feasible to conduct interventional, randomized, controlled trials in which antibiotics would be administered to cancer patients treated with ICIs to demonstrate their deleterious impact versus control, prospective observational studies and interventional trials involving microbiome modifiers are crucially needed to uncover the role of microbiome and improve patient outcomes. Such studies will reduce the existing publication bias by allowing analyses on more homogeneous populations, especially in terms of treatments received, which is not possible at this stage given the current state of the field. In the meantime, antibiotic prescription should be cautiously considered in cancer patients receiving ICIs. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42019145675.

Spare and repair the gut microbiota from antibiotic-induced dysbiosis: state-of-the-art.

Homeostasis of the intestinal microbiota is currently recognized as a major contributor to human health. Furthermore, intestinal dysbiosis is associated with a multitude of consequences, including intestinal colonization by antibiotic-resistant or pathogenic bacteria, such as Clostridioides difficile, and reduced efficacy of promising anticancer immunotherapies. By far, the most immediate and drastic exposure leading to dysbiosis is antibiotic treatment. Many attempts have been made to prevent or repair antibiotic-associated dysbiosis. Here, we review these innovations and the difficulties associated with their development.

Genome-edited, donor-derived allogeneic anti-CD19 chimeric antigen receptor T cells in paediatric and adult B-cell acute lymphoblastic leukaemia: results of two phase 1 studies.

BACKGROUND: Genome-edited donor-derived allogeneic anti-CD19 chimeric antigen receptor (CAR) T cells offer a novel form of CAR-T-cell product that is available for immediate clinical use, thereby broadening access and applicability. UCART19 is one such product investigated in children and adults with relapsed or refractory B-cell acute lymphoblastic leukaemia. Two multicentre phase 1 studies aimed to investigate the feasibility, safety, and antileukaemic activity of UCART19 in children and adults with relapsed or refractory B-cell acute lymphoblastic leukaemia. METHODS: We enrolled paediatric or adult patients in two ongoing, multicentre, phase 1 clinical trials to evaluate the safety and antileukaemic activity of UCART19. All patients underwent lymphodepletion with fludarabine and cyclophosphamide with or without alemtuzumab, then children received UCART19 at 1·1-2·3 × 106 cells per kg and adults received UCART19 doses of 6 × 106 cells, 6-8 × 107 cells, or 1·8-2·4 × 108 cells in a dose-escalation study. The primary outcome measure was adverse events in the period between first infusion and data cutoff. These studies were registered at ClinicalTrials.gov, NCT02808442 and NCT02746952. FINDINGS: Between June 3, 2016, and Oct 23, 2018, seven children and 14 adults were enrolled in the two studies and received UCART19. Cytokine release syndrome was the most common adverse event and was observed in 19 patients (91%); three (14%) had grade 3-4 cytokine release syndrome. Other adverse events were grade 1 or 2 neurotoxicity in eight patients (38%), grade 1 acute skin graft-versus-host disease in two patients (10%), and grade 4 prolonged cytopenia in six patients (32%). Two treatment-related deaths occurred; one caused by neutropenic sepsis in a patient with concurrent cytokine release syndrome and one from pulmonary haemorrhage in a patient with persistent cytopenia. 14 (67%) of 21 patients had a complete response or complete response with incomplete haematological recovery 28 days after infusion. Patients not receiving alemtuzumab (n=4) showed no UCART19 expansion or antileukaemic activity. The median duration of response was 4·1 months with ten (71%) of 14 responders proceeding to a subsequent allogeneic stem-cell transplant. Progression-free survival at 6 months was 27%, and overall survival was 55%. INTERPRETATION: These two studies show, for the first time, the feasibility of using allogeneic, genome-edited CAR T cells to treat patients with aggressive leukaemia. UCART19 exhibited in-vivo expansion and antileukaemic activity with a manageable safety profile in heavily pretreated paediatric and adult patients with relapsed or refractory B-cell acute lymphoblastic leukaemia. The results this study are an encouraging step forward for the field of allogeneic CAR T cells, and UCART19 offers the opportunity to treat patients with rapidly progressive disease and where autologous CAR-T-cell therapy is unavailable. FUNDING: Servier.

Sentinel lymph node biopsy or nodal observation in melanoma: a prospective study of patient choices.

BACKGROUND: There is no consensus regarding the therapeutic utility of sentinel lymph node biopsy (SLNB) versus that of nodal observation (NO) in melanoma. OBJECTIVE: To prospectively evaluate a standardized counseling procedure and its effect on patient choices to undergo SLNB or NO. METHODS: In four centers, patients with melanoma eligible for SLNB or NO received a complete counseling procedure that included verbal information from dermatologists and surgeons, a detailed information sheet, and a written consent form. Data collected included patient and tumor characteristics, counseling conditions, and specialties of informing doctors. Factors influencing patients' choices were studied using multivariate analysis. RESULTS: Of 343 consecutive patients, 309 were offered SLNB and NO and received complete verbal and written information from a dermatologist alone (62%) or in association with a surgeon (38%). Approximately half took advice from trusted persons, and half asked for additional time before making a decision; 268 (86.7%) ultimately decided to undergo SLNB. Multivariate analysis showed that older patients, those with a head and neck melanoma, and those informed without a surgeon present were more likely to prefer NO. CONCLUSIONS: This counseling procedure was easily implemented in clinical practice. Patients favored SLNB but were able to understand uncertainties and express preferences.

The role of circumstances of diagnosis and access to dermatological care in early diagnosis of cutaneous melanoma: a population-based study in France.

OBJECTIVES: To describe circumstances of the diagnosis and access to dermatological care for patients with cutaneous melanoma (CM) and to investigate factors associated with early detection. DESIGN: Retrospective population-based study of incident cases of invasive CM in 2004, using questionnaires to physicians and a survey of cancer registries and pathology laboratories. SETTING: Five regions in northeastern France. PATIENTS: Six hundred fifty-two patients who were referred to dermatologists by general practitioners (group 1) or by other specialists (group 2), who directly consulted a dermatologist for CM (group 3), or who were diagnosed as having CM during a prospective follow-up of nevi (group 4) or when consulting a dermatologist for other diseases (group 5). MAIN OUTCOME MEASURES: Characteristics of patients, tumors, and patients' residence in each group, including the geographical concentration of dermatologists. We performed multivariate analysis of these factors to determine association with Breslow thickness. RESULTS: Age, tumor location, Breslow thickness, ulceration, histological type, and geographical concentration of dermatologists significantly differed among groups. Patients consulting dermatologists directly formed the largest group (45.1%). Those referred by general practitioners (26.1%) were the oldest and had the highest frequency of thick (>3 mm), nodular, and/or ulcerated CM. Patients from groups 4 (8.4%) and 5 (14.1%) had the thinnest CMs. Ulcerated and/or thick tumors were absent in group 4. In multivariate analysis, histological types superficial spreading melanoma and lentigo maligna melanoma, younger age, high concentration of dermatologists, and detection by dermatologists were significantly associated with thinner CMs. CONCLUSION: Easy access of patients to dermatologists, information campaigns targeting elderly people, and education of general practitioners are complementary approaches to improving early detection.

Cancer mortality in patients with schizophrenia: an 11-year prospective cohort study.

BACKGROUND: Schizophrenia has been associated with a rate of premature mortality that is 2 to 3 times higher than that in the general population. Although the role of cancer in this excess mortality remains unclear, previous incidence or mortality studies found contradictory results. METHODS: In 1993, a large prospective study was initiated in a cohort of 3470 patients with schizophrenia to examine cancer-related mortality and predictors. Standardized mortality ratios (SMRs) were calculated, adjusting for age and sex relative to a representative sample of the French general population. RESULTS: During the 11-year follow-up, 476 (14%) patients died; the mortality rate was thus nearly 4-fold higher than in the general population. Cancer was the second most frequent cause of mortality (n=74), with a global SMR of 1.5 (95% confidence interval [95% CI], 1.2-1.9). For all cancers, the SMRs were 1.4 (not significant) for men and 1.9 (95% CI, 1.4-2.8) for women. For men, lung cancer was the most frequent localization (n=23; 50%), with an SMR of 2.2 (95% CI, 1.6-3.3). For women, breast cancer was the most frequent localization (n=11; 39%), with an SMR of 2.8 (95% CI, 1.6-4.9). In comparison with patients who did not die of cancer, there were 2 significant baseline predictors of death by lung cancer in the final logistic regression model: duration of smoking and age>38 years. CONCLUSIONS: The results of the current study demonstrated an increased risk of mortality by cancer in patients with schizophrenia, especially for women from breast cancer and for men from lung cancer.

Does the availability of positron emission tomography modify diagnostic strategies for solitary pulmonary nodules? An observational study in France.

BACKGROUND: Previous studies showed that at the individual level, positron emission tomography (PET) has some benefits for patients and physicians in terms of cancer management and staging. We aimed to describe the benefits of (PET) in the management of solitary pulmonary nodules (SPNs) in a population level, in terms of the number of diagnostic and invasive tests performed, time to diagnosis and factors determining PET utilization. METHODS: In an observational study, we examined reports of computed tomography (CT) performed and mentioning "spherical lesion", "nodule" or synonymous terms. We found 11,515 reports in a before-PET period, 2002-2003, and 20,075 in an after-PET period, 2004-2005. Patients were followed through their physician, who was responsible for diagnostic management. RESULTS: We had complete data for 112 patients (73.7%) with new cases of SPN in the before-PET period and 250 (81.4%) in the after-PET period. Patients did not differ in mean age (64.9 vs. 64.8 years). The before-PET patients underwent a mean of 4 tests as compared with 3 tests for the after-PET patients (p = 0.08). Patients in the before-PET period had to wait 41.4 days, on average, before receiving a diagnosis as compared with 24.0 days, on average, for patients in the after-PET period who did not undergo PET (p < 0.001). In the after-PET period, 11% of patients underwent PET during the diagnostic process. A spiculated nodule was more likely to determine prescription for PET (p < 0.001). Multivariate analysis revealed that patients in both periods underwent fewer tests when PET was prescribed by general practitioners (p < 0.001) and if the nodule was not spiculated (p < 0.001). The proportion of unnecessary invasive approaches prescribed (47% vs. 49%) did not differ between the groups. CONCLUSION: In our study, 1 year after the availability of PET, the technology was not the first choice for diagnostic management of SPN. Even though we observed a tendency for reduced number of tests and mean time to diagnosis with PET, these phenomena did not fully relate to PET availability in health communities. In addition, the availability of PET in the management of SPN diagnosis did not reduce the overall rate of unnecessary invasive approaches.

Detection of hepatic metastases from carcinoid tumor: prospective evaluation of contrast-enhanced ultrasonography.

The purpose of our study was to prospectively compare unenhanced ultrasonography (US) to contrast-enhanced US (CEUS) in the detection of hepatic metastases from carcinoid tumor. Thirty patients with carcinoid tumor prospectively underwent US, CEUS, and magnetic resonance imaging (MRI). Differences in sensitivity at US and CEUS were compared using a combination of the results of MR imaging, fine-needle biopsy, and follow-up imaging. Lesion conspicuity was assessed subjectively for US and CEUS. Seventeen patients had a total of 69 hepatic metastases. The addition of CEUS improved the detection of individual metastases from 47 (Se 68%; 95% CI: 57.0, 79.0) to 68 (Se 99%; 99% CI: 96.7, 100.0). Contrast enhancement improved the subjective conspicuity of metastases in 85% of patients. CEUS showed one more metastasis than did MRI in one patient, and MRI showed one more than did CEUS in one patient. CEUS is more sensitive than US in the detection of carcinoid liver metastases.

Compliance of abdominal aortic aneurysms before and after stenting with tissue doppler imaging: evolution during follow-up and correlation with aneurysm diameter.

Usual imaging after endovascular aneurysm repair (EVAR) of abdominal aortic aneurysm (AAA) consists of AAA diameter monitoring and endoleak detection. Among additional predictor parameters previously proposed to help clinicians in better identifying subgroups of AAA still at risk of rupture, AAA wall motion after EVAR has been studied, but its value was not clearly established. Tissue Doppler imaging (TDI) is an ultrasonographic modality which allows wall motion measurements along an arterial segment. The aim of the current study was to analyze AAA wall motion with TDI before and after EVAR and to describe its evolution in patients with more than 1 month of follow-up. Twenty-five consecutive patients undergoing EVAR between February 2005 and June 2007 gave informed consent to be prospectively investigated with the TDI system before EVAR and at each visit during follow-up. The mean (SD) follow-up was 13.7 (9.7) months. Maximum mean segmental dilation (MMSD), segmental compliance, dilation at maximum diameter, pressure strain elastic modulus (Ep), and stiffness were compared between three periods (before stenting, before discharge, and at last follow-up), and their relation with AAA diameter was analyzed. A significant decrease in AAA compliance was immediately observed after successful EVAR and remained stable during later follow-up. On the other hand, AAA diameter progressively decreased along time and was statistically lower at the last control compared to the initial value. MMSD, segmental compliance, and dilation at maximum diameter were positively related to AAA diameter. This means that the larger the AAA diameter after stenting, the higher the value for these parameters can be expected. On the contrary, percentage of AAA diameter decrease and percentage of MMSD decrease were not related after successful EVAR. There was no parallelism between loss in compliance and diameter decrease along time, and there is not a unique pattern of AAA diameter and compliance evolution after EVAR. Even if comparison between patients without and with endoleak was weak due to the small sample of the latter group (five patients with endoleak), compliance tended to be greater in case of endoleak. AAA wall motion after successful EVAR reflects complex interactions between all the components of the stented aneurysm which evolve over time, including true compliance of the aneurysm wall itself; intra-aneurysm sac pressure with possible different effects for peak, mean, and pulse pressures; remodeling of the thrombus; stiffness characteristics of the graft; and systemic pressure. Combining simultaneous MMSD records with actual intrasaccular pressure measurements in patients with and without endoleak would improve our understanding of the clinical pulsatility mechanism within AAA after EVAR.

Thiopurine S-methyltransferase genotypic analysis in autoimmune bullous diseases.

Thiopurine S-methyltransferase (TPMT) activity is inversely related to the risk of developing severe hematopoietic toxicity in patients treated with azathioprine. The aim of this study was to evaluate the usefulness of TPMT genotyping in severe cases of autoimmune bullous diseases treated with azathioprine. A retrospective study of TPMT genotyping was performed in patients with autoimmune bullous diseases hospitalized in a single centre between 1999 and 2006 and susceptible of being treated by azathioprine. Among 75 patients tested, 70 (93%) had a high TPMT activity and 5 (7%) an intermediate activity. TPMT genotyping was performed in 33/34 patients currently treated with azathioprine. Haematopoietic side-effects (usually moderate) were observed in 12/34 patients treated with a mean dosage of 2.7 mg/kg/day and occurred, despite a high predicted TPMT activity. No myelotoxicity was observed in the two patients with intermediate predicted TPMT activity (mean dosage: 1.7 mg/kg/day), who obtained a clinically complete remission. Although strongly recommended before azathioprine treatment, predicting TPMT activity appears only marginally helpful in patients with autoimmune bullous diseases, mainly for adjusting the azathioprine dosage. In addition, a normal TPMT genotyping is not a guarantee against the occurrence of haematological side-effects.

Dosimetric evaluation and therapeutic response to internal radiation therapy of hepatocarcinomas using iodine-131-labelled lipiodol.

OBJECTIVE: Vectorized internal radiation therapy using lipiodol-labelled with iodine-131 (131 I-lipiodol) is an effective treatment for inoperable hepatocellular carcinomas. However, few dosimetric data are available based on this approach. We have developed a dosimetric protocol based on scintiscan imaging and that is designed to calculate the tumoural absorbed dose during the treatment of hepatocarcinoma by 131 I-lipiodol. METHODS: This concept was developed on a gamma-camera coupled to a computed tomography scanner. It integrates corrections for attenuation phenomena, scattering and dead time. The tumoural absorbed dose calculation was carried out according to the Medical Internal Radiation Dose Committee formalism. This protocol was applied to a series of 41 patients in the framework of a retrospective study. RESULTS: The mean tumoural absorbed dose with the first treatment is 248 Gy (+/-176), as opposed to 152 Gy (+/-122) during the second. We highlighted a correlation between the tumoural absorbed dose, calculated in tomographic mode, and the morphological response to the first treatment (P=0.0071). Moreover, a tumoural absorbed dose of 280 Gy seems to be an effective absorbed dose threshold in our population. Above this absorbed dose, 84% of the patients are responders after the first treatment, whereas no responses are recorded below this threshold. CONCLUSION: These results are promising because, for the first time, they allow us to predict the effectiveness of a treatment by 131 I-lipiodol. They are required to be validated on a broader exploratory trial, including a dosimetric study of the critical organs, so an individualized dosimetry can be defined for each patient.

Receptor for advanced glycation end-products (RAGE) modulates neutrophil adhesion and migration on glycoxidated extracellular matrix.

AGEs (advanced glycation end-products) accumulate in collagen molecules during uraemia and diabetes, two diseases associated with high susceptibility to bacterial infection. Because neutrophils bind to collagen during their locomotion in extravascular tissue towards the infected area we investigated whether glycoxidation of collagen (AGE-collagen) alters neutrophil migration. Type I collagen extracted from rat tail tendons was used for in vitro glycoxidation (AGE-collagen). Neutrophils were obtained from peripheral blood of healthy adult volunteers and were used for the in vitro study of adhesion and migration on AGE- or control collagen. Glycoxidation of collagen increased adhesion of neutrophils to collagen surfaces. Neutrophil adhesion to AGE-collagen was inhibited by a rabbit anti-RAGE (receptor for AGEs) antibody and by PI3K (phosphoinositide 3-kinase) inhibitors. No effect was observed with ERK (extracellular-signal-regulated kinase) or p38 MAPK (mitogen-activated protein kinase) inhibitors. AGE-collagen was able to: (i) induce PI3K activation in neutrophils, and (ii) inhibit chemotaxis and chemokinesis of chemoattractant-stimulated neutrophils. Finally, we found that blocking RAGE with anti-RAGE antibodies or inhibiting PI3K with PI3K inhibitors restored fMLP (N-formylmethionyl-leucyl-phenylalanine)-induced neutrophil migration on AGE-collagen. These results show that RAGE and PI3K modulate adhesion and migration rate of neutrophils on AGE-collagen. Modulation of adhesiveness may account for the change in neutrophil migration rate on AGE-collagen. As neutrophils rely on their ability to move to perform their function as the first line of defence against bacterial invasion, glycoxidation of collagen may participate in the suppression of normal host defence in patients with diabetes and uraemia.

Variations in management of stage I to stage III cutaneous melanoma: a population-based study of clinical practices in France.

OBJECTIVE: To describe current management of cutaneous melanoma (CM) and identify factors accounting for disparities. DESIGN: Retrospective population-based study using survey of cancer registries and pathology laboratories, and questionnaires to physicians. SETTING: Five regions covering 19.2% of the French territory and including 8.2 million inhabitants. PATIENTS: Incident cases of patients with stage I to stage II (hereinafter, stage I-II) tumors staged according to the American Joint Committee on Cancer Staging guidelines and nodal stage III CM in 2004. MAIN OUTCOME MEASURES: Modalities of diagnosis and excision, surgical margins, sentinel lymph node biopsy, adjuvant therapies and surveillance procedures, and their variations according to age, sex, residence, location of primary CM, Breslow thickness, type of physicians, modalities of decisions, and health care patterns. RESULTS: Clinical stage I-II CMs (n = 710 cases) slightly predominated in females (53%), with a lower mean Breslow thickness (1.4 mm) than in males (1.9 mm). Initial excisions were most often performed by private dermatologists and wide excisions by surgeons. Narrow margins (8%) were associated with advanced age, higher Breslow thickness, and head location. Sentinel lymph node biopsy was performed in 34% of CMs thicker than 1.0 mm, depending on geographical regions, distance from reference centers, and health care patterns. Adjuvant therapies (mainly low-dose interferon) were proposed in 53% of thick CMs (>1.5 mm), depending on the patient's age and geographical region. In contrast with French recommendations, surveillance procedures frequently included systematic medical imaging. Stage III nodal CMs (n = 89 cases) predominated in males (62%). After lymphadenectomy, adjuvant therapies (including high-dose interferon in 32% of cases and chemotherapies in 24% of cases) were proposed in 68% of cases, depending on the patient's age and geographical region. A complete 1-year high-dose interferon regimen was administered in less than 10% of cases. CONCLUSION: Large disparities still exist in the management of CM in France, depending to a greater extent on medical and geographical environment than on the characteristics of either patients or tumors.

Comparison of operator radiation exposure with optimized radiation protection devices during coronary angiograms and ad hoc percutaneous coronary interventions by radial and femoral routes.

AIMS: Although underestimated by interventional cardiologists for a long time, radiation exposure of operators and patients is currently a major concern. The objective of the present operator-blinded registry was to compare related-peripheral arterial route radiation exposure of operators. METHODS AND RESULTS: During 420 consecutive coronary angiograms (CAs) and percutaneous coronary interventions (PCIs), four interventional cardiologists were blindly screened. Radiation exposures were assessed using electronic personal dosimeters. Protection of operator was ensured using a lead apron, low leaded flaps, and leaded glass. Radiation exposure of operators was significantly higher using the radial route when compared with the femoral route for both CAs and CAs followed by ad hoc PCIs: 29.0 [1.0-195.0] microSv vs. 13.0 [1.0-164.0] microSv; P < 0.0001 and 69.5 [4.0-531.0] microSv vs. 41.0 [2.0-360.0] microSv; P = 0.018, respectively. Similarly, radiation exposure of patients was significantly higher using the radial route when compared with the femoral route for both CAs and CAs followed by ad hoc PCIs. Moreover, procedural durations and fluoroscopy times were significantly higher throughout the radial route. CONCLUSIONS: Although the radial route decreases peripheral arterial complication rates, increased radiation exposure of operators despite extensive use of specific protection devices is currently a growing problem for the interventional cardiologist health. Radial route indication should be promptly reconsidered in the light of the present findings.

Characteristics and outcome of fetal cystic hygroma diagnosed in the first trimester.

OBJECTIVE: The aim of this study was to determine the course of pregnancy and the neonatal outcome of fetuses with cystic hygroma diagnosed at 10-14 weeks' gestation. METHODS: Maternal and fetal data (nuchal translucency, karyotype, pregnancy outcome) in cases of fetal cystic hygroma, admitted or referred to our antenatal diagnostic centre, were prospectively entered into a computer database. Paediatric outcome was analysed when relevant. RESULTS: Some 72 fetuses had cystic hygroma. The mean size of the cystic hygroma was 7.9 mm. Chromosomal abnormalities were present in 52.7% of cases (38/72), including 14 cases (36.8%) of Down syndrome. A total of 34 chromosomally normal pregnancies gave rise to 18 live births (52.9%), with no visible serious structural abnormalities. The outcome of pregnancy was unfavourable (miscarriage, elective termination, serious structural abnormalities) in 77.7% of cases (56/72). The 18 live-born infants were followed up for 17-98 months. Sixteen infants developed normally, while 1 developed Noonan's syndrome and 1 had a urinary tract abnormality (pyelo-ureteral junction; PUJ). CONCLUSION: These data suggest that the prognosis of fetal cystic hygroma detected during the first trimester is poor, and show that sonographic evaluation of fetal nuchal translucency thickness in the first trimester is crucial.

[Efficacy of percutaneous laser disc decompression for radiculalgia due to lumbar disc hernia (149 patients)]. / Efficacité de la nucléolyse laser dans le traitement des radiculalgies par hernie discale (149 patients).

OBJECTIVE: To assess the efficacy of percutaneous laser disc decompression for patients with radicular pain due to lumbar disc hernia and to identify factors that may predict outcome. METHODS: The study included all patients treated with percutaneous laser disc decompression from May 2003 through May 2005 at Reims University Hospital and the Courlancy Clinic of Reims. Each patient had previous undergone at least six weeks of conventional medical treatment. The same technique, with either a laser diode or Nd: YAG, was used under endoscopic control and with neuroleptanalgesia. They were seen at 1, 3, 6 and 12 months. The principal evaluation criteria were the course of radicular pain, return to work, and need for surgery. RESULTS: We reexamined 149 patients 1 month after the procedure, 135 after 3 months, 102 after 6 months and 59 a year after the procedure. At a month after surgery, radicular pain had decreased by at least half, and sometimes even completely disappeared in 63.1% of patients at 1 month, 66.6% at 3 months, 73.5% at 6 months, and 83.1% at 12 months, while 24%, 50,4%, 61.2%, and 67.3%, respectively, had returned to work. No patient had serious complications. Finally, 45 of the 149 (30.2%) patients chose to have a traditional surgical procedure after percutaneous laser disc decompression. CONCLUSION: Percutaneous laser disc decompression is effective, noninvasive and well tolerated for patients with radicular pain due to lumbar disc hernia.

Beneficial influence of microsatellite instability on gelatinase-tissue inhibitors of metalloproteinase balance in colorectal cancer.

BACKGROUND: Colorectal cancers (CRC) with high level of microsatellite instability (MSI-H) are characterized by lower metastasis propensity and better prognosis than their stable microsatellite (MSS) counterpart. It was hypothesized that the difference in cancer progression might be related to distinct gelatinase-tissue inhibitors of metalloproteinase (TIMPs) balance in MSI-H and MSS sporadic CRC. PATIENTS AND METHODS: Levels of gelatinase-A (MMP-2) and -B (MMP-9), TIMP-1 and -2 and membrane-type matrix metallo-proteinase-1 (MT1-MMP) were compared in tumors and normal mucosa from patients with MSI-H and MSS CRC. RESULTS: Active levels of MMP-2 and -9, normalized to normal mucosa, were lower in MSI-H than MSS CRC. There was a trend for higher levels of TIMP-1 and TIMP-2 within MSI-H tumors compared with MSS tumors (p=0.08 and p=0.15, respectively), while TIMP-2 amounts were significantly higher in adjacent normal tissue (p<0.001) in patients with MSI-H vs. MSS cancers. There was also a trend for lower MT1-MMP activity in MSI-H than in MSS CRC. CONCLUSION: Our data suggest that the distinct invasive and metastatic behaviors of MSI-H and MSS CRC may be related to different patterns of gelatinase secretion and regulation.

Overlap syndrome of primary biliary cirrhosis and autoimmune hepatitis: a retrospective study of 115 cases of autoimmune liver disease.

OBJECTIVE: The aim of this retrospective study was to compare clinical, biological, and histological features and treatment response in 115 patients with overlap syndrome (OS), autoimmune hepatitis (AIH) or primary biliary cirrhosis (PBC). METHODS: Consecutive patients with AIH, PBC or OS followed between 1984 and 2005 in five different centers were included. All data were re-evaluated using current diagnostic criteria of each disease. RESULTS: Fifteen patients had OS (13 females), 48 AIH (40 females) and 52 PBC (49 females). Patients with OS were significantly younger than patients with PBC (median age: 44 vs 59 years). Jaundice (20%) and pruritus (20%) were the main initial symptoms in OS. Patients with OS had serum transaminase and gammaglobulin levels significantly higher than patients with PBC; serum alkaline phosphatase, gamma-glutamyl-transpeptidase and IgM levels were significantly higher in OS than in patients with AIH. Histological analysis showed moderate or severe piecemeal necrosis in 86% and destructive cholangitis in 93% in OS group. Among 11 patients with OS treated with ursodeoxycholic acid (UDCA) or immunosuppressors alone, only 6 had a complete biochemical response. In contrast, all patients with OS receiving combined therapy, as first or second line, responded, 5 patients to the combination corticosteroids-azathioprine-UDCA and 2 to the combination cyclosporine-UDCA. CONCLUSION: OS is not rare and accounts for 13.9% of patients with autoimmune liver disease in our series. Combination of immunosuppressors and UDCA appears the most efficient treatment in these patients.

Interleukin-10 promoter polymorphism and venous thrombosis: a case-control study.

The human interleukin-10 promoter gene is highly polymorphic. IL-10 polymorphisms have been associated with various autoimmune and lymphoproliferative disorders. Although IL-10 has been shown to modulate thrombin generation in several experimental models, it is not known whether IL-10 polymorphisms could be a risk factor for venous thrombosis. We therefore conducted a case-control study comparing 74 consecutive patients who experienced at least one episode of documented venous thromboembolic event and 100 healthy controls. All subjects were Caucasians. Five polymorphisms of the IL-10 promoter gene were studied: two highly polymorphic dinucleotide repeats, IL-10 R and IL-10G, and three single nucleotide polymorphisms at position -1082, -819 and -592. Factor VG1691C Leiden mutation was systematically determined. Multivariate logistic regression analysis showed that IL-10 G13 and G10 alleles are independent risk factors for venous thrombosis (Odds ratio:OR = 3.33, p = 0.003 and OR = 2.83, p = 0.03, respectively). Furthermore, IL-10 G10 allele is more frequent in recurrent disease.