Hepatic arterial infusion of a replication-selective oncolytic adenovirus (dl1520): phase II viral,immunologic, and clinical endpoints

Replication-selective oncolytic adenoviruses are being developed for the treatment of cancer, but the safety and feasibility of repeated adenovirus delivery to tumors via the bloodstream was unknown, particularly in light of a patient death after hepatic artery infusion of a replication-defective adenovirus vector. We performed a Phase II trial of an oncolytic replication-selective adenovirus (dl1520, also known as Onyx-015) administered by hepatic artery infusion in patients with gastrointestinal carcinoma metastatic to the liver (n = 27). dl1520 was infused into the hepatic artery (2 x 10(12) particles) on days 1 and 8 as a single agent, and thereafter starting on day 22 in combination with i.v. 5-fluorouracil and leucovorin every 28 days. Repeated viral infusions were feasible, and no deaths occurred on study; reversible grade 3/4 hyperbilirubinemia occurred in 2 patients. Systemic inflammatory cytokine responses varied greatly between patients and even between cycles within a given patient. Proinflammatory cytokines [e.g., tumor necrosis factor, IFN-gamma, and interleukin (IL) 6] typically rose within 3 h and were followed at 18 h by a rise in IL-10. However, in the single patient who suffered a severe but reversible systemic inflammatory response, a unique cytokine profile was detected: marked acute increases of IL-6 (20-fold higher than average for all of the patients) and inhibition of IL-10 production. Delayed secondary peaks of viremia were reproducibly detected 3-6 days after treatment, even in the presence of high level neutralizing antibody titers and antiviral cytokines. Mathematical modeling was used to calculate the number of virus particles produced and shed into the blood with each replication cycle. The combination of virotherapy and chemotherapy had antitumoral activity in some chemotherapy-resistant colorectal tumors. The intra-arterial infusion of oncolytic adenoviruses warrants additional study.     

CHIR-258 is efficacious in a newly developed fibroblast growth factor receptor 3-expressing orthotopic multiple myeloma model in mice.

PURPOSE: The ectopically expressed and deregulated fibroblast growth factor receptor 3 (FGFR3) results from a t(4;14) chromosomal translocation that occurs in approximately 15% of multiple myeloma (MM) patients and confers a particularly poor prognosis. This study assesses the antimyeloma activity of CHIR-258, a small-molecule inhibitor of multiple receptor tyrosine kinases that is currently in phase I trials, in a newly developed FGFR3-driven preclinical MM animal model. EXPERIMENTAL DESIGN: We developed an orthotopic MM model in mice using a luciferase-expressing human KMS-11-luc line that expresses mutant FGFR3 (Y373C). The antimyeloma activity of CHIR-258 was evaluated at doses that inhibited FGFR3 signaling in vivo in this FGFR3-driven animal model. RESULTS: Noninvasive bioluminescence imaging detected MM lesions in nearly all mice injected with KMS-11-luc cells, which were mainly localized in the spine, skull, and pelvis, resulting in frequent development of paralysis. Daily oral administration of CHIR-258 at doses that inhibited FGFR3 signaling in KMS-11-luc tumors in vivo resulted in a significant inhibition of KMS-11-luc tumor growth, which translated into a significant improvement in animal survival. CONCLUSIONS: Our data provide a relevant preclinical basis for clinical trials of CHIR-258 in FGFR3-positive MM patients.     

CYP11β1 (11-beta-hydroxylase) deficiency in congenital adrenal hyperplasia

Objective : To review experience of CYP11β1 deficiency (previously known as 11β-hydroxylase) at the Royal Children's Hospital, Melbourne, Victoria.
Methodology : A retrospective case review was conducted from 1974 to 1995 with five cases identified.
Results : Age of presentation ranged from 1 day to 7 years. Presentation was with ambiguous genitatia at birth (two females), simple virilization (two males) and suspected early puberty in mid childhood (one female). Associated clinical features were hypertension (three cases) and tall stature with markedly advanced bone age (four cases). Biochemical abnormalities consistent with CYP11β1-deficiency were elevated urinary tetrahydro-11-deoxycortisol ( n = 5) and elevated serum 11-deoxycortisol ( n = 3). Additional abnormalities were elevated 17-hydroxyprogesterone ( n = 3), elevated androstenedione ( n = 4) and elevated dehydroepiandrosterone sulphate ( n = 4). The clinical features and investigations suggested CYP11β1-classical deficiency in four patients and CYP11β1-non-classical deficiency in one patient.
Conclusions : The five cases of CYP11β1-deficiency demonstrate a spectrum of clinical abnormalities, with diagnostic difficulties in two cases and delayed presentation in three cases. Prompt diagnosis of CYP11β1-deficiency is facilitated greatly by the availability of a gas chromatography-mass spectrometry instrument and is essential to avoid the long-term effects of hypertension and hyperandrogenism.     

Predictive Value of Facial Nerve Electrophysiologic Stimulation Thresholds in Cerebellopontine-Angle Surgery

The predictive value of intraoperative stimulation thresholds for facial nerve function, using a constant-current system, was examined in 49 patients undergoing resection of cerebellopontine-angle tumors. Immediately after surgery, 75% of the 0.1-mA threshold group, 42% of the 0.2-mA group, and 18% of the 0.3-mA or greater group had good (grade I or II) facial nerve function. One year after surgery, 90% of the 0.1-mA group, 58% of the 0.2-mA group, and 41% of the 0.3-mA or greater group had grade I or II function. A statistically significant breakpoint of 0.2 mA was found to predict good postoperative facial function. Delayed facial paralysis occurred in 22% of patients, but the prognosis for these patients was favorable. Both current stimulation threshold and duration are necessary for a meaningful comparison of data between investigators. Laryngoscope, 106:633-638, 1996     

Die intraoperative Messung der hydraulischen Impedanz—ein Prognosekriterium für die Offenheitsrate femorokruraler Bypässe

Zusammenfassung Bei 68 femorokruralen PTFE-Bypassanlagen wurde mit Hilfe der extrakorporalen Bypassflowmessung (EBF) die hydraulische Impedanz sowohl des gesamten Abstromgebietes als auch der selektiven distalen ante- und retrograden Ausstromregionen gemessen. Bei der EBF-Methode wird ein Silikonschlauch temporär zwischen die A. femoralis communis und dem kruralen Anschlussgefäß platziert. In diesem temporären Bypass befanden sich ein elektromagnetischer Flussmesskopf sowie ein Anschluss zur Druckmessung. Die gemessenen hämodynamischen und Impedanzparameter wurden mit den primären und sekundären Offenheitsraten der Bypässe nach 3 Jahren korreliert.Es zeigte sich, dass eine distale Flussaufteilung im Verhältnis von 1:1 bei kruralen Ausstromverhältnissen bestand. Im Mittel flossen 65 ml/min nach distal und 70 ml/min nach proximal. Von allen untersuchten Parametern zeigte sich lediglich der erste Impedanzphasenwinkel, welcher den Wellenwiderstand charakterisiert, als statistisch signifikant mit den Offenheitsraten nach 3 Jahren verbunden. Während der Grenzwert für den totalen Abstromwiderstand –40° (p<0,01) betrug, waren es -33° (p<0,05) beim selektiven retrograden und –45° (p<0,01) beim antegraden Ausstrom.     

The excretion of 17-ketosteroids in patients suffering from mastopathia fibrocystica and mammary carcinomas.

Comparative investigations of the urinary excretion of different 17-ketosteroids in healthy women and patients suffering from mastopathia fibrocystica and/or mammary carcinomas had the following results: 1. A clear age dependency of the excretion of 17 ketosteroids during the regenerative period has been shown in all groups investigated, but it could not be observed during the postmenopausal phase. 2. There are no hints by the excretion values for a remarkable contribution of mammary carcinomas to the hormone metabolism of the host. 3. The excretion values of patients suffering from mastopathia fibrocystica confirm epidemiological results, which consider this from of mastopathia a precancerous one.     

The Angiographic Findings in a Haemophilic Pseudotumour of Bone

The angiographic findings in a patient with haemophilic pseudotumour of the femur are presented. The examination showed the position of the displaced femoro-poplited vessels, enabling these structures to be avoided at operation. Under anti-haemophilic globulin cover no complications occurred. It is suggested that angiography may be safely employed provided the coagulation defect is controlled. The examination may be useful in differentiating other bone lesions and in defining more clearly the extent of a haemophilic pseudotumour.