[Risk of Stroke After Exacerbation of Ischemic Heart Disease: Data of 3­Years Follow-up].

PURPOSE: to analyze possible associations of clinical and genetic factors with development of ischemic stroke after exacerbation of ischemic heart disease (IHD). MATERIALS AND METHODS: The Russian multicenter study aimed at assessment of risk of unfavorable outcomes after exacerbation of IHD "Exacerbation of IHD: logical probabilistic ways to course prognostication for optimization of treatment" (meaning of Cyrillic acronym - oracle) was conducted in 16 centers of 7 cities in Russia. We included into the study 1 208 patients with unstable angina and ST-elevation or non-ST-elevation myocardial infarction (MI). Data on outcomes were known for 1 193 patients, 15 patients were lost for follow-up. RESULTS: Mean duration of follow-up was 644±14.45 (4-1 995) days. Shortest, longest, and mean time before development of stroke was 22, 1433 and 389±56.6 days after inclusion. Patients with strokes were older, more often had history of IHD prior to index hospitalization, arterial blood pressure level compatible with stage 3 arterial hypertension, less often were smokers, and more often had MI recurrences or repetitive episodes of severe ischemia during the index hospitalization. Patients also more often had documented atrial fibrillation during hospitalization, and lower level of glomerular filtration rate. Of studied genetic markers carriage of A allele of polymorphic marker G (-1082) A of interleukin-10 gene was significantly associated with risk of stroke development. Using linear regression analysis, we constructed a model of estimation of the stroke development risk. Comparison of diagnostic value of different scales for stroke risk assessment showed that area under the curve was 0.656, 0.686, and 0.756 for the GRACE, CHA2DS2­VASc, and ORACLE scores, respectively.

Phase I study of granulocyte colony-stimulating factor in patients with transitional cell carcinoma of the urothelium.

Recombinant human granulocyte colony-stimulating factor (rhG-CSF) was administered at a dose of 1-60 micrograms/kg of body weight to 22 patients with transitional cell carcinoma before chemotherapy as part of a Phase I/II study. In all patients, a specific dose-dependent increase in the absolute neutrophil count (ANC) of 1.8-12 fold was seen. In addition, this augmentation in the ANC was accompanied by an increase in leukocyte alkaline phosphatase, a marker of secondary granule formation. In six of eight patients analyzed, an increase in bone marrow myeloid to erythroid cell ratio was seen. Day 14 peripheral blood cell derived colony forming unit granulocyte macrophage were also increased by day 6 of rhG-CSF treatment. Circulating levels of eosinophils and basophils were unchanged; however, a 10-fold increase in monocytes was observed in patients treated at the highest doses. There was also a small increase in CD3+ lymphocytes that was not dose dependent. Hemoglobin, hematocrit, and platelet count remained near baseline throughout the period of rhG-CSF administration. These findings demonstrate that rhG-CSF is a potent stimulus for normal neutrophil proliferation and maturation.

Enhanced therapeutic effect of cis-diamminedichloroplatinum(II) against nude mouse grown human pancreatic adenocarcinoma when combined with 1-beta-D-arabinofuranosylcytosine and caffeine.

We demonstrated previously that the effect of cis-diamminedichloroplatinum(II) (cisplatin) against pancreatic cancer was substantially enhanced by the addition to the chemotherapeutic regimen of 1-beta-D-arabinofuranosylcytosine and caffeine. To obtain information on the factors influencing tumor response to this combination treatment, we investigated two adenocarcinomas of the exocrine pancreas grown in the nude mouse, tumors Capan-1 and SW-1990. Tumor response to cisplatin, characterized by tumor regression and tumor growth arrest, was observed when it was given in the upper limits of tolerance (5 mg/kg). Caffeine and 1-beta-D-arabinofuranosylcytosine singly and in combination had no effect on tumor growth; neither did they influence the effect of cisplatin when combined singly with the latter. However, the triple combination of cisplatin, 1-beta-D-arabinofuranosylcytosine, and caffeine resulted in complete tumor regression. The enhancing effect of the triple combination depended on tumor sensitivity to cisplatin and the amount of cisplatin administered and required rather large amounts of caffeine. The present report indicates that certain combination regimens may enhance the therapeutic effect of cisplatin against pancreatic carcinoma.

Response of nude mouse-grown human urothelial cancer to cis-diamminedichloroplatinum(II), diammine[1,1-cyclobutanedicarboxylato(2-)-O,O'-platinum], and mitoguazone dihydrochloride.

A comparative study of the effect of cis-diamminedichloroplatinum(II) (cisplatin), diammine[1,1-cyclobutanedicarboxylato(2-)-O,O'-platinum] (carboplatin), and mitoguazone dihydrochloride on urothelial cancer was conducted using transitional cell carcinomas of the urinary bladder grown in the nude mouse. Tumors SW-780 and TCC-K1 represented transitional cell carcinoma, Grade II, whereas Tumor PR49 represented a fast-growing Grade III neoplasm. Of the agents studied, cisplatin was most effective, resulting in tumor response related to the dose administered. Response to carboplatin was clearly related to treatment schedule. For the same amount of total dose administered, better results were obtained when treatment was given three times weekly instead of once every week. Furthermore, cisplatin was more effective against the less differentiated PR49 tumor in contrast to carboplatin, which showed more activity against the better differentiated SW-780 and TCC-K1 tumors. None of the tumors tested responded to mitoguazone dihydrochloride. The results of the present study may assist in formulating better treatment modalities against urothelial cancer, taking into account factors such as tumor grade, growth rate, treatment schedule, and the patient's tolerance which may ultimately influence tumor response.

Response of nude mouse-grown adenocarcinomas of the human exocrine pancreas to cis-diamminedichloroplatinum(II), diammine[1,1-cyclobutanedicarboxylato(2-)-O,O'-platinum], and mitoguazone dihydrochloride.

The effect of cisplatin, carboplatin, and mitoguazone dihydrochloride on pancreatic cancer was evaluated using pancreatic ductal adenocarcinomas Capan-1, Capan-2, and PR54 grown in the nude mouse. In single agent treatments, cisplatin, given in the amount of 5 mg/kg once/week for 4 consecutive weeks, was most effective, resulting in tumor regression, growth arrest, and a growth delay period of 6 and 4 months for tumors Capan-1 and PR54, respectively. Treatment with carboplatin was less effective, with a tumor response related to treatment schedule. For the same amount of total dose of carboplatin administered, best results were obtained when treatment was given 3 times weekly instead of in single weekly injections. Mitoguazone dihydrochloride exhibited no antitumor effect. The results of the present work may be of significance in the management of pancreatic cancer patients.

Deoxycytidine and deoxythymidine kinase activities in plasma of mice and patients with neoplastic disease.

In C57BL x DBA/2 F1 (hereafter called BD2F1) mice inoculated with P815 neoplasms and in AKR mice with spontaneously developing leukemia, significant amounts of plasma deoxycytidine and thymidine kinase activities were detected in advanced disease. Undetectable or low levels of such kinase activities were observed in normal BD2F1 and in control AKR mice. Initial studies with leukemia patients revealed increased amounts of plasma deoxycytidine and thymidine kinase activities correlating favorably with the peripheral white blood cell counts. Initial studies with small numbers of patients with solid tumors revealed significant activities of both kinases in plasma of patients with four different cancers. Healthy volunteers revealed enzyme activities only insignificantly above background.

Similar specificity of membrane transport for folate analogues and their metabolites by murine and human tumor cells: a clinically directed laboratory study.

Mediated transport of folate compounds exhibited similar kinetic characteristics and structural specificity in a series of cultured murine and human tumor cells examined in a parallel fashion. In each case, influx was characterized by a single saturable component with an approach to steady-state conforming to a single exponential, while efflux was first order (poorly saturable). Both mediated fluxes exhibited high temperature dependence (Q10 27-37 degrees = 6 to 8). During competition studies with various analogues, it was found that positions 4, 5, 7, and 10 and the gamma-carboxyl position of the folate molecule were specified for influx in tumor cells from each species. Also, short-chain alkyl substitution at position 10 was specified in the case of N10, but not in the case of C10. None of the modifications at position 10 affected mediated efflux in either cell type. The linkage of additional glutamyl residues at the gamma-carboxyl-position resulted in reduced saturability (increased value for Ki) of influx in both murine and human tumor cells in a manner proportional to the number of glutamyl residues. Mediated influx in human ovarian carcinoma cells obtained from malignant effusions in several patients and in an established cell line derived from one of these patients showed similar kinetics for folate analogue transport and specificity for modification at position 10 of the 4-amino-folate molecule. Mediated entry of 10-deazaaminopterin and its 10-ethyl derivative compared to entry of methotrexate was 4- to 11-fold greater in murine tumor cells and 4- to 9-fold greater in human tumor cells in culture or when clinically derived. Mediated efflux was not specified for position 10 on the 4-amino folate structure in any tumor cell type. These findings appear to provide some basis for concluding that the results of studies of this type in model murine systems or with tumor cell lines established in culture have relevance to clinical cancer.

Methylglyoxal-bis(guanylhydrazone) in hormone-resistant adenocarcinoma of the prostate.

Methylglyoxal-bis(guanylhydrazone) (MGBG), an inhibitor of polyamine synthesis, was administered to 35 patients with hormone-resistant advanced adenocarcinoma of the prostate in doses of 500 or 600 mg/m2 per week intravenously. Of 31 patients with bidimensional measurable soft-tissue lesions, 25 had an adequate trial, defined as four or more doses. Six (24%; 95% confidence limits, 8% to 32%) patients achieved a partial remission (greater than or equal to 50% reduction in tumor size) in soft-tissue disease. Response was noted to start after one to two doses and persisted for a median of three months (range, 1 to 4 months). Toxicity was tolerable, and significant myelosuppression was not observed. The lack of response in osseous metastases may be secondary to the short duration of remission or to the presence or inducibility of the enzyme ornithine decarboxylase in bone. Since some animal prostatic cancer tumor models are sensitive to cytotoxic drugs that produce polyamine inhibition, clinical trials of MGBG combined with other inhibitors of the polyamine pathway should be explored.

Surgical treatment of spinal cord compression in kidney cancer.

Forty-three patients with renal-cell carcinoma underwent treatment for spinal cord compression over a 7-year period. Of these, 32 patients underwent surgery, while 11 patients underwent radiation alone. Before operation, 25 patients had relapsed following prior radiation, while seven others received postoperative radiation. A more aggressive surgical approach, tailored to the site of compression within the spinal canal, was used with the majority undergoing gross total tumor resection by an anterior approach. Immediate stability of the spine was achieved with methyl-methacrylate reconstruction of the resected segments. Preoperative spinal angiography with embolization of hypervascular tumors was carried out in eight patients. Patient parameters in the surgical and irradiated groups were comparable, except that a greater proportion of the radiation alone group had more than one organ system involved (64% v 44%). The median survival of the surgically treated patients was 13 months, compared with 3 months for those treated by radiation alone. In addition, a greater proportion of the surgically treated patients were benefitted neurologically (70%) compared with those treated by radiation (45%). With the development of effective surgical treatment for spinal metastases, early consideration for surgical treatment (before radiation) should be considered in selected patients. Preoperative spinal angiography and embolization are recommended whenever feasible to minimize intraoperative blood loss.

A randomized trial of etoposide + cisplatin versus vinblastine + bleomycin + cisplatin + cyclophosphamide + dactinomycin in patients with good-prognosis germ cell tumors.

Standard chemotherapy for disseminated germ cell tumors (GCT) cures most patients but causes considerable acute toxicity, including treatment-related death due to septicemia during neutropenia and pulmonary fibrosis. In addition, chronic and delayed toxicities, particularly Raynaud's phenomenon, have been reported in 6% to 37% of treated patients. In an attempt to minimize the acute and chronic effects of treatment which are related primarily to vinblastine and bleomycin, a randomized trial comparing the efficacy and toxicity of vinblastine + bleomycin + cisplatin + cyclophosphamide + dactinomycin (VAB-6) and etoposide + cisplatin (EP) was conducted on 164 eligible patients with good-prognosis GCT. Seventy-nine of 82 (96%) patients receiving VAB-6 and 76/82 (93%) receiving EP achieved a complete remission (CR) with or without adjunctive surgery. Similar proportions of patients in both arms were found at surgery to have necrosis/fibrosis or mature teratoma. With a median follow-up of 24.4 months in the VAB-6 arm and 25.9 months in the EP arm, the total, relapse-free, and event-free survival distributions were similar in the two arms. Patients receiving EP experienced less emesis (P = .05), higher nadir WBC (P = .06) and platelet counts (P = .01), less magnesium wasting (P = .0001), less mucositis (P = .09), and no pulmonary toxicity. No treatment-related mortality was observed. EP is an efficacious and less toxic regimen and is recommended for good-prognosis patients with disseminated GCT.

The role of cisplatin-based chemotherapy in advanced urothelial tract cancer.

Cisplatin and methotrexate used singly are the most active agents against transitional cell carcinoma of the urothelium, inducing remission in approximately 30% of cases. Other agents demonstrating some activity include vinblastine, vincristine, and, to a lesser extent, fluorouracil, mitomycin C, and amsacrine. Most multidrug combinations have not proven to be more effective than single-drug therapy; however, there is some indication that response and percent of complete remission (CR) is increased with cisplatin plus doxorubicin, and with CMV (cisplatin, methotrexate, vinblastine) and M-VAC (methotrexate, vinblastine, doxorubicin, cisplatin) regimens. With the latter two regimens, approximately 20% to 35% of cases achieve CR that persists in selected cases for 2 to 4 years. Such results against advanced transitional cell carcinoma with CMV and M-VAC have led to their use in neoadjuvant trials for this chemotherapeutically responsive tumor.

Bone metastases: pathogenesis, treatment, and rationale for use of resorption inhibitors.

Tumors in bone are usually metastatic, with breast, prostate, and lung tumors accounting for more than 80 percent of clinically manifest lesions. Untreated, such metastases can produce the symptoms that most concern cancer patients--pain, pathologic fractures, and paralysis through epidural cord compression. Recent advances in the understanding of the metastatic cascade and the regulation of bone formation and resorption provide unique therapeutic approaches for prevention and treatment of these lesions. This article reviews the prevalence, distribution, diagnosis, and treatment of metastatic cancer in the skeleton, as well as the processes involved in the development of such metastases, the local mediators responsible for some of the destructive changes in bone, and their pathologic results. In addition to considering some of the conventional therapeutic approaches, a rationale for the use of bone resorption inhibitors, such as the diphosphonates (bisphosphonates), is presented for the prevention and amelioration of the pathologic consequences of skeletal metastases.

Role of etoposide-based chemotherapy in the treatment of patients with refractory or relapsing germ cell tumors.

Forty-nine patients with metastatic germ cell tumors were treated with etoposide 100 mg/m2 and cisplatin 20 mg/m2 intravenously each day for five days as "salvage" chemotherapy. Forty-seven patients had received standard induction regimens for metastatic germ cell tumors before receiving etoposide and cisplatin. Four patients were treated after surgical resection of a single site of relapse (Group I). Forty-five patients had measurable or evaluable disease at the time of treatment. In 17 patients with evaluable disease who had either achieved a prior complete remission or received no prior cisplatin (Group II), eight (47 percent) complete and four (24 percent) partial remission were observed. In 28 patients who had never achieved a prior complete remission (Group III), no complete and five (18 percent) partial responses were observed. Seven of 21 patients in Groups I and II and none of 28 patients in Group III remain alive and free of disease. Assuming prior treatment with cisplatin-based chemotherapy, these data and a review of the published experience with similar salvage regimens for patients with relapsing or refractory germ cell tumors suggest that combination chemotherapy based on etoposide and cisplatin is effective primarily in those patients who achieved a prior complete remission. Such therapy is ineffective in the absence of a prior complete remission probably because the patients have tumors that are largely resistant to cisplatin. Observed responses are probably due to etoposide alone. Investigational therapies should be pursued in those patients whose disease is refractory to current induction regimens.

Chemotherapy in the management of bladder tumours.

For patients with superficial bladder tumours intravesical treatment or prophylaxis with thiotepa, doxorubicin, mitomycin C or Bacillus Calmette-Guerin has added a useful dimension to management, although the precise indications for each regimen remain to be better defined. For patients with metastatic bladder cancer cisplatin and methotrexate (amethopterin), and to a lesser extent vinblastine and doxorubicin, are active single agents. Combinations of cisplatin and doxorubicin (adriamycin), and cisplatin and methotrexate +/- vinblastine +/- doxorubicin appear to induce complete remission in 20 to 35% of cases and partial remission in an additional 20 to 40% of cases. In some patients, complete remission has persisted from 2 to more than 10 years. Few randomised Phase III studies have been carried out to determine the relative effectiveness of different drug combinations, but the results of Phase II trials have encouraged investigations of adjuvant and neoadjuvant programmes combining such regimens with radiation or surgery, or both, in patients with clinically localised muscle infiltrating tumours.

Preclinical studies of gossypol in prostate carcinoma.

Hormone refractory prostate cancer remains an incurable disease and the discovery of newer agents with higher cytotoxic activity is required. Gossypol is a phenolic compound isolated from cottonseed oil which has been shown to have anti-spermatogenic effects. In in vitro studies, gossypol appears to inhibit the growth of rat prostate cancer cell line MAT-LyLu and human prostate adenocarcinoma cell lines PC-3, LNCaP and DU-145. In vive, gossypol appeared to inhibit tumor growth of subcutaneously implanted MAT-LyLu cells in Copenhagen rats. Gossypol may be an active agent for the treatment of hormone refractory metastatic prostate cancer.

Phase-II trials in patients with urothelial tract tumors. Memorial Sloan-Kettering Cancer Center.

Major progress has been made in the treatment of patients with advanced urothelial tract tumors, using a systematic phase II approach in selected patients. At this time, DDP and MTX, singly, seem to induce the largest number of responses, while VLB and ADM, singly, are good secondary agents. The combinations of DDP + ADM, and VLB + MTX appear to be somewhat more effective than the single drug components, and hopefully a four-drug combination may be even more effective. Since significant antitumor activity is achieved with the drugs now available, we plan to initiate a randomized phase-III study in patients with stage-D tumors after preoperative irradiation and radical cystectomy with lymph node dissection. The data at Memorial Sloan-Kettering Cancer Center indicate a 70% death rate at 1 year, and 87% at 2 years, despite radiation therapy and cystectomy; for such cases, therefore, chemotherapy may be useful in prolonging survival. While new drugs still need to be defined, transitional cell carcinoma of the urothelial tract must be considered a tumor responsive to chemotherapy; we may possibly be on the threshold of chemotherapeutically curative therapies.

Phase-II trial of 4-demethoxydaunorubicin (DMDR) for advanced hypernephroma.

A phase-II trial of 4-demethoxydaunorubicin (4-DMDR) was performed in 21 patients with advanced renal cell carcinoma. The drug had demonstrated a broader spectrum of activity with less cardiotoxicity in preclinical evaluation than the parent compound daunorubicin. The starting dose was 12.5 mg/m2, with escalations to 15 and 17.5 mg/m2 in the absence of toxicity. Myelosuppression was the primary toxicity and cardiac toxicity was not seen in four patients who received four or more doses of DMDR. No responses were seen in 19 adequately treated patients, including 14 who had received no prior therapy.

Etoposide in prostatic cancer: experimental studies and phase II trial in patients with bidimensionally measurable disease.

Etoposide, a semisynthetic derivative of podophyllotoxin, was evaluated concurrently in vitro against a human derived hormone-resistant cell line, PC-3, and in vivo in bidimensionally measurable hormone-resistant human prostatic cancer. In vitro, a dose-response relationship was observed, with 74% inhibition at 10 micrograms/ml (1 h incubation) and greater than 99% inhibition at 90 micrograms/ml, both in the range of clinically achievable concentrations. In vivo, 1 PR (5%, 95% confidence limits 0-12%) of 18+ months was observed in 20 adequately treated patients. The results confirm the limited role of etoposide in hormone-refractory disease and the need for new model systems for evaluation of potential chemotherapeutic compounds in this disease.

Phase I/II trial of intravesical methotrexate for superficial bladder tumors.

Twenty-one patients with superficial transitional cell carcinoma of the bladder received a total of 121 doses of intravesical methotrexate (MTX) at 11 different concentrations of drug, ranging from 40 mg/m2 (mean concentration of 2.9 X 10(-3) M) to 500 mg/m2 (4.9 X 10(-2) M). Biochemical evidence of absorption was minimal in all cases. The maximum serum level was observed within 0.5-2 h in all patients and ranged from 1.8 X 10(-8) M to 5.0 X 10(-7) M. By 24 h the serum levels were negligible and ranged from 5.5 X 10(-9) M (the lowest limit detectable by the assay) to 4.4 X 10(-8) M in the patient who received the highest dosage of 500 mg/m2. Biologic evidence of absorption was minimal. Myelosuppression, mucositis, and nausea were not observed. Eighteen patients received six consecutive weekly doses ranging from 40 to 500 mg/m2. All patients had repeat cytoscopy performed within 2-4 weeks after six consecutive doses to evaluate local toxicity and efficacy. Flow cytometry was performed on the bladder washings of 22 patients, illustrating the use of flow cytometry, in conjunction with conventional cytology, as an additional means of objectively quantifying results. Despite MTX's established activity in systemic treatment of advanced bladder carcinoma, this study failed to demonstrate any clinical response to intravesically administered MTX, in doses of up to 500 mg/m2, and in concentrations of up to 4.9 X 10(-2) M.

Chemotherapy of seminoma.

1. Seminoma may occasionally be rapidly growing, aggressive, radioresistant, and chemotherapy-resistant tumor. 2. Alkylating agents have had the greatest number of trials and have produced the best response rates in the management of seminoma, but a wide range of other agents warrants trials. 3. Adjunct chemotherapy is a logical consideration in patients with stage II and stage III seminoma.