Giant endometrial cyst of the liver: a case report and review of the literature.

Endometriosis is a benign condition described as the presence of endometrial- like tissue found outside the uterine cavity. Hepatic endometriosis is one of the rarest localization of extrapelvic endometriosis, only 22 cases have been reported in the literature. The preoperative diagnosis of hepatic endometriosis is rather difficult because in about the half of the patient affected they had no history of endometriosis. Moreover radiological images reveal no characteristic findings for hepatic endometriosis. It is often described as cystic mass with or without solid component, difficult to distinguish from hepatic abscess, hematoma, cystoadenoma or malignant neoplasia. We report a case of a 27-year-old female with a large cystic mass involving the left lobe of the liver. The patient underwent laparoscopic exploration and converted to laparotomy for resection of giant hepatic endometriosis.

Busulfan pharmacokinetics following intravenous and oral dosing regimens in children receiving high-dose myeloablative chemotherapy for high-risk neuroblastoma as part of the HR-NBL-1/SIOPEN trial.

INTRODUCTION: Busulfan is widely used in a neuroblastoma setting, with several studies reporting marked inter-patient variability in busulfan pharmacokinetics and pharmacodynamics. The current study reports on the pharmacokinetics of oral versus intravenous (IV) busulfan in high-risk neuroblastoma patients treated on the European HR-NBL-1/SIOPEN study. METHODS: Busulfan was administered four times daily for 4 days to children aged 0.7-13.1 years, either orally (1.45-1.55 mg/kg) or by the IV route (0.8-1.2mg/kg according to body weight strata). Blood samples were obtained prior to administration, 2, 4, and 6h after the start of administration on dose 1. Busulfan analysis was carried out by gas chromatography-mass spectrometry and data analysed using a NONMEM population pharmacokinetic approach. RESULTS: Busulfan plasma concentrations obtained from 38 patients receiving IV busulfan and 25 patients receiving oral busulfan, were fitted simultaneously using a one-compartment pharmacokinetic model. Lower variability in drug exposure was observed following IV administration, with a mean busulfan area under the plasma concentration versus time curve (AUC) of 1146 ± 187 µM.min (range 838-1622), as compared to 953 ± 290 µM.min (range 434-1427) following oral busulfan. A total of 87% of children treated with IV busulfan achieved AUC values within the target of 900-1500 µM.min versus 56% of patients following oral busulfan. Busulfan AUC values were significantly higher in HR-NBL-1/SIOPEN trial patients who experienced hepatic toxicity or veno-occlusive disease (VOD) (1177 ± 189 µM.min versus 913 ± 256 µM.min; p=0.0086). Further stratification based on route of administration suggested that the incidence of hepatic toxicity was related to both high busulfan AUC and oral drug administration. CONCLUSION: The reduced pharmacokinetic variability and improved control of busulfan AUC observed following IV administration support its utility within the ongoing HR-NBL-1/SIOPEN trial.

Idarubicinol myelotoxicity: a comparison of in vitro data with clinical outcome in patients treated with high-dose idarubicin.

We evaluated in vitro the toxicity of idarubicin and its active metabolite idarubicinol on haematopoietic progenitors, using human umbilical cord blood and peripheral blood progenitors to obtain dose-response curves. We treated 16 patients with poor prognosis lymphoma in a phase I-II trial of high-dose idarubicin and melphalan and investigated if idarubicinol persisting in patients' plasma at the time of transplantation (day 0), on day +1 and +2 could result in an inhibition of infused progenitors. Colony inhibition was correlated with pharmacokinetic data and with the time of patients' engraftment. Plasma samples obtained before idarubicin treatment demonstrated a colony-stimulating effect, increasing the cloning efficiency by 72%. The inhibitory activity on colony forming unit granulocyte-macrophage (CFU-GM) of patients' plasma collected on the day of transplantation was lower than expected from dose-response curves (21% measured vs 70% expected). The time to patients' WBC and PLT recovery correlated with the amount of CD34+ cells reinfused and, to a lesser extent, with the colony-inhibiting effect of patients' plasma. The correlation between idarubicinol concentration and CFU-GM inhibition was not significant. These data suggest that plasma drug concentration on the day of stem cell reinfusion may overestimate the toxicity of residual anthracyclines to the transplanted cells.

Results of a European comparative randomized study comparing oral bropirimine versus intravesical BCG treatment in BCG-naive patients with carcinoma in situ of the urinary bladder. European Bropirimine Study Group.

OBJECTIVES: This European phase III clinical trial was part of an intercontinental study which was closed prematurely by the sponsor. The study was designed to compare the effects of oral bropirimine with intravesical BCG, the current standard treatment in patients with newly diagnosed bladder carcinoma in situ (CIS). METHODS: A total of 55 BCG-naive patients with bladder CIS were randomized to receive bropirimine (n = 27) or BCG (n = 28). Bropirimine was orally administered at a dose of 3 g/day for 3 consecutive days with a 4-day drug-free interval for up to 1 year. BCG-Tice instillations were administered weekly for 2 x 6 weeks. Both biopsies and cytology had to be negative for the patient to be considered a complete responder (CR). RESULTS: The percentage of dropouts for all of the adverse events was 4% for bropirimine and 14% for BCG. The most frequently reported local events in the bropirimine- versus the BCG-treated group were irritative complaints, 64 vs. 89% (p = 0.03) and hematuria, 24 vs. 61% (p < 0.01). The most frequently reported systemic events in the bropirimine- versus the BCG-treated group were fever 4 vs. 21%, flu syndrome 24 vs. 7%, headache 28 vs. 11% and nausea 24 vs. 11% (all p > 0.05). A total of 92% of the patients treated with bropirimine had a CR with a mean duration of 12.6 months (95% CI 9.2-15.9). In the BCG group, all of the patients had a CR with a mean of 12.3 months (95% CI 8.5-16.0). CONCLUSIONS: This study shows that bropirimine, an orally administered drug that can be self-administered to outpatients with more acceptable local toxicity compared to BCG, could be an effective first-line therapy in patients with CIS of the urinary bladder. Continued investigation of bropirimine is warranted to increase its clinical utility.

Phase I study of high-dose epirubicin and vinorelbine in previously untreated non-small-cell lung cancer stage IIIB-IV.

The aim of the study was to determine the maximum tolerated dose (MTD) for the combination of high-dose epirubicin and vinorelbine in chemotherapy-naive patients with inoperable non-small-cell lung cancer (NSCLC). Twenty-one patients with stage IIIB and IV NSCLC were treated in a single-centre study with escalating doses of epirubicin and vinorelbine given on an outpatient basis. The first dose level comprised epirubicin 100 mg m-2 on day 1 and vinorelbine 20 mg m-2 (days 1 and 8) given intravenously every 3 weeks. Escalating doses for epirubicin and vinorelbine were respectively 120 (day 1) and 20 (days 1 and 8), 120 (day 1) and 25 (days 1 and 8) and 135 (day 1) and 25 (days 1 and 8) mg m-2. Inclusion criteria were age < or = 75 years, ECOG performance score < or = 2 and normal renal, hepatic and bone marrow functions. Dose-limiting toxicities were thrombocytopenia grade II and neutropenia grade III on day 8, febrile neutropenia, and neutropenia lasting > 7 days. No dose-limiting toxicity (DLT) was observed at the first dose level; at the 135/25 mg m-2 dose level three out of six patients had a DLT which was considered as unacceptable. The only non-haematological toxicity reaching grade III was nausea/vomiting. One patient showed cardiac toxicity. No neurotoxicity and no treatment-related deaths were seen. The maximum tolerated dose of epirubicin and vinorelbine is 135 mg m-2 (day 1) and 25 mg m-2 (days 1 and 8) respectively, causing mainly haematological toxicity. The recommended dose of epirubicin and vinorelbine for phase II studies is found to be 120 mg m-2 and 20 mg m-2 respectively.

Pharmacokinetic and pharmacodynamic advantages of pirarubicin over adriamycin after intraarterial hepatic administration in the rabbit VX2 tumor model.

Intraarterial chemotherapy with Adriamycin (ADM) has shown limited advantages over i.v. administration, with no reduction in systemic toxicities and modest decrease in peripheral plasma levels. In an effort to improve the selectivity of i.a. anthracycline chemotherapy, we compared pirarubicin (4'-O-tetrahydropyranyladriamycin, THP) and ADM in the surgically implanted VX2 rabbit tumor model. Both drugs were administered at the same dose (0.5 mg/kg) either by the intraarterial hepatic route (i.a.h.) or by the i.v. route. Anthracycline plasma and tissue levels were determined by high-performance liquid chromatography with fluorescence detection. ADM peak plasma concentration and area under the curve were not significantly reduced after i.a.h. administration compared to the i.v. route; however, ADM tumor concentration was 1.9-fold higher following i.a.h. administration compared to the i.v. infusion. After THP administration by the i.a.h. route, systemic exposure (area under the curve) was markedly reduced (8-fold) compared to the same dose administered i.v. These findings correlated well with the very low concentration of the drug in heart tissue following i.a.h. infusion. After i.a.h. administration, tumor THP concentrations were 10.5 times higher compared to the i.v. route. The pharmacokinetic advantage of i.a.h. administration of THP also led to a better antitumoral effect, as shown by a significantly lower tumor growth rate [3 +/- 2% (SD)] in the i.a.h.-treated animals compared to the i.v.-treated groups (58 +/- 9%). Administration of ADM by the i.a.h. route was also inferior to i.a.h. THP. Taken together, our results suggest a clear-cut advantage of THP over ADM for i.a.h. locoregional chemotherapy, because of higher local tumor concentrations, greater antitumoral effect, and lower systemic exposure following the i.a.h. administration of THP. This anthracycline analogue could also be of therapeutic advantage in tumors partially resistant to anthracyclines that would become vulnerable to the high local concentrations achieved with i.a.h. administration. Based on these encouraging results, clinical trials using THP administered by the i.a.h. route were initiated.

Influence of pretreatment clinical characteristics on the response rate to mitomycin/vindesine/cisplatin (MVP) in unresectable non-small cell lung cancer. ATTIT (Association pour le Traitement des Tumeurs Intra-Thoraciques).

The authors report their experience with the MVP (mitomycin/vindesine/cisplatin) regimen of the Memorial Sloan-Kettering Cancer Center (MSKCC) which showed the highest response rate in non-small cell lung cancer (NSCLC). The aim was to respect the original reported schedule to appreciate its activity, because the same drug combination with dose and schedule variations used by other investigators has failed to reproduce the original report results. 82 consecutive previously untreated patients with unresectable and/or metastatic NSCLC received mitomycin (8 mg/m2 days 1, 29, 71), vindesine (3 mg/m2, days 1, 8, 15, 22, 29, 43, 57, 71) and cisplatin (120 mg/m2, days 1, 29, 71), with evaluation on day 71. 24 objective responses were noted (29%) (2 complete response/22 partial response) (95% CI 19%-39%), without differences according to histology. Differences in median survival were noted according to the performance status and type of response. Overall survival rates in responding patients were similar to those noted with the original schedules. Analysis of selection criteria showed that there were more patients with bone (P less than 0.01) or liver metastases (P less than 0.05), less women (P less than 0.001) and less adenocarcinoma (P less than 0.001) than the MSKCC trial. A dose intensity analysis showed only a minimal difference in the average weekly doses of vindesine (10% lower than MSKCC trial: 1.8 mg/m2 vs. 2.25 mg/m2). Disease improvement, a subjective response criterion used in the MSKCC trial, was probably underestimated in the current study. We conclude that the potential benefit of chemotherapy with a three-drug combination in NSCLC is greatest in patients with stage IIIa and IIIb disease or stage IV disease with a good performance status and a low metastatic volume.

Ultrastructural changes of the pulmonary parenchyma after experimentally induced endotoxic shock in dogs with and without drug protection.

The authors describe the ultrastructural alterations of the pulmonary parenchyma produced in dogs by endotoxic shock, and they examine the effects that a 'secretolytic' drug (bromexine) has in modifying those changes. In the animals under shock there is a complete breakdown of the normal structure of the pulmonary parenchyma. According to the authors, these lesions are caused by the damage of the lining layer and of the cells which produce the constituents of the surfactant system. In dogs under shock and treated with bromexine the authors have seen a better organization of the pulmonary parenchyma: the cellular limits of the pneumocytes of types I and II were more clearly defined and the osmiophilic bodies were increased both in number and volume. The authors conclude that the damage of the lining layer and of the pneumocytes of type II plays an important role in the development of the ARDS and they say that bromexine can improve clinical and morphological aspects of that syndrome.

[A case of retroareolar leiomyoma of the breast]. / Su un caso di leiomioma retroareolare della mammella.

The authors, showing a case of breast retroareolar leiomyoma, study the literature thereabout, and emphasize the rareness of such disease, the impossibility of a correct preoperative diagnosis and the features of absolute benignity of this lesion.

[Bochdalek's hernia with retroperitoneal contents in adults]. / L'ernia di Bochdalek a contenuto retroperitoneale nell'adulto.

The authors report a case they had the opportunity to observe, surgically treated (thoraco-phrenotomy, removal of the herniated mass, repair of the diaphragmatic breach). They illustrate the genesis of such abnormality, its incidence and symptomatology. The Authors, moreover, dwell upon the diagnostic problems caused by Bochdalek's hernia with retroperitoneal contents, and upon the advantages shown by the thoracic way of aggression in the light of their own experience.

Immunologic alterations and active aspecific immunotherapy in lung cancer patients.

An immunologic study was undertaken on 89 lung cancer patients and on the basis of results obtained so far, a protocol of active, aspecific immunotherapy by living bacterial vaccines (BCG) and/or synthetic immunopotentiator (methisoprinol) was carried out. First results obtained in patients undergoing immunostimulation are reported together with the observation that while positive humoral effects seem present in stage I and II patients, in cases of spread of the disease results are substantially negative.