Mobilization of peripheral blood stem cells with chemotherapy and cytokines in multiple myeloma.

In an attempt to offset the impaired hematopoietic progenitors' mobilization and collection which are frequently encountered in multiple myeloma (MM), we have started a pilot study to evaluate the ability of a combination of high-dose melphalan (HDM) and sequential s.c. administration of recombinant human interleukin 3 (rhIL-3) and rh-granulocyte colony-stimulating factor (G-CSF) to mobilize blood cells (BC) in MM patients. Two different schedules for administration were successively tested. Schedule A consisted of IL-3 (5 micrograms/kg/d) from day 7 to day 11 after HDM followed by G-CSF (5 micrograms/kg/d) from day 12 to day 20. Under schedule B, HDM was followed by IL-3 alone at the same dosage from day 1 to day 3, IL-3 and G-CSF (idem) from day 4 to day 7 and G-CSF alone from day 8 until completion of apheresis. Two patients (one previously untreated, one having received prior chemotherapy for one year) underwent schedule A; three patients (one previously untreated, two pretreated) underwent schedule B. The post-HDM aplasia was not shortened in schedule A patients in comparison to what we usually observed following HDM alone (25 days) correlated with a very moderate two- to three-fold CD34+ cell increase. Only one patient was further transplanted with apheresis products: the post-transplant granulocyte recovery was slower than usual (16 days versus 12 days) while platelet count never recovered over 20 x 10(9)/l. In contrast, the post-HDM aplasia was significantly shortened in two of the schedule B patients (3 to 10 days) and was followed by a 25- to 165-fold increase in CD34+ cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative survival, quality of life and cost-effectiveness of intensive therapy with autologous blood cell transplantation or conventional chemotherapy in multiple myeloma.

We retrospectively compared survival time, quality of life, and the therapy costs in 37 patients suffering from newly diagnosed multiple myeloma (MM), divided into 3 groups. Twelve patients with grade III MM, according to the classification of Durie-Salmon, all with widespread lytic lesions (group I), underwent a two-phase intensive therapy. They first received high-dose melphalan (HDM), both as tumor-reducing and blood cell (BC)-mobilizing chemotherapy, subsequently followed by BC transplantation. Group II comprising 10 patients, also with grade III MM and with characteristics similar to those of group I, were treated with conventional polychemotherapy. Finally, group III enrolled 15 patients with lower grade disease (grade II) who were also treated with conventional chemotherapy. The median overall survival time and the quality of life index were significantly lower in group II than in group I (P = 0.0013 and < 0.001 respectively). Although the overall survival time of group III (43 months) was similar to that of group I, its quality of life index was also significantly lower (P < 0.05). However, the total therapy costs of group I were globally higher than those of the 2 other groups, but when absolute cost-effectiveness as well as qualitative cost-effectiveness (corrected for quality of life) were analyzed, the costs per week of life gained of group I compared extremely favorably with those of group II and, to a lower degree, of group III. Intensive therapy therefore seems capable of substantially improving the survival time for high-risk MM patients with satisfactory quality of life and at a reasonable cost.

Oral diclofenac combined with intra-portal pirarubicin: increased efficacy on liver VX2 tumour and hepatotoxicity in rabbits.

VX2 is a carcinoma established in rabbits and producing an autocrine growth factor, prostaglandin E2. Pirarubicin is a potent anti-VX2 agent. We investigated whether the oral intake of enprostil--a synthetic prostaglandin E2--or of diclofenac--a potent non-steroidal anti-inflammatory drug--increases the efficacy and decreases the hepatotoxicity of pirarubicin when injected in the portal trunk. Enprostil increased the number of hepatic tumoral nodules and induced hepatic alterations, especially venous dilatation. Paradoxically the combination of enprostil and pirarubicin was at least as effective as pirarubicin or diclofenac on VX2 cells. However, the toxicity was increased, especially with respect to sclerosing cholangitis. Diclofenac proved to be as effective as pirarubicin, and the addition of oral diclofenac to local pirarubicin injection increased its antitumoral effect (P < 0.02). However, the combination of diclofenac and pirarubicin was more toxic than pirarubicin alone and induced centrolobular necrosis and sclerosing cholangitis.

Acute overdosage with thioridazine: a review of the available clinical exposure.

Two hundred and twenty-three cases of acute overdosage associated with thioridazine were reviewed. The most frequent feature was impairment of consciousness which was linearly dose-related and occasionally resulted in life-threatening complications. Arrhythmia was the most frequently reported serious toxic effect. Patients presenting with anoxia were at risk for arrhythmia, as were patients ingesting a high dose. Arrhythmia may, by decreasing cardiac output, predispose to the occurrence of all other observed complications (ie, pulmonary edema, severe hypotension and renal failure). Therefore, treatment of arrhythmias should be the keystone of management of thioridazine overdosage. Torsade de pointes was reported only once with overdosage. Isolated ventricular arrhythmias (VA) occurred at high doses (median 12 g). At lower doses (median 5 g), VA were frequently associated with conduction disturbances, which were not, as such, statistically predictive of arrhythmias. Since thioridazine in high doses exhibits a beta-adrenoceptor and a verapamil-like calcium channel blocking effect, drugs with these types of properties are contraindicated. VA may be refractory to lidocaine or recur after such therapy. Transient cardiac pacing appears to be the most appropriate management of VA. Although its efficacy is established for the treatment of phenothiazine-induced arrhythmias, its use remains rare (only 3/50 cases).

Acute ketotifen overdosage. A review of present clinical experience.

Ketotifen (Zaditen) is a widely used prophylactic antiasthmatic drug with pronounced antianaphylactic properties and a specific H1-antihistaminic effect. This article summarises the available information on acute overdosage of this drug, which was reported in 13 adults and 8 children. The symptoms of acute overdosage observed with ketotifen are similar to those described for antihistaminic agents. However, it would appear that the acute toxicity of ketotifen is rather low, since no serious effects have been reported either in children or in adults after the intake of up to 20mg of ketotifen, which is 10 times the recommended dose. No lethal outcome of acute overdosage has been described in association with this drug. Ketotifen seems to be better tolerated in children than in adults. Based on present clinical experience, management of acute overdosage includes gastric lavage within 2 to 4h after ingestion or activated charcoal after this period. Symptomatic treatment is indicated if arrhythmias, hypotension or seizures develop, and the patient should be kept under surveillance for at least 6 to 8h.

Transient cardiac pacing is insufficiently used to treat arrhythmia associated with thioridazine.

All cases of arrhythmias associated with thioridazine were reviewed (177 cases). No case of severe ventricular arrhythmia was reported in children. In adults, at therapeutic doses, ventricular tachycardia or fibrillation (VT/VF) or torsade de pointes was observed mainly in patients with concomitant risk factors. At doses higher than 800 mg, atrioventricular (A-V) and bundle branch blocks were associated with VT/VF. Mortality was higher in patients with A-V blocks. Although transient cardiac pacing is known to be efficacious to control phenothiazine-induced arrhythmias, it was rarely used.

Routes of lymphatic drainage from the pancreas: a suggested segmentation.

The peripancreatic lymphatics were dissected after intrapancreatic injections of different colorants by territory. The aim of this study was partly to determine the lymphatic drainage routes specific to each pancreatic segment, and partly to define the nodal relay stations for each territory. Whatever the site of injection in the segment of the body and tail, the dye followed the splenic and inferior pancreatic pathways before reaching a left intercelio-mesenteric node (ICMN) and then the supra- and infrarenal nodal groups. However, three distinct drainage routes emerged for the head of the pancreas. The lymphatics of the uncus (anterior and posterior aspects) follow the superior mesenteric route to reach a right ICMN and then the supra- and infrarenal relays bilaterally. Rarely, the lymphatics of the posterior uncus may pass directly to the supra- and infrarenal relays. The anterosuperior segment of the head drains by the gastroduodenal route. This route crosses the superior border of the pancreas and joins the right ICMN. There is an inferior route for this segment which turns back along the inferior border of the isthmus. After injection into the posterosuperior segment of the head, the dye frequently refluxes along the common bile duct and hepatic artery and stains the pericholedochal and hepatic pedicular nodes. When the dye is not entirely collected by these large nodal stations, it goes to join the right ICMN. The right ICMN is the principle relay station for the head of the pancreas. The dye flows only from the pericholedochal relays towards the right ICMN, never in the opposite direction (right ICMN to pericholedochal relays).(ABSTRACT TRUNCATED AT 250 WORDS)

Ki67 index and S-phase fraction in human breast carcinomas. Comparison and correlations with prognostic factors.

In a prospective study of 148 consecutive breast adenocarcinomas, proliferative indices of the same surgical tumor sample were performed by immunohistologic staining (Ki67 index) with the use of the Ki67 monoclonal antibody, which binds to a nuclear antigen only expressed in cycling cells, and by flow cytometry-derived S-phase fraction (SPF). Measurable Ki67 and SPF indices were obtained in 142 cases and 99 cases, respectively, and in 96 cases by both methods. In aneuploid tumors, a significant but low (P less than 0.05, r = 0.3) relationship was observed between Ki67 index and SPF. When compared with clinical, pathologic, and biochemical parameters these two proliferative indices were shown to be associated with nuclear grading and mitotic index. Additionally, correlations were observed between Ki67 index and node involvement (P less than 0.02) and between SPF and estrogen receptors (P = 0.002). These results show that (1) proliferative indices are obtained in 96% of surgical samples with Ki67 versus 67% with SPF and that (2) Ki67 index and SPF may provide complementary data with respect to prognosis.

A systematic study of the vascularisation of the pancreas.

The anatomy of the vessels of the pancreas is well known. However, some refinement is necessary in response to new requirements. In this study 40 specimens of pancreas plus duodenum were dissected after injecting the vessels with latex. Arteries and veins were measured and drawn. The origin and course of the vessels and their anastomoses were studied. If the vessels less than 0.5 mm in diameter are disregarded, it is seen that the vascularisation of the head of the pancreas can be systematized. Since the development of very selective arteriography and phlebography, two main types of artery and of vein have been discerned. Charts of the vessels for such an identification have been suggested. The two types of vessel are either terminal or anastomotic. Determination of the type of vessel can be useful: for the localisation of endocrine tumors of the pancreas by selective catheterisation; in making the decision for a limited operative intervention when immediate effective blood supply of the remaining tissue is important.