With the recent sequencing of its entire genome, the yeast Saccharomyces cerevisiae has gained considerable interest in the field of anticancer research. The genetic properties of the yeast allow easy selection of a variety of mutants, as their related phenotypes provide valuable information on anticancer drugs effects in vivo. Moreover, the yeast has been extensively studied as a model system to decipher basic cellular processes that are well conserved from yeast to human and implicated in cancer establishment and progression. We discuss the advantages of Saccharomyces cerevisiae for investigating the metabolism of pyrimidines, a major target for anticancer chemotherapy. We also emphasize the links between basic science in the pyrimidine metabolism and new anticancer antimetabolites as well as future prospects in this field. Keywords: saccharomyces cerevisiae, cancer, chemotherapy, pyrimidine metabolism

The onset of liver abscess due to Clostridium septicum an anaerobic gram-positive bacillus- is a rare condition, generally arising in cancer patients. The radiological picture is that of gas-containing pyogenic abscess, that predominates within preexisting liver metastases.We report a case of a 50-year-old patient with metastatic colon cancer who was referred with multiple Clostridium septicum liver abscesses. The patient under-went parenteral antibiotherapy as well as transcutaneous drainage of the largest liver abscess. However the outcome was unfavorable in a clinical picture of liver failure that was likely due to disease progression rather than sepsis.Clostridium septicum liver abscess is a life-threatening condition that occurs in fragile patients, mostly with metastatic cancers. A review of the reported cases is presented and treatment options are discussed.

Human androgen receptor (AR) mutation is a possible alternative used by prostate adenocarcinoma (PCA) cells to escape androgen dependence. These mutations may broaden the specificity and/or the sensitivity of the AR to other hormones, resulting in the inappropriate receptor activation, and thus, affecting the PCA response to hormonal therapies. We have developed a yeast-based functional assay to detect mutant ARs in PCA by analyzing their transactivation capacities in response to different ligands. We report herein the detection of two different mutant ARs within the same metastatic tumor sample. Concomitantly to the T877A mutant AR, we identified an additional double mutant AR harboring the nonsense mutation Q640Stop, just downstream of the DNA binding domain together with the T877A point mutation. This mutation leads to a C-terminal truncated AR. This study is the first description of this type of mutation in PCA. We demonstrated that this truncated AR exhibited constitutive transactivation properties. In conclusion, our data suggest that mutation-induced constitutive activation of the AR may be an alternative mechanism used by PCA cells to escape androgen deprivation.

Objectives We studied clinical factors that may influence the duration of hematological recovery to reach neutrophil counts and thus, indirectly, the prognosis in patients with life-threatening drug-induced agranulocytosis (DIA).Methods Using univariate and multivariate analyses with Cox's proportional hazard models, we determined the prognostic factors for hematological recovery defined as neutrophil counts > 05 and > 1.5.10(9)/L, in 91 patients with established life-threatening DIA.Results Multivariable analysis showed that neutrophil count < 0.1.10(9)/L (at diagnosis) and infection profile: severe infections or septic shock, adversely influenced the neutrophil recovery (for the two neutrophil levels). Hematopoietic growth factors were significantly associated with rapid hematological recovery (for the two neutrophil levels). Documented microbial infections and antiplatelet DIA were also associated with rapid hematological recovery (for a neutrophil count > 15.10(9)/L).Conclusion Our findings demonstrate that in life-threatening DIA, hematological recovery is mainly dependant of the neutrophil level, the type of infections and the utilization of hematopoietic growth factors.

BACKGROUND:Adults with chronic idiopathic thrombocytopenic purpura (ITP) in whom standard-dose corticosteroids and splenectomy have failed or who have contraindications to these therapies often require further treatment for life-threatening thrombocytopenia or bleeding. We studied whether danazol, an attenuated androgen, is useful in this setting. METHODS:To assess both clinical outcome and tolerance issues, 57 patients who had refractory chronic ITP (n = 27) or who had contraindications to splenectomy or corticosteroids or who refused these therapeutic options (n = 30) were studied. RESULTS:Thirty-eight patients experienced a partial or complete response to therapy (67%), among whom 27 (46%) remained in remission at a median (+/- SD) of 119 +/- 45 months. Treatment tolerance was acceptable, although severe adverse events were reported in 9 patients (16%). CONCLUSION:Our findings suggest that danazol therapy may be beneficial in the management of refractory chronic ITP or when there are contraindications to splenectomy or corticosteroids (or both).

Caffeine has been widely described as a chemo/radiosensitizing agent, presumably by inhibiting DNA repair, and affecting preferentially cells with an altered p53 status. We evaluated the effects of caffeine using isogenic and isophenotypic K1 cells derived from a papillary thyroid carcinoma and displaying either a wild type or a mutated p53 status. Apoptosis and clonogenic survival were examined after exposure of the cells to cisplatin or UVc irradiation. We find that at the most currently used concentration, 2mM, caffeine hinders cisplatin or UVc induced apoptosis in K1 cells. In addition, at this already barely achievable concentration in vivo, caffeine does not decrease their clonogenic survival. Hence in our cellular model, caffeine does not behave as a chemo- or a radiosensitizer. Although surprising, these results (1) are in agreement with the delayed G2/M block caused by caffeine that we previously observed in normal human fibroblasts and K1 cells and (2) allow us to elucidate some discrepancies concerning this molecule throughout the literature such as increase or decrease of apoptosis and clonogenic survival, activation or deactivation of molecules involved in DNA damage repair and proliferation inhibition but accelerated G2/M traverse.

BACKGROUND/AIMS:Chemotherapy provides dismal results in advanced pancreatic cancer patients, even when new compounds, such as gemcitabine, are used. Phase I studies of single-drug therapy with docetaxel or irinotecan suggested a response rate of about 15% in these patients. We report here a phase II study of docetaxel-irinotecan combination in advanced pancreatic cancer patients.METHODOLOGY:Docetaxel 60 mg/m2 was given in combination with irinotecan 250 mg/m2 every 3 weeks. Prednisolone premedication and anti-HT3 drugs were systematically administered. Hematopoietic growth factors were given in case of febrile neutropenia or grade 4 neutropenia at the previous cycle. Endpoints were response rate, progression-free survival, and tolerance.RESULTS:Twenty-seven patients were enrolled, of whom 25 had metastatic disease. We observed 3 partial responses and 11 stabilizations. The median progression-free survival was 4.3 months. Myelosuppression was the main toxicity with 18% of patients experiencing a grade 3-4 event. One patient died of neglected febrile neutropenia. Gastrointestinal toxicity was well controlled. Other toxicities were mild.CONCLUSIONS:This combination has acceptable tolerance and, despite an 11% response rate, some partial responses and prolonged stabilizations were observed. The treatment induced clinical benefit in 33% of the patients. Further trials should focus on docetaxel or irinotecan, possibly used in combination with more conventional strategies (gemcitabine).

OBJECTIVE: Mutations in the ligand-binding domain of the human androgen receptor (AR) figure among the ways used by prostate adenocarcinoma (PCa) cells to escape androgen dependence. These mutations may broaden the specificity and/or affinity of the AR to other hormones, resulting in inappropriate receptor activation and thus affecting the PCa response to physiological stimuli and hormonal therapies. DESIGN: In order to clarify the impact of these mutations on disease progression and treatment, we have developed a yeast-based functional assay that allows the detection of mutant ARs and the analysis of their transactivation capacities in response to different ligands. METHODS: AR cDNA was directly cloned into an expression vector in a yeast strain that carries a reporter gene (ADE2) linked to an androgen-dependent promoter. The expression of the ADE2 gene and consequently the yeast cell growth in a selective medium depleted in adenine depends on the specificity of the AR for the ligand added to the medium. RESULTS: By analysing the transactivation capacities of different AR molecules in response to a broad range of steroid and non-steroid ligands, we have demonstrated that this assay can discriminate among wild-type AR, T877A, C685Y and L701H mutant ARs and that at least 1% of mutant ARs could be detected when mutant and wild-type ARs were mixed at the cDNA level. CONCLUSIONS: The data presented here show that this simple AR assay is convenient for the routine detection of mutant ARs in PCa and is also suitable to evaluate the antagonist activities of anti-androgen molecules.

BACKGROUND/AIMS:Adult Still's disease is one of the febrile disorders of unknown etiology, characterized by high fever, transient cutaneous rash and leukocytosis. Liver dysfunction in adult Still's disease has been described in some case reports. The objective of this study was to analyze the pattern and the frequency of liver abnormalities in a monocenter series of adult Still's disease patients.METHODOLOGY:Data of 17 patients with adult Still's disease (fulfilling Yamaguchi's diagnostic criteria) were retrospectively reviewed. These patients were followed in an Internal Medicine Department over a period of 7 years.RESULTS:The median age was 27 years with a sex ratio M/F of 1.4. Fever was present in 100% of the cases and hepatomegaly occurred in 47% of the cases. Abnormalities in liver biochemistry, apparent in 76% of the subjects were characterized from moderate (elevation of transaminases between 2 and 5 N) (65%) to severe cytolysis (level of transaminases > 5 N) (12%), cholestasis (elevation of gamma GT and/or PAL) (65%), and increase in the level of LDH (35%). All of these symptoms disappeared either spontaneously or under treatment (83%), within a median period of 18 days.CONCLUSIONS:This study confirms the high frequency of liver dysfunction in adult Still's disease patients. Although it is moderate and asymptomatic in most cases, severe cytolytic hepatitis has been described. This study especially puts forward the need for exploring the possibility of adult Still's disease in the presence of a fever and hepatic cytolysis.

Aim of the study. Digestive surgery is often necessary for surgical management of advanced ovarian carcinoma.Patients and methods: In a series of 62 patients with stage III ovarian carcinoma, postoperative morbidity and mortality, overall survival after 5 years and disease-free survival after 2 years were studied and corelated with several patients criteria (age, stage of the disease, residual disease, type of surgery, CA 125 normalisation delay, postoperative complications and hospital stay). Patients were divided into two groups according to the surgical treatment. The first group (n=17) included patients treated by gynecologic and digestive surgery, the second group (n=45) included patients treated by gynecologic surgery only. All patients were proposed for chemotherapy included platyn salt. Mean age was 60 years (range: 20-83). The stage of the cancer was stage IIIa in 7 cases, stage IIIb in ten and stage IIIc in 45.Results: Postoperative mortality was 3.5% (2/62). Postoperative morbidity was 26% (13/62). No statistical differences were noted for hospital stay, general morbidity, surgical morbidity when a gastric resection or a colon resections or a splenectomy were performed. Overall survival at 5 years was 56%. Residual disease less than 2 cm(3) is the only prognostic factor for overall survival (56% vs 23% [P=0.03]) and disease-free survival (86% vs 46% [P=0.02]).Conclusion: This study including 62 patients confirmed the prognostic significance of extensive cytoreductive surgery for treatment in advanced ovarian epithelial cancer without increasing the postoperative morbidy and mortality. (C) 2002 Editions scientifiques et medicales Elsevier SAS.

Digestive surgery is often necessary for surgical management of advanced ovarian carcinoma.In a series of 62 patients with stage III ovarian carcinoma, postoperative morbidity and mortality, overall survival after 5 years and disease-free survival after 2 years were studied and corelated with several patients criteria (age, stage of the disease, residual disease, type of surgery, CA125 normalisation delay, postoperative complications and hospital stay). Patients were divided into two groups according to the surgical treatment. The first group (n = 17) included patients treated by gynecologic and digestive surgery, the second group (n = 45) included patients treated by gynecologic surgery only. All patients were proposed for chemotherapy included platyn salt. Mean age was 60 years (range: 20-83). The stage of the cancer was stage IIIa in 7 cases, stage IIIb in ten and stage IIIc in 45.Postoperative mortality was 3.5% (2/62). Postoperative morbidity was 26% (13/62). No statistical differences were noted for hospital stay, general morbidity, surgical morbidity when a gastric resection or a colon resections or a splenectomy were performed. Overall survival at 5 years was 56%. Residual disease less than 2 cm3 is the only prognostic factor for overall survival (56% vs 23% [P = 0.03]) and disease-free survival (86% vs 46% [P = 0.02]).This study including 62 patients confirmed the prognostic significance of extensive cytoreductive surgery for treatment in advanced ovarian epithelial cancer without increasing the postoperative morbidy and mortality.

PURPOSE. Elderly patients with nonchemotherapy drug-induced agranulocytosis present commonly with severe infections and have a mortality of at Least 20%. We studied whether granulocyte colony-stimulating factor (G-CSF), a hematopoietic growth factor that shortens the duration of neutropenia, is useful in these patients.SUBJECTS AND METHODS: We studied 54 patients greater than or equal to65 years of age who had drug-induced agranulocytosis some of whom had been treated with G-CSF. We determined the times until hematologic recovery (defined as 2 neutrophil count >1.5 X 10(9)/L), tolerance of G-CSF, and clinical outcomes.RESULTS: Of the 54 patients, 20 received G-CSF. Two patients who had not been treated with G-CSF died of uncontrolled septic shock and extensive pneumonia. The mean (+/- SD) time until hematologic recovery was significantly less in patients treated with G-CSF (6.6 +/- 3-9 days vs. 8-8 +/- 4-9.dals, P < 0.04). Compliance with G-CSF therapy was good, only mild flu-like symptoms and transient bone pain were reported in 12 patients.CONCLUSION: Our findings suggest that G-CSF therapy may be beneficial in the management of drug-induced agranulocytosis in elderly patients. (C) 2002 by Excerpta Medica, Inc.

PURPOSE: To assess the Aspergillus galactomannan enzyme-linked immunosorbent assay (ELISA) in the diagnosis of invasive aspergillosis (IA) in adult and pediatric oncohematologic patients. PATIENTS AND METHODS: The study was conducted in four patient groups: those with fever of unknown origin (FUO) during neutropenia, suspected pulmonary infection (PI), or nonpulmonary aspergillosis (NPA) and those undergoing surveillance (S) after hematopoietic stem-cell transplantation (HSCT). IA was classified as definite, probable, or possible, according to European Organization for Research and Treatment of Cancer/Mycosis Study Group definitions. RESULTS: A total of 3,294 serum samples were collected during 797 episodes (FUO, 261; PI, 297; NPA, 28; and surveillance, 211), and 153 episodes of IA were diagnosed (31 definite, 67 probable, and 55 possible). Three episodes were first suspected from galactomannan ELISA; the remaining 150 cases were diagnosed from clinical or radiologic evidence. Sensitivity of the ELISA was 64.5%, 16.4%, and 25.5% in definite, probable, and possible episodes of IA, respectively, and was lower in patients positive for anti-Aspergillus antibodies than in antibody-negative patients. Most false-positive results occurred in children and in allogeneic HSCT (allo-HSCT) patients. Overall specificity of the ELISA was 94.8%. It was lower in children compared with adults (P < .0001) and in allo-HSCT patients compared with non–allo-HSCT adults (P = .0002). Lowering the ELISA cutoff value from 1.500 to 0.700 seemed more relevant for non–allo-HSCT adults (sensitivity, 73.1%, 44.3%, and 44.7% in definite, probable, and possible IA, respectively; specificity, 94%). CONCLUSION: Galactomannan ELISA seems less sensitive than previously described, and sensitivity can be further reduced by the presence of anti-Aspergillus antibodies. A new cutoff value for the ELISA of 0.700 is proposed for non–allo-HSCT adults.

INTRODUCTION:In young subjects, the discovery of a cobalamine deficiency (Biermer's disease) at the time of neuropsychiatric disorders even of isolated MRI anomalies is a rare event (less than 0.01%).EXEGESIS:We report two observations of cobalamine deficiency, in patients 30 and 37 years old, revealed by acroparesthesia and spontaneous hypersignal in the T2 sequence of MRI and by a peripheral sensitive neuropathy respectively.CONCLUSION:The neuropsychiatric demonstrations of pernicious anemia are polymorphic with, sometimes, isolated spinothalamic attacks. The MRI can contribute to the diagnosis but more often leads to an erroneous diagnosis. Our observations are of special interest because symptoms occurred apart from supplementation of folates and recovered ad integrum with an early treatment by vitamin B12.