Results of a prospective study with high-dose etoposide, thiotepa and carboplatin and peripheral blood stem cell rescue for high-risk stage II-IIIA and selected stage IV breast cancer patients

AIMS AND BACKGROUND: To investigate the safety and efficacy of a high-dose chemotherapy regimen with etoposide, carboplatin and thiotepa in high-risk stage II-IIIA breast cancer and in responsive metastatic patients. STUDY DESIGN: From April 1992 to December 1998, 24 patients with high-risk stage II-IIIA breast cancer (> or = 9 positive nodes) and 9 responsive metastatic patients were enrolled in the trial. After induction chemotherapy with an anthracycline-based regimen, peripheral blood stem cells were mobilized with cyclophosphamide (7 g/m2) and G-CSF (5-16 microg/kg/s.c./day). The high-dose chemotherapy regimen consisted of etoposide (1000 mg/m2), carboplatin (800 mg/m2) and thiotepa (500 mg/m2). At the end of the high-dose chemotherapy, all stage II-IIIA patients received radiotherapy to the breast or chest wall and draining nodes; stage IV patients were irradiated to sites of disease, if feasible. All ER+ and/or PgR+ patients were treated with hormone therapy. RESULTS: For stage II-IIIA high-risk patients, the median follow-up was 4.36 years (range, 1.93-6.94), and the Kaplan-Meier estimate at 5 years of disease-free survival and overall survival was 54.8 +/- 11% SE and 76.73 +/- 9.4% SE, respectively. For metastatic patients, the median follow-up was 4.93 years (range, 4.15-7.95), and the Kaplan-Meier estimate at 5 years of progression-free survival and overall survival was 22.2 +/- 13.9% SE and 76.2 +/- 14.8% SE, respectively. No treatment-related deaths were observed. CONCLUSIONS: Our results are comparable to those obtained in other high-dose chemotherapy trials but do not seem to be superior to conventional-dose therapy given to similar patients.     

CHS 828, a novel pyridyl cyanoguanidine with potent antitumor activity in vitro and in vivo

A new class of recently discovered antineoplastic agents, the pyridyl cyanoguanidines, exert a potent antitumor activity in rodents after oral administration. Optimization in vitro and in vivo has resulted in the selection of the lead candidate CHS 828 (N-(6-chlorophenoxyhexyl)-N'cyano-N"-4-pyridylguanidine). CHS 828 was found to exert potent cytotoxic effects in human breast and lung cancer cell lines, with lesser effects on normal fibroblasts and endothelial cells. In a study using a panel of cell lines with different resistance patterns, the effects of CHS 828 showed a low correlation with the activity patterns of known anticancer agents, and no sensitivity to known mechanisms of multidrug resistance was observed. In nude mice bearing human tumor xenografts, CHS 828, at doses from 20 to 50 mg/kg/day p.o., inhibited the growth of MCF-7 breast cancer tumors and caused regression of NYH small cell lung cancer tumors. Oral administration of CHS 828 once weekly improved efficacy without increasing toxicity. CHS 828 was found to compare favorably with established chemotherapeutic agents such as cyclophosphamide, etoposide, methotrexate, and paclitaxel. In mice with NYH tumors, long-term survival (>6 months) was observed after treatment with CHS 828 was stopped. In conclusion, CHS 828 is an effective new antitumor agent, with a potentially new mechanism of action. CHS 828 is presently being tested in Phase I clinical trials in collaboration with the European Organization for Research and Treatment of Cancer.     

Molecular analysis of PTEN and MXI1 in primary bladder carcinoma

Loss of heterozygosity (LOH) on 10q is associated with late-stage events in urothelial neoplastic progression. The tumor suppressor gene PTEN, which is mutated or homozygously deleted in numerous cancers, maps to a region of 10q within the reported region of minimal loss in bladder tumors. In two recent studies alterations in the PTEN gene occur at a low frequency in bladder tumors displaying 10q LOH. We have screened 35 late-stage bladder tumors for mutations in PTEN and MXI1, both genes mapping to chromosome 10q. Using single-strand conformation polymorphism analysis, we identified 6 tumors harboring mutations in PTEN and 2 additional tumors displaying homozygous deletion at this locus. No MXI1 mutations were identified within the same tumor panel. Of 16 bladder tumor cell lines analyzed, 2 showed homozygous deletion of PTEN and 3 harbored point mutations resulting in an amino acid change. Two cell lines harbored missense mutations in MXI1. We report a significantly higher frequency of PTEN alterations in bladder carcinoma (23%) than was previously recorded, with no accompanying mutations in the MXI1 gene.     

An Update on Cardiac Troponins as Circulating Biomarkers in Heart Failure

Circulating troponins and natriuretic peptides are the only biomarkers specifically released from cardiac myocytes that can be determined with robust and sensitive analytical methods, even in healthy subjects. These intracellular proteins are released from reversibly or irreversibly damaged cardiac myocytes into the bloodstream by mechanisms that are not entirely clear. The recent introduction of a new generation of highly sensitive assays of cardiac troponin I or T has not only improved the early diagnosis of acute myocardial infarction but also suggested that there are several causes for troponin release other than acute coronary syndromes. Circulating troponins are elevated in patients with acute or chronic heart failure and are strongly associated with outcome, independently of natriuretic peptides, the benchmark biomarkers in heart failure. In the absence of further experimental evidences, the pathophysiologic basis for the elevation of circulating cardiac troponins in patients with stable chronic heart failure remains speculative.     

Radiation therapy in metastatic spinal cord compression. A prospective analysis of 105 consecutive patients

One hundred thirty consecutive patients with metastatic spinal cord compression (MSCC) were entered in a therapeutic protocol in which radiation therapy (RT) played the main role. When MSCC is diagnosed by clinical-radiologic methods such as myelography with or without computed tomography (CT) or magnetic resonance imaging (MRI), steroids are given and RT treatment started within 24 hours. When diagnostic doubts exist or stabilization is necessary, surgery precedes RT. Chemohormonal potentially responsive tumors are also treated with chemotherapy or hormonal therapy. Twelve patients (9.2%) underwent surgery plus RT, and 118 (90.8%) received RT alone. Thirteen (11%) early death patients were not evaluable. The 105 evaluable cases that received RT alone were analyzed. Median follow-up was 15 months (range, 4 to 38 months). Response among patients with back pain was 80%. In cases with motor dysfunction, 48.6% improved, and in 33 of 105 patients (31.4%) without motor disability there was no deterioration. Forty percent of patients with autonomic dysfunction responded to RT. Median survival time was 7 months with a 36% probability of survival for 1 year. The median duration of improvement was 8 months. The most important prognostic factor was early diagnosis. Radiosensitivity of tumor was only important in paraparetic patients in predicting response to RT. Complete myelographic block significantly diminished response to RT. Vertebral collapse did not influence response or survival.     

Preventive measures reduce exposure to polycyclic aromatic hydrocarbons at a graphite electrode plant

OBJECTIVE: This study assessed the efficacy of preventive measures in a graphite electrode plant aimed at reducing occupational exposure to polycyclic aromatic hydrocarbons (PAHs). METHODS: Electrode workers (n = 146) answered a questionnaire and provided an end of shift urine sample. Urinary 1-hydroxypyrene (1-hpur), a biological marker of exposure to PAHs, was measured by high performance liquid chromatography coupled with: (a) fluorescence detection. 1- Hydroxypyrene concentrations were compared with the concentrations measured before implementing the preventive measures; and (b) those of a control group of 54 men not occupationally exposed to PAHs. RESULTS: After implementation of preventive measures, median concentrations 1- hpur were significantly reduced in some groups of workers: by -24%, - 37% and -30% in workers at the green electrode unit, one baking impregnation unit, and the laboratory, respectively. In workers at a second baking impregnation unit, in end product finishing and in the power station 1-hpur concentrations were unchanged. Urinary 1-hp concentrations were still significantly higher in each group of workers than in the control group (p < 0.001 for any comparison). Concentrations in the workers varied with the type of job, the highest values being found in workers engaged in the power station, in the two baking impregnation units and in the green electrode unit. CONCLUSIONS: Implementing preventive measures significantly reduced exposure to PAHs at a graphite electrode plant. The reduction in median and peak concentrations of 1-hpur, which reflects total exposure to, and internal dose of PAHs, was most evident in workers employed in the units where preventive measures had been taken. Despite an overall reduction, further preventive measures are needed to minimise exposure to PAHs and consequently the risk of adverse health effects.

 

     

Diagnostic-therapeutic integration in metastatic spinal cord compression. Analysis of a prospective study

Metastatic Spinal Cord Compression (MSCC), an oncologic emergency, is a frequent complication of many neoplastic diseases in an advanced stage. Our experience is reported, which was obtained with a series of 61 patients following a diagnostic-therapeutic protocol aimed at early diagnosing MSCC and at assigning the major role in therapy to radiotherapy (RT) alone. Fifty-seven patients with an average follow-up of 13 months (range 4-26) were evaluable. Diagnosis was always made by means of myelography and/or myelography plus CT. In 50 cases the treatment consisted in RT alone and the remaining 7 patients had surgery before RT because of diagnostic doubts; in 1 case the patient was operated on because stabilization was necessary. A dose of 30 Gy was delivered, over 2 weeks, (TDF = 62) to those tumors which were considered as radiation-responsive and having a better prognosis (myeloma, lymphoma), whereas all the other histologies were given a split-course regimen (5 Gy x 3 days, stop x 4 days, +/- 3 Gy x 5 days; TDF = 68). All patients received medium or high doses of steroid depending on the degree of neurologic involvement. Patients with chemo/hormone-responsive primary tumors also received chemotherapy and/or hormone therapy. The clinical parameters considered in evaluating the response to treatment were backache, motor performance, and sphincter function. Respectively 86%, 47% and 44% of patients responded. Early diagnosis was the most important prognostic factor, whereas histology of the primary tumor was important in cases with severe neurologic damage only. The results obtained are similar to those reported in literature and confirm the value of the diagnostic-therapeutic approach used, which suggests continuing this trial.     

Long-term durability of pubovaginal fascial slings in women who then become pregnant and deliver

Introduction and hypothesis  

Pubovaginal fascial slings are commonly performed after childbearing is completed. Limited data is available regarding women who become pregnant following a sling procedure.