Quantitative systems pharmacology modeling sheds light into the dose response relationship of a trispecific T cell engager in multiple myeloma.

In relapsed and refractory multiple myeloma (RRMM), there are few treatment options once patients progress from the established standard of care. Several bispecific T-cell engagers (TCE) are in clinical development for multiple myeloma (MM), designed to promote T-cell activation and tumor killing by binding a T-cell receptor and a myeloma target. In this study we employ both computational and experimental tools to investigate how a novel trispecific TCE improves activation, proliferation, and cytolytic activity of T-cells against MM cells. In addition to binding CD3 on T-cells and CD38 on tumor cells, the trispecific binds CD28, which serves as both co-stimulation for T-cell activation and an additional tumor target. We have established a robust rule-based quantitative systems pharmacology (QSP) model trained against T-cell activation, cytotoxicity, and cytokine data, and used it to gain insight into the complex dose response of this drug. We predict that CD3-CD28-CD38 killing capacity increases rapidly in low dose levels, and with higher doses, killing plateaus rather than following the bell-shaped curve typical of bispecific TCEs. We further predict that dose-response curves are driven by the ability of tumor cells to form synapses with activated T-cells. When competition between cells limits tumor engagement with active T-cells, response to therapy may be diminished. We finally suggest a metric related to drug efficacy in our analysis-"effective" receptor occupancy, or the proportion of receptors engaged in synapses. Overall, this study predicts that the CD28 arm on the trispecific antibody improves efficacy, and identifies metrics to inform potency of novel TCEs.

[Epidemiology of urinary infections in the Menzel-Bourguiba region: 933 cases]. / Epidémiologie des infections urinaires dans la région de Menzel-Bourguiba: à propos de 933 cas.

The author presents a study about épidémiology of urinary tract infection (UTI) diagnosed in Menzel-Bourguiba hospital laboratory. These UTI are fréquent (933 in 18 months) and often concern ambulatory practice (63.4%). UTI in hospital (36.6%) are most fréquent in internal medicine unit (15.9%) and in pédiatric unit (7.2%). The UTI are most fréquent in female gender (sex ratio F/H = 3.0). The most fréquent isolates are Enterobacteriacae family (91.7%), and E. coli the major species (73.7%). Resistances to beta-lactams are fréquent either concerning hospital strains or ambulatory patients strains. Beta-lactams family are the most used antibiotics (80% of prescriptions). In hospital, some isolates were shown to possess extended spectrum betalactamase, but these strains became confined in the unit where appear because of the architectural conception of the hospital (pavilion system). Aminoglycosids and fluoroquinolones are very active antibiotics, but cotrimoxazole resistance is frequent. Consequently, before any prescription, it would be necessary an antimicrobial susceptibility study, either for hospital UTI, or for UTI in ambulatory practice.

[Epidemiology of hepatitis C virus infection in the Menzel-Bourguiba region]. / Epidémiologie de l'infection par le virus de l'hépatite C dans la region de Menzel--Bourguiba.

This study include 151 serum samples HCV + which has been diagnosed during 3 years. The number of patients HCV + (110) is increasing every year, but the rate of blood donors HCV + remain stable (1.18%). An epidemiological study was made about 81 patients HCV + from gastroenterologic unit. It appears that these patients are old (60.4 years on average), often women (ratio H/F = 0.68), and treated for chronic diseases. The source of infection usually known (blood transfusion, hemodialysis, surgical operation,...) are not predominant (33.2%), and we think about nosocomial transmission. The serotype 1 is predominant (60.7%), but he is associated with poor therapeutic efficiency. There is not vaccine, and obviously preventive measures are essentials to limit the progression of HCV infection.

[Crohn's disease of the esophagus. Apropos of a case]. / Maladie de Crohn de l'oesophage. A propos d'une observation.

The authors report a case of Crohn's disease of the esophagus, stomach, small intestine, colon and rectum in a 34-year-old patient. The esophagus was affected three months after diagnosis of the ileo-rectal lesion. They discuss clinical and therapeutic aspects of the condition. They stress the value of upper endoscopy with multiple biopsies in providing the diagnosis. Treatment is essentially medical, surgery being restricted to fistulas after failure of medical treatment and parenteral nutrition, and to severe stenoses after failure of endoscopic dilatation.

[Tuberculous abscess of the liver. Apropos of 2 cases]. / Abcès tuberculeux du foie. A propos de deux observations.

The authors report two cases of tuberculous liver abscess. They stress the rarity of this site, and differential diagnostic difficulties with other types of infection and liver tumors, notably amebiasis, hydatid cyst and carcinoma. Echo- or Scan-guided needle biopsy is useful for diagnosis and, in some cases, treatment by drainage of the purulent cavity.

[A new technic of continent urinary diversion: preliminary results]. / Une nouvelle technique de dérivation urinaire continente: résultats préliminaires.

This paper presents the results of a series of 10 continent urinary valves performed in the urology department of Ibnou-Rochd hospital in Casablanca according to an original technique between 1991 and 1993. These 10 patients (6 men and 4 women) suffered from various diseases of the lower urinary tract: 4 bladder tumrous, 3 complex vesicovaginal fistulae, two of which were associated with a rectovaginal fistula, one bladder exstrophy, one neurogenic bladder and one extensive urethral stricture. The authors describe the surgical technique and the postoperative course. A detubularized ileal graft was used to create a monoblock valve-reservoir. An effective antireflux system protects the upper urinary tract and continence is ensured by a robust hydraulic valve whose flexibility and patency allow very easy self-catheterization. The physical and urodynamic characteristics of this new diversion make it a solid, perfectly continent solution providing undeniable comfort for the patient. Although based on a limited series, these results illustrate the advantages of this new continent detubularized ileal graft diversion.

[Staphylococcus aureus in the hospital milieu]. / Staphylococcus aureus en milieu hospitalier.

This study concern the distribution and sensibility towards some antibiotics of 318 Staphylococcus aureus strains isolated in bacteriological samples coming from la Rabta hospital units. The study of distribution shows that 75% of these strains are isolated in bacteriological samples coming from surgery and intensive care unit dermatology unit, and ear nose and throat unit. The bacteriological samples are matter, blood, and intensive care materials. The study of sensibility found a high frequency of methicillin resistant Staphylococcus aureus. These strains are also resistant towards macrolide and lincosamide. MLSB resistance is the predominant phenotypic aspect. It was also observed that all of Staphylococcus aureus gentamicin resistant strains were also resistant toward methicillin. At last is seems that pritinamicin, sulfamethoxazole-trimethoprim, and ofloxacin, are good alternatives for treatment of staphylococcus aureus infections diseases.