Long-term safety and efficacy of lentiviral hematopoietic stem/progenitor cell gene therapy for Wiskott-Aldrich syndrome.

Patients with Wiskott-Aldrich syndrome (WAS) lacking a human leukocyte antigen-matched donor may benefit from gene therapy through the provision of gene-corrected, autologous hematopoietic stem/progenitor cells. Here, we present comprehensive, long-term follow-up results (median follow-up, 7.6 years) (phase I/II trial no. NCT02333760 ) for eight patients with WAS having undergone phase I/II lentiviral vector-based gene therapy trials (nos. NCT01347346 and NCT01347242 ), with a focus on thrombocytopenia and autoimmunity. Primary outcomes of the long-term study were to establish clinical and biological safety, efficacy and tolerability by evaluating the incidence and type of serious adverse events and clinical status and biological parameters including lentiviral genomic integration sites in different cell subpopulations from 3 years to 15 years after gene therapy. Secondary outcomes included monitoring the need for additional treatment and T cell repertoire diversity. An interim analysis shows that the study meets the primary outcome criteria tested given that the gene-corrected cells engrafted stably, and no serious treatment-associated adverse events occurred. Overall, severe infections and eczema resolved. Autoimmune disorders and bleeding episodes were significantly less frequent, despite only partial correction of the platelet compartment. The results suggest that lentiviral gene therapy provides sustained clinical benefits for patients with WAS.

Disposition of intact liposomes of different compositions and of liposomal degradation products.

Small unilamellar liposomes containing bovine serum albumin were prepared by a new double-emulsion technique and administered to mice and rats in intravenous injections. The elimination of intact liposomes, the association of phospholipid marker with lipoproteins, and the appearance of released internal marker and its degradation products were followed by column chromatography of plasma samples. In vitro labelled lipoproteins were administered to the animals in intravenous injections together with free bovine serum albumin and the elimination of the two substances was studied by closely related techniques. The clearance of intact PC:PS (4:1) liposomes from plasma was biphasic and much faster than that of labelled lipoproteins and bovine serum albumin either originating from liposomes or injected as such. The second elimination phase for these liposomes was barely detectable by our analytical methods. In contrast, DSPC:CHOL (2:1) liposomes showed a very significant second-phase elimination, with a half-life of 12 hr for the intact liposomes. In tissue distribution studies in mice, the major accumulation of liposomal markers was found in the liver and spleen, and less in the kidneys and intestinal wall. Uptake into liver and spleen appeared to be due to the uptake of intact liposomes, whereas the uptake into kidneys and gut wall was caused by the uptake of liposomal degradation products. The uptake of PC:PS (4:1) liposomes into the liver was higher than that of DSPC:CHOL (2:1) liposomes; the opposite was the case with their uptake into the spleen. In rats, too, liposomes of different compositions showed significant variations in stability and in plasma half-lives of intact liposomes. Generally, there was a considerable increase in the liposomal stability in the presence of cholesterol and when use was made of a phospholipid with a high transition temperature.

[Current role of doxycycline in the chemoprophylaxis of Plasmodium falciparum malaria]. / Place actuelle de la doxycycline dans la chimioprophylaxie du paludisme à Plasmodium falciparum.

In countries where chemoresistance of Plasmodium falciparum is high (group III), mefloquine must be advocated for malaria prophylaxis for a stay less than 3 months. If it is more and particularly in Indo-china peninsular countries (Thailand, Birmania, Kamputchéa, Laos, Vietnam) and in Amazonia, advocated chemoprophylaxis is doxycycline 100 mg per day. Authors remind action mechanism, contraindication and side effects of this drug. Others publications underline the good tolerance of doxycycline now used by 1,400 french soldiers staying for 6 months with United Nations Organisation in Kamputchéa. An evaluation of tolerance and efficiency of this chemoprophylaxis is now in progress.

[Sicca syndrome and low-grade chronic viral hepatitis C. Apropos of a series of 50 cases]. / Syndrome sec et hépatite virale chronique C de bas grade. A propos d'une série de 50 cas.

Systemic manifestations are described in chronic hepatitis C. Haddad et al have showed the prevalence of sicca syndrome with lymphocytic sialadenitis. We analysed prevalence in 50 patients suffering from chronic hepatitis C with histologic low rank. 50% of them have pronounced abnormality of lachrymal secretion without sialadenitis. It seems that sicca syndrome is present in low rank hepatitis. In that case xerophtalmia preceded xerostomia.

[Chronic diarrhea since returning from Black Africa. "Think of tropical sprue"!]. / Diarrhée chronique au retour d'Afrique noire "penser à la sprue tropicale"!

Tropical sprue is a diagnosis about which we have to think when we are confronted to a patient back from overseas. We examined a young man back from Central African Republic where he got diarrhoea which keeps going on in France, with alteration of his general condition and stigmata of malabsorption. Taking advantage of such observation, the authors report on the present knowledge about that disease peculiar to tropical zone. Biological elements of malabsorption are associated to partial emaciation of villi of small intestine. As a matter of fact, diagnosis is made by elimination. Its pathogenesis remains unknown and is linked to some troubles of intestinal microbism of which exact causes has not been yet put into evidence. An easy treatment by tetracycline and folic acid is a true diagnosis test, as general condition is set up again, as well as villi intestinalis.

[Acute infectious diarrhea: current treatment and perspectives]. / Diarrhées aiguës infectieuses: traitement actuel et perspectives.

Acute infectious diarrhea is a worldwide public health problem. In developing countries it remains a major cause infant mortality despite therapeutic progress, especially with regard to the efficacy of oral rehydration, during the last two decades. Mortality in industrialized countries is much lower and generally stable. In most cases, acute diarrhea is a self-limiting illness that resolves with or without symptomatic treatment in a few days. In view of the high frequency and generally benign course of diarrheal diseases, management must emphasize a cost-effective approach with selective use of available diagnostic methods. The initial approach should be based on the patient's history, physical examination, and risk factors to identify infections that require more specific measures. The purpose of this report is to review currently available drug therapies and to describe treatment guidelines for adolescents and adults with uncompromised immune systems. Early rehydration is still the mainstay of treatment. Use of "etiological" treatment using antimicrobial or antiparasitic agents depends on the severity of disease and risk factors.

[Helicobacter pylori infection in developing countries]. / L'infection à Helicobacter pylori dans les pays en dévelopment.

Helicobacter pylori infection is probably the most common bacterial infection in the world. The pathogenicity of this bacteria has been recognized since 1989 in the developed world where prevalence is 20 to 40%. Its role in gastric and duodenal disease is certain and its low recurrence rate justifies eradication. In the developing world prevalence of Helicobacter pylori infection is over 80% with contamination being maximal in children. Transmission is oro-oral and even feco-oral. Crowded living conditions is the determinant factor. Helicobacter pylori infection exhibits special features in developing world. The prevalence of gastroduodenal disease varies according to geographic area independently of the prevalence of Helicobacter pylori infection and stomach cancer is uncommon. In newborns Helicobacter pylori infection seems to be the primary event for chronic malnutrition and diarrhea syndrome with failure to thrive. In practice detection of Helicobacter pylori is difficult in the developing world and presumptive treatment is always followed by recurrence. In the future active or passive immunization will be the solution.

[Eosinophilic gastroenteritis: an example of gastrointestinal toxicity of eosinophils]. / La gastroenterite a eosinophiles: un exemple de la toxicite digestive de l'eosinophile.

Toxicity of polynuclear eosinophils in the digestive tract results from a cascade of immune responses involving various mediators including mastocytes and T-lymphocyte helpers. Polynuclear eosinophils may be implicated in many digestive disorders. This involvement is well established in eosinophilic gastroenteritis which has become the model for study of eosinophil toxicity on the digestive tract. Considered to be of uncertain etiology up until 1998, this mechanism is well illustrated by the case described in this report involving infiltration of all layers of the small intestinal mucosa in a 23-year-old patients who responded well to corticosteroid treatment. This case provides the opportunity to update physiopathologic and therapeutic data concerning this unpredictable syndrome. Current evidence of transition forms from idiopathic hypereosinophilic syndrome casts doubt on the conventional classification of eosinophilic gastroenteritis and underlines the need for careful diagnostic work-up and prolonged follow-up.

[Chronic tropical pancreatitis: a case report]. / La pancréatite chronique tropicale: à propos d'un cas.

The purpose of this report is to describe a case of tropical calcific pancreatitis (TCP). This disease is specific to tropical regions and constitutes the main cause of chronic pancreatitis in children worldwide. It can also be observed in young adults (2nd and 3rd decade). Shortage of dietary lipids during childhood has been implicated in the development of TCP and mutation of the SPINK1 gene has been cited as a predisposing genetic factor. The underlying pathophysiology of TCP is the same as chronic calcific pancreatitis (CCP) due to alcohol abuse. The main features are a sex ratio of 1, absence of alcohol consumption, occurrence of childhood diabetes in one third of cases, low incidence of acidoketosis, and presence of macro-calcifications especially in ducts. In 10% of cases TCP is complicated by pancreatic carcinoma occurring at an early age, located mainly in the body and tail of the pancreas, and having a less favorable prognosis than primary cancer. Treatment of patients with TCP is the same as for patients with CCP due to alcohol abuse. Prevention depends on improvement of nutritional status of the population.

Adenocarcinoma of the upper esophagus.

Glandular heterotopia of the upper esophagus is a congenital abnormality that is frequently discovered during upper digestive tract endoscopy (in 0.26-4.9% of cases), but usually with no malignant potential. Indeed, adenocarcinoma of the upper esophagus related to such lesions is a rare entity. We report here the 27th observation of this rare type of tumor in an 87-year-old man complaining of cervical dysphagia. This adenocarcinoma had developed from an area of gastric heterotopia 3 cm below the upper sphincter of the esophagus. The treatment regimen was based on exclusive radiochemotherapy, which led to a complete endoscopic response at the end of treatment. The patient's symptom-free survival was six months and overall survival was 17 months from diagnosis. This case of a rare tumor of the upper esophagus raises the question of whether the detection and surveillance of this type of heterotopia would be useful and, thus, to be recommended.