Survival after adjuvant 5-FU treatment for stage III colon cancer in hereditary nonpolyposis colorectal cancer

In vitro studies suggest that a deficient mismatch repair (MMR) system reduces 5-Fluorouracil cytotoxicity. Colon cancer (CC) in hereditary nonpolyposis colorectal cancer (HNPCC) is due to a dysfunctioning MMR gene that leads to microsatellite instability (MSI). Clinical studies on the efficacy of 5-Fluorouracil (5-FU) in MSI high tumours are contradictory. In a retrospective study, we compared the survival of subjects with stage III CC from HNPCC families that were treated with and without adjuvant 5-FU. The Dutch HNPCC family registry was used. Information on adjuvant chemotherapy for stage III CC was obtained from subjects of families with a mutation and/or who fulfilled the AMS criteria or who were strongly suspicious for HNPCC. CC specific survival was calculated. Observation time was measured either until the date of death, date of a second primary CC or until the closing date of the study, i.e., June 1, 2001. Statistical analysis was done by Kaplan-Meier survival analysis. A total of 92 subjects with stage III CC were included. Twenty-eight of them (17 males) had adjuvant treatment with 5-FU. The median follow-up was 4 (range: 1-17) years; 8 subjects died of CC. The 5-year survival was 70% (95% Cl: 49-90). Sixty-four subjects (36 males) did not have adjuvant therapy. Their median follow-up was 6 (range: 0-23) years. Twenty of them died of CC. The 5-year survival in this group was also 70% (95% Cl: 59-83). To date, the selection of patients with CC for 5-FU treatment is based on the stage rather than the biology of the tumour. In our study, the 5-year survival of subjects treated with and without adjuvant 5-FU did not differ. Further studies are necessary to elucidate the role of MSI in 5-FU treatment of MSI-H tumours in HNPCC.     

Bile resistance of coated transjugular intrahepatic portosystemic shunt stents in a flow-model

PURPOSE: We sought to test the bile resistance of transjugular intrahepatic portosystemic shunt (TIPS) stents with 3 different coatings. MATERIALS AND METHODS: Three stents with different coating materials (monolayer polyethylene terephthalate [PETP], monolayer polytetrafluoroethylene [PTFE], and double layer [PTFE]) were tested in a flow model. After testing the sealing of the system with isotonic saline solution, fresh human bile was circulated. Constant pressure was 50 cm H2O. Bile resistance of the stent membranes was analyzed. RESULTS: Two of the 3 stents proved completely resistant to water. Only the PETP stent was resistant to bile. The PTFE-coated stents were not bile resistant. CONCLUSION: The bile resistance of coated TIPS stents and, thus, the dependency of TIPS shunt patency is called into question. The stent with the reported superior patency rates does not show experimental bile resistance.     

Resistance to platinum-containing chemotherapy in testicular germ cell tumors is associated with downregulation of the protein kinase SRPK1

Male germ cell tumors (GCTs) are extremely sensitive to platinum-containing chemotherapy, with only 10% of patients showing therapy resistance. However, the biological basis of the high curability of disseminated GCTs by chemotherapy is still unknown. Recently, we demonstrated that the mammalian serine/arginine-rich protein-specific kinase 1 (SRPK1) is a cisplatin-sensitive gene, inactivation of which leads to cisplatin resistance. Because, in mammalians, the expression of SRPK1 is preferentially high in testicular tissues, cisplatin responsiveness of male GCTs might be associated with SRPK1 levels. In the present study, we monitored SRPK1 protein expression in a unique series of nonseminomatous GCTs by immunohistochemistry. Randomly selected GCTs (n = 70) and tumors from patients responding to standard chemotherapy (n = 20) generally showed strong SRPK1 staining. In contrast, expression in refractory GCTs (n = 20) as well as in GCTs from poor-prognosis patients responding to high-dose chemotherapy only (n = 11) was significantly lower (two-sided Wilcoxon rank sum test: P < .001). In conclusion, our data suggest that SRPK1 expression might be an important prognostic indicator for the chemoresponsiveness of nonseminomatous GCTs.     

Human immunodeficiency virus infection in children hospitalised with tuberculosis

The impact of HIV infection on clinical presentation and outcome of tuberculosis (TB) was studied in children hospitalised at the Brooklyn Hospital for Chest Diseases (BCH), Cape Town over the 2-year period January 1998 to December 1999. Clinical data were extracted from a prospectively compiled patient register. Of 261 children with TB, 114 (median age 24 mths) were not HIV-infected and 36 (median age 23 mths) were HIV-infected. The HIV status of 111 children (median age 37 mths) was not determined. Pulmonary TB with or without extrapulmonary TB occurred in 97 (85%) children who were not HIV-infected, 35 (97%) HIV-infected children and 87 (78%) of those not tested (p = 0.025). A tuberculin reaction > or = 15 mm was elicited in ten (31%) of 32 HIV-infected children, 76 (72%) of 106 non-HIV-infected and 62 (71%) of those not tested (p < 0.001). Mycobacterium tuberculosis was cultured from 116 (49%) of 238 children and drug sensitivity was evaluated in 79. Nine isolates (11%) were resistant to isoniazid (INH) and 11 (14%) to INH and rifampicin (RMP). Two HIV-infected children treated previously in BCH for drug-sensitive TB were re-admitted with INH and RMP resistance. Two (2%) non-HIV-infected children, six (17%) HIV-infected children and one (1%) child with undetermined HIV status died (p < 0.001).     

A generic model for the assessment of disease epidemiology: the computational basis of DisMod II

Reliable and comparable analysis of risks to health is key for preventing disease and injury. Causal attribution of morbidity and mortality to risk factors has traditionally been conducted in the context of methodological traditions of individual risk factors, often in a limited number of settings, restricting comparability.     

Diazonamide A and a synthetic structural analog: disruptive effects on mitosis and cellular microtubules and analysis of their interactions with tubulin

The marine ascidian Diazona angulata was the source organism for the complex cytotoxic peptide diazonamide A. The molecular structure of this peptide was recently revised after synthesis of a biologically active analog of diazonamide A in which a single nitrogen atom was replaced by an oxygen atom. Diazonamide A causes cells to arrest in mitosis, and, after exposure to the drug, treated cells lose both interphase and spindle microtubules. Both diazonamide A and the oxygen analog are potent inhibitors of microtubule assembly, equivalent in activity to dolastatin 10 and therefore far more potent than dolastatin 15. This inhibition of microtubule assembly is accompanied by potent inhibition of tubulin-dependent GTP hydrolysis, also comparable with the effects observed with dolastatin 10. However, the remaining biochemical properties of diazonamide A and its analog differ markedly from those of dolastatin 10 and closely resemble the properties of dolastatin 15. Neither diazonamide A nor the analog inhibited the binding of [3H]vinblastine, [3H]dolastatin 10, or [8-14C]GTP to tubulin. Nor were they able to stabilize the colchicine binding activity of tubulin. These observations indicate either that diazonamide A and the analog have a unique binding site on tubulin differing from the vinca alkaloid and dolastatin 10 binding sites, or that diazonamide A and the analog bind weakly to unpolymerized tubulin but strongly to microtubule ends. If the latter is correct, diazonamide A and its oxygen analog should have uniquely potent inhibitory effects on the dynamic properties of microtubules.     

Induction of tumor cell death by high hydrostatic pressure as a novel supporting technique in orthopedic surgery

As vegetative forms of microorganisms are impaired by high hydrostatic pressure (HHP) in the range of 400-600 MPa, the non-thermal inactivation of vegetative bacteria, yeasts, and moulds present in foods such as jams, fruit juices, and dressings by HHP is now well-established. Eukaryotic cells, when subjected to HHP are also damaged. In the present study, the effect of HHP on cell viability of human osteoblasts (HOB), human fibroblasts (HFB), and different tumor cell lines such as osteosarcoma cells SAOS-2, human histiocytic leukemia cells U-937, and the ovarian cancer cell line OV-MZ-6 was investigated. Therefore the different cell lines were subjected to pressures between 50 and 400 MPa and tested for viability. At HHP of 100 MPa (10 min) about 80% of the various cell lines were still alive. At 350 MPa all of the cells were damaged and dead. The three tumor cell lines investigated were slightly more resistant to HHP (50% dead at 170-193 MPa) than HOB and HFB (50% dead at 130-145 MPa). The present study demonstrates that both normal cells and tumor cells are rapidly inactivated by HHP treatment.     

Audiotaped social comparison information for cancer patients undergoing radiotherapy: differential effects of procedural,emotional and coping information

The present study focused on the effects of social comparison information on subjective understanding of radiation therapy, validation of emotions, and self-efficacy of cancer patients undergoing radiation therapy. The effects of three different audiotapes, containing different kinds of social comparison information, were examined. On the procedural tape a man and woman discussed their illness and radiation treatment, on the emotion tape they focused on the emotional aspects of these issues, and on the coping tape they focused on the way they had been coping. The effects of these tapes were measured on subjective understanding about radiation therapy, validation and recognition of emotions, self-efficacy, and mood. The results indicate positive effects of the tapes, especially of the procedural and the coping tape. These audiotapes increased understanding of radiation therapy, self-efficacy and the feeling of validation of emotions. Therefore, these tapes may be an important supplement to existing patient education information. Possible explanations and practical implications are discussed.