Dynamics of Charge-Transfer Processes with Time-Dependent Density Functional Theory.

We show that whenever an electron transfers between closed-shell molecular fragments, the exact correlation potential of time-dependent density functional theory develops a step and peak structure in the bonding region. This structure has a density dependence that is nonlocal both in space and in time that even the exact adiabatic ground-state exchange-correlation functional fails to capture it. For charge-transfer between open-shell fragments, an initial step and peak vanish as the charge-transfer state is reached. The inability of usual approximations to develop these structures leads to inaccurate charge-transfer dynamics. This is illustrated by the complete lack of Rabi oscillations in the dipole moment under conditions of resonant charge transfer for an exactly solvable model system. The results transcend the model and are applicable to more realistic molecular complexes.

Universal dynamical steps in the exact time-dependent exchange-correlation potential.

We show that the exact exchange-correlation potential of time-dependent density-functional theory displays dynamical step structures that have a spatially nonlocal and time nonlocal dependence on the density. Using one-dimensional two-electron model systems, we illustrate these steps for a range of nonequilibrium dynamical situations relevant for modeling of photochemical or physical processes: field-free evolution of a nonstationary state, resonant local excitation, resonant complete charge transfer, and evolution under an arbitrary field. A lack of these steps in the usual approximations yields inaccurate dynamics, for example, predicting faster dynamics and incomplete charge transfer.

Pilot study with weekly chemotherapy for patients with extensive small cell lung cancer: an Eastern Cooperative Oncology Group Study (PA586).

PURPOSE: Six of the most active chemotherapy agents in small cell lung cancer were administered sequentially in a weekly fashion in an attempt to optimize the dose and the number of agents received over a 12-week period. The purpose of this study was to estimate the efficacy and to characterize the toxicity of this approach. PATIENTS AND METHODS: Thirty-six patients with extensive-stage small cell lung cancer received weekly treatments with cisplatin and etoposide (weeks 1, 5, and 11), cyclophosphamide (weeks 2, 7, and 10), vincristine (weeks 2, 4, 7, 8, 10, and 12), methotrexate (weeks 3, 6, and 9), and doxorubicin (weeks 4, 8, and 12). Patients achieving a partial response received a second 12-week course. Patients achieving a complete response received prophylactic cranial radiation. RESULTS: Twenty-nine of the 36 patients completed the initial 12-week program over a median of 16 weeks. Hematologic toxicity was most prominent, with two deaths from sepsis and 31 patients having grade 3 or 4 neutropenia The overall response rate was 85%, with 33% of patients achieving a complete response. The median survival was 10.5 months, and the median time to progression was 8.2 months. DISCUSSION: This 12-week program, consisting of administration of six active agents for small cell lung cancer, caused significant myelosuppression that resulted in significant treatment delays and dose reductions. Although a high response rate was achieved, the median overall survival of 10.5 months was not significantly longer than expected from other standard two- to three-drug regimens.

Clostridium cadaveris bacteremia in the immunocompromised host.

Clostridium cadaveris, usually considered a non-pathogen, was isolated from blood cultures of two febrile patients with cancer. The bacteremias appeared to have originated from the abdomen. This organism has not been previously reported as the etiological agent in this setting.

Disseminated strongyloidiasis with central nervous system involvement diagnosed antemortem in a patient with acquired immunodeficiency syndrome and Burkitts lymphoma.

A 45-year-old man presented with central nervous system involvement as the initial manifestation of disseminated infection with Strongyloides stercoralis. Several concurrent clinical factors contributed to this event, all related to the patient's immunosuppression, including high-grade lymphoma, corticosteroid therapy, and acquired immunodeficiency syndrome. This is only the third case of CNS involvement in disseminated strongyloidiasis diagnosed antemortem.

Leptomeningeal metastases: comparison of clinical features and laboratory data of solid tumors, lymphomas and leukemias.

We reviewed 63 cases of cytologically confirmed leptomeningeal metastases (LM). 31 (49%) had solid tumors 17 (27%) had leukemia and 15 (24%) had lymphoma. The most common presenting symptom was pain (76%) with radicular discomfort (58%), headache (32%), neck or back pain (17%). The predominant neurological signs were mental status abnormalities (49%), weakness (47%), seizures (14%). The mode of presentation varied with tumor type. Patients with leukemia (18%) and lymphoma (13%) tended to present frequently with LM without systemic involvement, or during periods of apparent remission (leukemia 35%, lymphoma 27%), while patients with solid tumors had established systemic metastases (90%) at time of presentation. Laboratory studies did not vary among the groups. 71% had positive cytology on the first lumbar puncture (LP) and only 8% required more than 2 LPs. The cell count was a poor predictor of positive cytology as 29% of LP's with positive cytology and 36% of all LP's had less than 4 cells/mm. We conclude that 1) LM presents with pain and seizures more frequently than has been previously recognized; 2) LM is frequently the mode of presentation in patients with leukemia and lymphoma and; 3) cytology is positive frequently in CSF specimens with normal cell counts and chemistries.

Peripheral T-cell lymphoma presenting as a soft-tissue mass of the extremity.

An 87-year-old man was found to have a lymphoma in the deep soft tissue of the right shoulder with concomitant central nervous system involvement. There was no evidence of cutaneous, peripheral lymph node, mediastinal, abdominal, or bone marrow involvement. Light microscopic, ultrastructural, and immunohistochemical evaluation characterized the neoplasm as a peripheral T-cell lymphoma. Lymphomas presenting in soft tissue are rare, and the few well-documented cases in the literature are of B-cell origin. We report a T-cell lymphoma presenting in the soft tissue of the extremity, and delineate its clinicopathologic features.

Phase I and II agents in cancer therapy: two cisplatin analogues and high-dose cisplatin in hypertonic saline or with thiosulfate protection.

Cisplatin is a chemotherapeutic coordination complex that has been evaluated extensively. It is particularly active against testicular cancer, but carcinomas of the ovary, bladder, cervix, and head and neck are also responsive. To increase efficacy and decrease toxicity, a number of platinum analogues have been developed and tested. One of these, carboplatin, is of particular interest. In clinical trials, it has demonstrated antitumor activity comparable to that of cisplatin, without evidence of significant renal toxicity or neurotoxicity. A second interesting platinum analogue is iproplatin. Preliminary phase I studies suggest reduced adverse renal and neurologic effects similar to those seen with carboplatin, with efficacy comparable to cisplatin. Attempts to overcome the dose-limiting toxicity of cisplatin by administering high-dose cisplatin (40 mg/m2/d for five days) in hypertonic saline or with thiosulfate protection are also reviewed. These techniques have eliminated nephrotoxicity as the dose-limiting toxicity of cisplatin. However, nonrenal toxicity, especially neurotoxicity, remains substantial. The extent to which high-dose cisplatin-based chemotherapy should be used in routine clinical practice has not been determined.

Phase I and II agents in cancer therapy: I. Anthracyclines and related compounds.

Anthracycline antibiotics remain among the most potent anticancer drugs, but their efficacy is limited by the development of a dose-dependent irreversible cardiomyopathy and by the emergence of clones of tumor cells resistant to the effects of the drug. Modifications of the basic anthracycline structure have resulted in molecules that may share the activity of the parent compound, with amelioration of some toxicities, absence of cross-resistance, or activity against tumors insensitive to the parent drug. Epirubicin has a unique metabolic pathway, glucuronidation, that may result in more rapid plasma clearance and reduced toxicity as compared with doxorubicin. Epirubicin has demonstrated comparable activity to doxorubicin in breast cancer, with possibly reduced toxicity. Idarubicin is of interest because of its cytotoxic activity when given orally. Idarubicin has prolonged retention in the plasma and has equal cytotoxic activity to the parent compound. Idarubicin has demonstrated activity against acute leukemia and breast cancer; in the latter tumor category, some doxorubicin-resistant tumors have responded. Esorubicin is of interest because of its nearly absent cardiac toxicity. This agent has some activity against solid tumors and is currently being clinically tested. Aclacinomycin A is an anthracycline in which a trisaccharide is substituted for the aminosugar. Aclacinomycin A and the related compound marcellomycin are of interest as both cytotoxic and differentiating agents. Menogaril is an anthracycline with the aminosugar on the D ring; it does not exhibit cross-resistance with doxorubicin or cardiotoxicity. Mitoxantrone is a compound that is related to the anthracyclines but has a different mechanism of action. This agent has significant activity against acute leukemia and breast cancer and is currently being compared with doxorubicin. Amsacrine is another compound related to the anthracyclines that possesses major activity against acute leukemias. Minor modifications of the anthracycline molecule have had major impact on the biologic activity of these drugs. New anthracycline analogues with up to 100 times the potency of currently available anthracyclines are being developed for clinical testing, and these complex molecules retain a nearly unlimited potential for structural modification.

CT evaluation of patients during treatment of advanced non-small cell lung carcinoma.

Twenty-one patients with Stage III non-small cell bronchogenic carcinoma were studied by chest radiograph and computed tomography (CT) before and after chemotherapy. In three patients (14%), the prechemotherapy CT showed measurable disease not seen on chest radiograph. Postchemotherapy CT scans showed additional measurable disease not seen on chest x-ray films in nine of 56 (16%) follow-up exams. This represented additional disease in seven of the 21 patients (33%). The CT findings resulted in a significant change in therapy in six of the 21 patients (29%).

Infections in patients with non-small-cell lung cancer treated with intensive induction chemotherapy.

The records of 65 consecutive patients with non-small-cell lung cancer (NSCLC) treated with intensive induction chemotherapy were reviewed to study the infectious complications during therapy and to analyze the relationship of the frequency of infections to various predisposing factors. A total of 44 infectious episodes were observed among 30 of the 65 patients. Of the 44 infections, 18 were microbiologically documented and 19 clinically. Seven (16%) infections were without microbiological or clinical documentation and were categorized as "possible" infections. Among the 18 microbiologically documented infections, fifteen (83%) were caused by bacteria and three by fungi. The most frequent bacteria identified in 11 (61%) of the 18 infections were gram-negative organisms, Escherichia coli and Klebsiella pneumoniae being the most frequent. Eight of the 44 infections were associated with bacteremia and three with microbiologically documented pneumonias. There were three drug-related infectious deaths, two associated with bacteremia and one with possible infections. All 44 infectious episodes presented with WBC counts of less than 1,000/microliter, and 34 (79%) had WBC counts of less than 500/microliter. We observed that during therapy, patients with poor performance status (less than 80%) are at a much higher risk to develop infectious complications than those with good performance status (greater than 80%; p less than .001). Although encouraging responses with intensive chemotherapy have been reported for NSCLC in several studies, a major impact of chemotherapy on the survival of patients with this disease has yet not been established. Thus, intensive chemotherapy for NSCLC should remain an experimental treatment modality and should be offered only to patients with good prognostic factors such as those defined by pretreatment performance status.

Thyroid cancer following radiotherapy for Hodgkin's disease: a case report and review of the literature.

Improved survival resulting from advances in therapy in patients with Hodgkin's disease is associated with long-term morbidity, including the potential for the development of a second solid malignancy. We report a 44-year-old man with an unusually aggressive course of thyroid carcinoma 15 years after treatment for Hodgkin's disease. In a review of the English-language literature, we found 21 cases of thyroid cancer following radiotherapy for Hodgkin's disease, with latency periods ranging from 6 to 48 years. The development of secondary thyroid cancer after high-dose neck irradiation may be related to hypothyroidism, itself a complication of radiotherapy. Thyroid function should be measured at least once a year in all patients given neck irradiation, with initiation of thyroid hormone replacement if there is evidence of sustained hypothyroidism.

Vindesine and high-dose cisplatin in the treatment of advanced non-small-cell lung cancer.

Seventeen patients with advanced non-small-cell lung cancer (NSCLC) were entered on a combination chemotherapy protocol including vindesine and high-dose cisplatin. All patients had measurable disease and had not previously received chemotherapy. All patients entered were evaluable for toxicity and response. Tumor regression was limited to one complete and one partial response (response rate, 11.7%; 95% confidence limits, 0 to 27%). The complete and partial response lasted 260 + and 82 days, respectively. For the 15 nonresponding patients, the median time to disease progression was 76 days. Median survival was 141 days for the whole group. Significant toxic effects were vindesine-related peripheral neuropathy and cisplatin-induced emesis. Myelosuppression was mild and manageable. The response for the vindesine-cisplatin combination observed in our study is inferior to that seen in a previous vindesine-cisplatin trial reported by others. Thus, the true value of this two-drug regimen in the treatment of NSCLC remains to be established.

Mantenimiento de equipos en los sistemas de agua potable y alcantarillado

Manual que pretende servir como guía para el desarrollo de sistemas de mantenimiento en las empresas de agua potable y saneamiento. Dirigido a los gerentes de mantenimiento de tales con empresas, bajo los siguientes enfoques: conceptual, que presenta el mantenimiento como una parte que se interrelaciona con las otras partes de la empresa; la otra muestra los fundamentos a tomarse en cuenta para implantar un sistema de mantenimiento preventivo

Computed tomography of the chest in small cell lung cancer: potential new prognostic signs.

Computed tomography (CT) of the chest was performed as part of the initial and subsequent staging evaluations in 33 patients with small cell lung carcinoma. In 25 of the 33 patients, CT demonstrated findings not observed on standard radiography. Eleven of the 33 would have been staged higher using CT. Before treatment, CT revealed more mediastinal and nodal involvement than conventional films. After chemotherapy, CT demonstrated areas of residual or early recurrent disease in nine of 28 patients that were not apparent on chest films. Initially thickened pericardium in patients with limited disease and persistent bronchial narrowing after chemotherapy were demonstrated to be associated with early relapse in the chest and short survival. These initial data suggest that the CT scan, in addition to more accurately assessing the extent of disease, can provide a new risk classification for early chest relapse. Initial thickened pericardium in limited disease and continued bronchial narrowing after chemotherapy may allow patient selection for future treatment trials with radiation as an adjuvant to chemotherapy.

Randomized study of cyclophosphamide, doxorubicin, and etoposide (VP16-213) with or without cisplatinum in non-small cell lung cancer.

Sixty-eight patients with non-small cell lung cancer were treated in a prospectively randomized study with cyclophosphamide, doxorubicin (Adriamycin), and etoposide (VP16-213) with cisplatinum (CAE +/- P). Response rate, time to progression, and survival of CAE-P treated patients were each superior compared to those of patients who received CAE therapy. Of 36 patients, 10 (4 complete remissions, 6 partial remissions) responded to CAE-P and of 29 patients 3 (1 complete remission, 2 partial remissions) responded to CAE (p = 0.073). The median time to treatment failure was 22.9 wk for the CAE-P regimen and 15.0 wk for CAE (p = 0.032). The median survival for patients treated on the regimen with and without cisplatinum was 34.5 and 22.5 wk, respectively (p = 0.04). There were two CAE-P and one CAE drug-related deaths. Toxic effects were more severe in the CAE-P regimen. The addition of cisplatinum to the CAE combination produced an increase in response rate with significant prolongation in both time to progression and survival, but did add morbidity. These results suggest that the combined use of cisplatinum with at least one of the chemotherapeutic agents in the CAE regimen is synergistic.

Phase II trial of aziridinylbenzoquinone (AZQ) in patients with refractory small cell carcinoma of the lung.

Sixteen previously treated patients received AZQ in a phase II study to test therapeutic efficacy in refractory small cell lung cancer. The dose and schedule of AZQ was 20 mg/m2 day 1 and 8, with treatments repeated every 28 days. No objective responses were noted among 16 evaluable patients. Myelosuppression was the major toxicity. AZQ does not appear to have antitumor activity in patients with previously treated small cell carcinoma.

Therapeutic efficacy and pharmacokinetics of vindesine and vindesine-cisplatin in previously treated patients with non-small cell lung carcinoma.

Twenty-nine patients with non-small cell lung cancer refractory to prior therapy were treated with either vindesine (VDS) alone (3 mg/m2 every week) or the combination of VDS plus cisplatin (DDP) (100 mg/m2 every 28 days). Serial blood and urine samples were collected to assess the pharmacokinetics of VDS and DDP. All patients were evaluable for toxicity and 27 were evaluable for response. No objective antitumor responses were observed. Peripheral neuropathy manifested by paresthesias, muscle weakness, and constipation were observed in 20 treated patients, and hematologic toxicity consisting of thrombocytopenia and/or leukopenia occurred in 18 patients. The plasma and urinary pharmacokinetics of VDS and DDP measured in this study indicate that VDS and DDP do not interfere with each other and that the pharmacokinetics in previously treated and untreated patients are similar. The antitumor responses and degree of toxicity observed in this trial compare unfavorably with previously reported VDS and VDS-DDP trials in previously untreated patients with this disease and suggest that prior exposure to chemotherapy might both decrease antitumor activity and enhance toxicity of these chemotherapeutic agents.