Cumulative detection of anal high-grade squamous intraepithelial lesions over two-year follow-up in men who have sex with men living with HIV in France.

We assessed cumulative detection and determinants of anal high-grade squamous intraepithelial lesions (HSIL) in men who have sex with men living with HIV who underwent three visits over two years, with cytology and high-resolution anoscopy (HRA), within the ANRS-EP57-APACHES study. Cumulative HSIL detection was 33% (134/410), of which 48% were detected at baseline. HSIL detection varied considerably by center (13-51%). Strongest HSIL determinants were baseline HPV16 (adjusted odds ratio [aOR] 8.2; 95% confidence interval [95%CI] 3.6-18.9), and p16/Ki67 (aOR 4.6; 95%CI 2.3-9.1). Repeat annual cytology and HRA improved HSIL detection but did not fully compensate between-center heterogeneity.

"Helicobacter pylori in familial mediterranean fever: A series of 120 patients from literature and from france".

INTRODUCTION: Familial Mediterranean Fever (FMF), the most common monogenic auto-inflammatory disease, is characterized by recurrent febrile abdominal pain. Helicobacter pylori infection (HPI), one of the most frequent infections worldwide, can mimic an FMF attack. OBJECTIVES: Identify FMF patients with HPI in a cohort of French FMF patients and the literature and identify features allowing to distinguish HPI from an FMF attack. METHODS: A retrospective study of all HPI cases was performed on the cohort of FMF patients fulfilling the Livneh criteria from the French Reference Center for rare Auto-Inflammatory Diseases and Amyloidosis (CEREMAIA). A systematic literature review of HPI in FMF patients was conducted according to the PRISMA guidelines. RESULTS: Eight French patients developed HPI, whose symptoms of epigastralgia, diarrhea, anorexia/weight loss, and nausea/vomiting differed from their typical abdominal FMF attacks. A total of 112 FMF patients with HPI have been described in the literature, including 61 adults. Diagnosis of HPI was made by gastroscopy (n = 43), labelled urea test (n = 55) or IgG serology by ELISA (n = 12). When performed, C-reactive protein was always elevated. Ten cases of interaction between colchicine and antibiotic therapy for HPI (clarithromycin (n = 9) and azithromycin (n = 1)) were reported. CONCLUSION: We described a total of 120 patients with typical FMF and HPI. When FMF patients develop atypical abdominal symptoms, upper gastrointestinal endoscopy with biopsies is essential to eliminate underlying HPI. Untreated HPI can lead to misdiagnosis of colchicine resistance with inappropriate prescription of an interleukin-1 inhibitor at a non-negligible cost.

AA amyloidosis revealing mevalonate kinase deficiency: A report of 20 cases including two new French cases and a comprehensive review of literature.

INTRODUCTION: Mevalonate kinase deficiency (MKD) is a rare autosomal recessive autoinflammatory disease that can lead to an inflammatory A amyloidosis (AA). METHODS: To study the occurrence of AA in MKD patients we performed a systemic review of the literature and described two novel patients. RESULTS: Amyloidosis occurred in 20 MKD patients, renal impairment being always the revealing symptom of AA. Although an accurate prevalence estimation is not possible since exact MKD prevalence is unknown, AA seems rare in MKD (about 6% if we estimate MKD prevalence at 300 patients worldwide). MVK gene study, available in 18 out of the 20 patients, confirmed two pathogenic mutations in all tested individuals. The most frequent genotype was V377I/I268T (n = 9/18). Retrospective search of clinical signs of MKD established, in all patients carrying MVK pathogenic mutations, a disease onset within the first four years of life. Nephrotic syndrome (n = 15), end-stage renal failure (n = 5) or both (n = 8) pointed out kidney amyloidosis. The youngest patient with renal amyloidosis was a European four-year-old girl previously misdiagnosed with PFAPA syndrome. Five patients died of AA amyloidosis despite the use of a biotherapy for two of them; kidney transplant was performed in nine individuals. Colchicine was not effective in any patient. Anti-interleukin-1 anakinra (n = 8), anti TNF etanercept (n = 7) and anti-interleukin 6 tocilizumab (n = 5) treatments were partially effective. CONCLUSION: Inflammatory A amyloidosis, a rare complication of MKD, can cause death or necessitate kidney transplantation. Early diagnosis and cytokine blocking biotherapy using anti-IL1, anti-TNF or anti-IL6 agents are required to prevent terminal renal failure.

Nancy Index Scores of Chronic Inflammatory Bowel Disease Activity Associate With Development of Colorectal Neoplasia.

BACKGROUND & AIMS: The degree of histologic and endoscopic disease activity has been associated with an increased risk of colorectal neoplasia (CRN) in patients with inflammatory bowel diseases (IBDs), but no histologic scoring systems have been validated for determining risk of CRN. We investigated the association between histologic and endoscopic disease activity and risk of first CRN in patients with IBD who had negative findings from a surveillance colonoscopy. METHODS: We performed a retrospective analysis of consecutive patients who underwent at least 2 colonoscopies at Saint Antoine Hospital in France from January 1, 1996, through March 1, 2015, and whose first procedure was a surveillance colonoscopy. Histologic IBD activity was assessed by the Nancy histologic index. Patients were followed up for a mean 5.7 ± 3.3 years. Logistic regression and generalized estimating equations were used to identify clinical, endoscopic, and histologic factors associated with detection of neoplasia in the inflamed colon mucosa. RESULTS: Among 398 patients who underwent 1277 colonoscopies, we identified 45 patients with CRN. Factors associated with CRN were primary sclerosing cholangitis (odds ratio [OR], 2.65; 95% CI, 1.06-6.61; P = .04), age (OR per 1-year increase, 1.04; 95% CI, 1.01-1.07; P = .003), and mean Nancy histologic index during follow-up evaluation (per 1-unit increase, OR, 1.69; 95% CI, 1.29-2.21; P < .001). After adjustment for established factors, chronic disease activity defined as detection of ulcerations at more than 50% of colonoscopies was not associated with an increased risk of CRN (OR, 1.24; 95% CI, 0.53-2.91; P = .62). CONCLUSIONS: In addition to established risk factors, we associated Nancy histologic index scores with development of CRN. Histologic findings based on the Nancy histologic index therefore should be included in determining the risk of colonic neoplasia in patients with IBD.

Early Detection of Anal High-Grade Squamous Intraepithelial Lesion: Do We Have an Impact on Progression to Invasive Anal Carcinoma?

OBJECTIVE: Anal high-grade squamous intraepithelial lesion (HSIL) may precede invasive cancer and can be detected clinically or during high-resolution anoscopy (HRA). The aims of this study were to compare the characteristics of HSIL discovered by HRA or in a surgical specimen without clinically visible lesion when diagnosed versus macroscopic HSIL when first diagnosed and then to compare their progression to invasive cancer. PATIENTS AND METHODS: Clinical records of all patients with at least one HSIL lesion confirmed by histology and evaluated by HRA in a single center between September 1, 2009, and April 30, 2017, were retrospectively reviewed. The center's histological anal cancer data base was questioned in December 2017 to identify all cases. RESULTS: During a median (interquartile range) follow-up of 19.1 (5.6-40.2) months, 12 (2.9%) anal cancers were diagnosed in patients with a diagnosis of HSIL. Period of time between the first diagnosis of anal lesion and the cancer was 28.8 months (interquartile range = 15.4-65.6), and 11 (92%) of 12 were diagnosed as superficially invasive squamous cell carcinoma or T1N0M0. The rate of progression to anal cancer differed significantly between patients with macroscopic HSIL at diagnosis (5.4%) and patients with microscopic HSIL diagnosed during HRA (0.9%) (p = .01). CONCLUSIONS: Patients with macroscopic histologically proven HSIL at first diagnosis of anal intraepithelial lesion have a significantly higher risk of anal cancer compared with patients with microscopic lesions diagnosed during HRA, but the duration between the first diagnosis of HSIL and cancer does not differ between the 2 groups.

Modulation of lung cancer cell plasticity and heterogeneity with the restoration of cisplatin sensitivity by neurotensin antibody.

Overall survival of patients with metastatic non-small cell lung cancer (NSCLC) has significantly improved with platinum-based salt treatments and recently with targeted therapies and immunotherapies. However, treatment failure occurs due to acquired or emerging tumor resistance. We developed a monoclonal antibody against the proform of neurotensin (LF-NTS mAb) that alters the homeostasis of tumors overexpressing NTSR1. Neurotensin is frequently overexpressed along with its high affinity receptor (NTSR1) in tumors from epithelial origins. This ligand/receptor complex contributes to the progression of many tumor types by activation of the cellular effects involved in tumor progression (proliferation, survival, migration, and invasion). We demonstrate that LF-NTS mAb operates on the plasticity of tumor cells overexpressing NTSR1 and lowers their aggressiveness. The mAb enables the restoration of platinum-based therapies responsiveness, while also decreasing metastatic processes. Efficacy dosage with long-term treatment showed no obvious adverse events, while demonstrating improvement in the performance status. Our data suggests that LF-NTS mAb is an ideal candidate to be safely added to the conventional standard of care in order to improve its efficacy.

[Diagnosis of Helicobacter pylori infection on gastric biopsies: Standard stain, special stain or immunohistochemistry?] / Diagnostic d'infection à Helicobacter pylori sur biopsies gastriques : coloration standard, coloration spéciale ou immunohistochimie ?

INTRODUCTION: There is no consensus on the benefit of performing a systematic complementary technique for the diagnosis of Helicobacter pylori infection. In our laboratory, a cresyl violet was carried out systematically until July 2014; since that date, a cresyl violet or immunohistochemistry is only made on request. We evaluated the value of cresyl violet staining of gastric biopsies to diagnose H. pylori infection by comparing a period of systematic staining to a time when it was made on demand. MATERIAL AND METHODS: We retrospectively studied the gastric biopsy of 786 consecutive patients from April to November 2014, taken in the absence of focal endoscopic lesion. During the first period, hematoxylin-eosin and cresyl violet were performed on all biopsies. During the second period, hematoxylin-eosin was performed and then, if necessary, cresyl violet or immunohistochemistry. All hematoxylin-eosin stained slides were revised to identify H. pylori. We performed immunohistochemistry in cases of active chronic gastritis without H. pylori identified on hematoxylin-eosin or cresyl violet. RESULTS: We have shown that gastric biopsy performed in the absence of focal mucosal lesion are normal in 55% of cases. The percentage of H. pylori infection was similar in both groups. In cases of active chronic gastritis, H. pylori infection is visible, in most cases, on hematoxylin-eosin (94%). Immunohistochemistry should be prescribed only in case of chronic active gastritis without H. pylori identified on standard staining, with bacteria rare or atypically located. CONCLUSION: In our experiment, H. pylori is present only in case of active gastritis (33% of the biopsies in our series) and being almost always identifiable on the standard staining with H-E (in 94% of the cases), it is not It is not necessary to systematically perform, on all gastric biopsies, a complementary histo- or immunohistochemical technique.

Acute pancreatitis in immunocompromised patients: beware of varicella zoster virus primo-infection.

Varicella zoster virus (VZV) primo-infection can be severe in the elderly and in immunocompromised patients. Atypical presentations are not uncommon and may mislead the diagnosis and delay adequate treatment. Valacyclovir prophylaxis should be systematically proposed in immunocompromised patients.

Which lesions should be biopsied during high-resolution anoscopy? Prospective descriptive study of simple morphological criteria.

OBJECTIVE: High-resolution anoscopy (HRA) is a useful screening tool for anal intraepithelial neoplasia (AIN), although reputedly challenging for interpretation of suspected lesions. MATERIALS AND METHODS: All consecutive patients who underwent biopsies for at least 1 lesion suspicious for AIN during HRA from November 2010 to March 2012 were prospectively included. The characteristics (borders, staining with acetic acid and Lugol iodine solution, and patterns of epithelium and vascularization) of the lesions detected during HRA were compared with histology. RESULTS: A total of 168 suspicious anal lesions were biopsied and analyzed in 103 patients (68% men, mean age ± standard deviation = 49.8 ± 9 y, 57% positive status on human immunodeficiency virus infection). According to histology, 41.7% of the lesions were high grade, 34.5% were low grade, and 23.8% were nondysplastic. Lesions with irregular epithelial pattern (or irregular vascularization) were twice as likely to be high grade compared with lesions with regular epithelial pattern (or regular vascularization). The incidences of acetic acid-induced whitening were 91.4%, 94.8%, and 70% among the high-grade AIN, low-grade AIN, and nondysplastic samples, respectively. Among the high-grade AIN, 62.9% were not stained by Lugol solution (vs 31% of the low-grade AIN). The positive predictive value of a combination of these simple morphological criteria was 68.6%. CONCLUSIONS: Several simple morphological criteria are significantly associated with high-grade AIN and are found less often in low-grade AIN. A combination of these morphological criteria provides sufficient positive predictive value to guide biopsy placement during HRA.

Knockout of insulin-like growth factor-1 receptor impairs distal lung morphogenesis.

BACKGROUND: Insulin-like growth factors (IGF-I and -II) are pleiotropic regulators of somatic growth and development in vertebrate species. Endocrine and paracrine effects of both hormones are mediated by a common IGF type 1 receptor (IGF-1R). Lethal respiratory failure in neonatal IGF-1R knockout mice suggested a particular role for this receptor in pulmonary development, and we therefore investigated the consequences of IGF-1R inactivation in lung tissue. METHODS AND FINDINGS: We first generated compound heterozygous mutant mice harboring a hypomorphic (Igf1r(neo)) and a null (Igf1r(-)) allele. These IGF-1R(neo/-) mice express only 22% of normal IGF-1R levels and are viable. In adult IGF-1R(neo/-) mice, we assessed lung morphology and respiratory physiology and found normal histomorphometric characteristics and normal breathing response to hypercapnia. We then generated homozygous IGF-1R knockout mutants (IGF-1R(-/-)) and analyzed their lung development during late gestation using histomorphometric and immunohistochemical methods. IGF-1R(-/-) embryos displayed severe lung hypoplasia and markedly underdeveloped diaphragms, leading to lethal neonatal respiratory distress. Importantly, IGF-1R(-/-) lungs from late gestation embryos were four times smaller than control lungs and showed markedly thickened intersaccular mesenchyme, indicating strongly delayed lung maturation. Cell proliferation and apoptosis were significantly increased in IGF-1R(-/-) lung tissue as compared with IGF-1R(+/+) controls. Immunohistochemistry using pro-SP-C, NKX2-1, CD31 and vWF as markers revealed a delay in cell differentiation and arrest in the canalicular stage of prenatal respiratory organ development in IGF-1R(-/-) mutant mice. CONCLUSIONS/SIGNIFICANCE: We found that low levels of IGF-1R were sufficient to ensure normal lung development in mice. In contrast, complete absence of IGF-1R significantly delayed end-gestational lung maturation. Results indicate that IGF-1R plays essential roles in cell proliferation and timing of cell differentiation during fetal lung development.