Total pancreatectomy with islet autotransplantation: an overview

Pain control is one of the most challenging aspects in the management of chronic pancreatitis. Total pancreatectomy can successfully relieve the intractable abdominal pain in these patients but will inevitably result in insulin-dependent diabetes. Islet autotransplantation aims to preserve, as far as possible, the insulin secretory function of the islet cell mass thereby reducing (or even removing) the requirement for exogenous insulin administration after a total pancreactomy. Despite the relatively small number of centres able to perform these procedures, there are important technical variations in the details of their approaches. The aim of this review is to provide details of the current surgical practice for total pancreatectomy combined with islet autotransplantation, and outline the potential advantages and disadvantages of the variations adopted in each centre.     

Thrombin regulates components of the fibrinolytic system in human mesangial cells

Besides its procoagulant activity, thrombin has been shown to stimulate cell proliferation and to regulate the fibrinolytic pathway. We report here the effect of purified human alpha thrombin on the synthesis of tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor 1 (PAI-1) by cultured human mesangial cells. Thrombin (0 to 2.5 U/ml) increased in a time- and dose-dependent manner the production of t-PA and PAI-1 (2- to 3-fold increase of secreted t-PA and PAI-1 release during a 24 hour incubation). This effect was associated with a twofold increase in DNA synthesis measured by 3H-thymidine incorporation. Zymographic analysis and reverse fibrin autography showed that thrombin also increased the level of the 110 Kd t-PA-PAI-1 complex, whereas PAI-1 was present as a free 50 Kd form in the culture medium conditioned by unstimulated and thrombin-stimulated cells. Free t-PA was never observed. Both membrane binding and catalytic activity of thrombin were required since the effects of 1 U/ml thrombin were inhibited by addition 2 U/ml hirudin, which inhibits the membrane binding and catalytic activity of thrombin, and since DFP-inactivated thrombin, which has the ability to bind but which has no enzymatic activity, did not induce t-PA or PAI-1. Gamma thrombin, which does not bind to thrombin receptor, did not increase t-PA and PAI-1 releases. The effects of thrombin were probably mediated by protein kinase C activation since H7, an inhibitor of protein kinases, inhibited significantly thrombin effects on t-PA and PAI-1 production, and since addition of an activator of protein kinase A, 8-bromocyclic AMP (100 microM), induced a significant inhibition of the thrombin effect. The effects of thrombin were also suppressed by 1.25 micrograms/ml alpha amanitin, suggesting a requirement of de novo RNA synthesis. Northern blot analysis indicated that thrombin induced an increase in the mRNA levels of t-PA and of PAI-1. We conclude that thrombin increases DNA synthesis in human mesangial cells and enhances the synthesis of both t-PA and PAI-1. The latter is released in a large excess as compared to t-PA. Hence, thrombin may have a role in provoking a localized hypofibrinolytic state and may contribute to the persistence of glomerular fibrin deposits during proliferative glomerulonephritis.     

Benzamide derivatives provide evidence for the involvement of a 5-HT4 receptor type in the mechanism of action of serotonin in frog adrenocortical cells.

We have previously shown that serotonin (5-HT) is a potent stimulator of corticosterone and aldosterone secretion by frog adrenocortical cells and we have demonstrated that the action of 5-HT is not mediated by the classical 5-HT receptor subtypes i.e. 5-HT1, 5-HT2 and 5-HT3. Recently, a non-classical 5-HT receptor (termed 5-HT4) has been characterized using 4-amino-5-chloro-2-methoxy-benzamide derivatives as serotonergic agonists. In the present report, we have investigated the possible involvement of the 5-HT4 receptor subtype in the mechanism of action of 5-HT on steroid secretion. Increasing concentrations of benzamide derivatives (zacopride, cisapride and BRL 24924) gave rise to a dose-related stimulation of corticosteroid production, zacopride being the most potent compound of this series to enhance steroidogenesis. Prolonged administration (230 min) of zacopride induced a rapid increase in corticosterone and aldosterone output followed by a gradual decline of corticosteroid secretion. During prolonged exposure of adrenal tissue to zacopride (10(-5) M), the corticotropic activity of 5-HT (10(-6) M) was totally abolished. The stimulatory effects of 5-HT and zacopride were abolished by the non-selective 5-HT3 antagonist ICS 205 930. In contrast methysergide, a 5-HT1 receptor antagonist, and MDL 72222, a selective 5-HT3 antagonist did not block zacopride-induced corticosteroid secretion. Both 5-HT and zacopride induced a dose-related increase in cAMP production by frog adrenal slices. Taken together, these results indicate that the stimulatory effect of 5-HT on frog adrenocortical tissue is mediated by activation of a 5-HT4 receptor subtype positively coupled to adenylate cyclase.     

Evaluation after four years of exercise therapy for chronic low back pain]

OBJECTIVE: To assess at four years follow-up the efficiency of exercise therapy for chronic low back pain in terms of pain, physical ability, quality of life and return to work. MATERIALS AND METHODS: Patients who graduated from a functional restoration program between April 1997 and June 1999, answered a questionnaire at one year follow-up. The patients who had answered this questionnaire were evaluated 48 months later: they first answered another questionnaire and then most underwent a clinical examination assessing pain on a visual analogue scale, flexibility by use of the Sch?ber index and the finger-ground distance test, endurance of abdominal and spinal muscles, and quality of life as assessed by the Dallas pain questionnaire. RESULTS: Thirty-four patients graduated from the program; 26 were studied at four-year follow-up. Pain intensity was significantly reduced. Improvement in flexibility after the program remained at four-year follow-up, whereas improvement in endurance did not. Scores on the Dallas pain questionnaire remained as improved as those at one-year follow-up. Initially, 23 of the 26 patients had a job; 19 were on sick leave for an average of 35 weeks. At four-year follow-up, 16 patients were still working, and 56% had changed jobs. Six patients pursued a regular activity before entering the program; at four-year follow-up, 17 were regularly active. No significant relationship was found between the pursuit of physical activity and return to work. Nevertheless, a significant relationship was found between having a regular physical activity and improvement of the finger-ground distance and endurance of spinal muscles. This observation was not true for the Dallas pain questionnaire scores. CONCLUSION: Despite the lack of a control group, this study seems to favour a benefit in the functional restoration program.     

Epidermal growth factor receptor in human breast cancers: Correlation with estrogen and progesterone receptors

Epidermal growth factor receptor (EGFR), determined by the Scatchard curve method, was found in 22 cases of a random series of 100 patients with breast carcinoma. Two groups of patients were identified, one (n = 16) with a low concentration (0–50 fm/mg protein) of EGFR but with a high affinity (Kd = 3.2 nM), and the other (n = 6) with a high concentration (90–210 fm/mg protein) of EGFR but with a lower affinity (Kd = 6.3 nM).A significant inverse relationship was found between the presence of EGFR and receptors for estrogen (p<0.001) and progesterone (p = 0.001). EGFR was found in no (0/8) tumors with Grade I histoprognostic grade, 17% (10/58) Grade II, and 38% (11/29) Grade III (p<0.05). EGFR is present therefore in poorly differentiated tumors and associated with other factors of poor prognosis. Ourin vivo analyses confirm results found in tissue culture derived from human breast carcinoma cells.With the technical assistance of J. Barraque.     

Videosurgery in oncological pediatrics

As a recent innovation, videosurgery (VS) has enjoyed rapid and widespread development. While colon cancers in adults are quite commonly removed using laparoscopic techniques, children could also benefit from the improved diagnostic and interventional possibilities using VS techniques. From January 1992 to February 1994, we carried out 15 procedures. Eight thoracic operations were performed on 7 patients: diagnostic in 5 cases and metastasis resection in 3. Six patients underwent 7 laparoscopic operations for biopsies (5) or lymph-node harvesting (2). Based on this experience, we discuss the advantages of VS (noninvasive technique for primary or second-look exploration, guided biopsies, and removal of tumors) and its risks (spillage of malignant cells, subjective palpation) in the management of pediatric malignancies.     

Combined treatment with arsenic trioxide and all-trans-retinoic acid in patients with relapsed acute promyelocytic leukemia.

PURPOSE: Arsenic trioxide (ATO) is capable of inducing a high hematologic response rate in patients with relapsed acute promyelocytic leukemia (APL). Preclinical observations have indicated that all-trans-retinoic acid (ATRA) may strongly enhance the response to ATO. PATIENTS AND METHODS: Between 1998 and 2001, we conducted a randomized study of ATO alone versus ATO plus ATRA in 20 patients with relapsed APL, all previously treated with ATRA-containing chemotherapy. The primary objective was to demonstrate a significant reduction in the time necessary to obtain a complete remission (CR) in the ATO/ATRA group compared with the ATO group. Secondary objectives were safety and molecular response. RESULTS: The CR rate after one ATO with or without ATRA induction cycle was 80%. Clinical and pharmacokinetic observations indicated that the main mechanism of action of ATO in vivo was the induction of APL cell differentiation. Hematologic and molecular response, time necessary to reach CR, and outcome were comparable in both treatment groups. Of 16 CR patients, three patients who reached a molecular remission after one induction cycle had all received chemotherapy for a treatment-induced hyperleukocytosis. Three additional patients who received further additional ATO with or without ATRA cycles converted later to molecular negativity. CONCLUSION: ATRA did not seem to significantly improve the response to ATO in patients relapsing from APL. Other potential combinations, including ATO plus chemotherapy, have to be tested.     

Congenital infiltrating lipomatosis of the face with lingual mucosal neuromas associated with a PIK3CA mutation

We report the case of a 5-year-old girl with congenital right-sided facial hemihypertrophy and right hemi-macroglossia with lingual mucosal neuromas. The segmental presentation of findings suggested the diagnosis of congenital infiltrating lipomatosis of the face (CILF), which belongs within the PIK3CA-related overgrowth spectrum (PROS). This was confirmed by genetic analysis showing a mosaic mutation in PIK3CA H1047R. CILF/PROS should be considered in the differential diagnosis of mucosal neuromas.