Technical assessment of fuel cell operation on anaerobic digester gas at the Yonkers, NY, wastewater treatment plant.

This paper summarizes the results of a 2-year field test to assess the performance of a specially modified commercial phosphoric acid 200-kW fuel cell power plant to recover energy from anaerobic digester gas (ADG) which has been cleansed of contaminants (sulfur and halide compounds) using a patented gas pretreatment unit (GPU). Specific project goals include characterization of the fuel cell power plant emissions and verification of the GPU performance for removing sulfur contaminants. To remove halide contaminants from the ADG, a halide guard, consisting of a vessel with a metal oxide supported on alumina, was incorporated into the fuel cell reactant supply. This first-of-a-kind demonstration was conducted at the Yonkers, NY, wastewater treatment plant, a sewage processing facility owned and operated by Westchester County. Results have demonstrated that the ADG fuel cell power plant can produce electrical output levels close to full power (200 kW) with negligible air emissions of CO, NO(x), and SO(2). The GPU removed virtually 100% of H(2)S and 88% of organic sulfur, bringing the overall sulfur removal efficiency of the GPU to over 99%. The halide guard removed up to 96% of the halides exiting the GPU.

Complete remission induction with combined VBMCP chemotherapy and interferon (rIFN alpha 2b) in patients with multiple myeloma.

The purpose of this study was to evaluate a new regimen for the treatment of multiple myeloma based on alternating 3-week cycles of chemotherapy and interferon (rIFN alpha 2). In this prospective phase II clinical trial the Eastern Cooperative Oncology Group evaluated a regimen consisting of 2 cycles of VBMCP (Vincristine 1.2 mg/M(2) IV d1, BCNU 20 mg/M(2) IV d1, Melphalan 8 mg/M(2) PO dl-4, Cyclophosphamide 400 mg/M2 IV d1, Prednisone 40 mg/M(2) PO d1-7) followed by alternating 3-week cycles of VBMCP and rIFN alpha2 5 Mu/M(2) SC 3x/week. Treatment was administered for 2 years. Fifty-eight patients with previously untreated multiple myeloma were entered. Objective response (OR) required 50% decrease in M-protein with correction of severe anemia and no progression of skeletal disease. Complete remission (CR) was defined by disappearance of M-protein and normalization of the bone marrow morphology. Life table analysis was utilized to express survival and response duration. Fifty-four patients were evaluable. Objective response was seen in 80% of patients including CR in 30% (16 patients). The median response duration is 35 months, 46 months for patients with CR. The median survival is 42 months for all patients. Five year survival is 42%. Although 78% of patients had neutrophil nadirs <1000 x 10(9)/L, the incidence of severe infection was only 9%. These data demonstrate that VBMCP + interferon is an effective new regimen combining chemotherapy with a biological response modifier for the treatment of multiple myeloma. The incidence of CR is high, and the response and survival durations appear to be 1 year longer than usually seen with standard chemotherapy. A current ECOG randomized trial compares VBMCP + interferon with VBMCP alone.

Alpha interferons: a clinical overview.

The development of the recombinant alpha interferons has provided a prototype for the clinical development of biological compounds. Over 5,000 patients have now been treated with alpha interferons, and from this experience, some general principles relating to the phase I-III testing of biologicals have emerged. Clinical trials of alpha interferon have suggested dose-response relationships and provided a clearer picture of schedule dependence. These trials have also indicated that the extent of tumor burden and identification of sensitive patient subtypes may be critical factors affecting the potential activity of biological compounds. Recent studies using interferon in the treatment of chronic viral hepatitis have also generated promising results, suggesting an even greater antiviral role for the drug. The toxicity profile of the alpha interferons is unusual. Fever and influenza-like symptoms occur in almost all patients at all doses and schedules, and are usually dose limiting. Somnolence and other generally mild CNS effects occur in a small percentage of patients. Hematologic toxicity occurs but is minimal at lower doses and is noncumulative and rapidly reversible at all doses. Gastrointestinal toxicity is mild. No other unusual or unexpected toxicities have been reported, and early reports of cardiovascular toxicity have not been confirmed in large trials. The full role of alpha interferon in antineoplastic and antiviral therapy will be resolved in the coming years. This review summarizes existing safety and efficacy data for the alpha interferons.

Anti-interferon antibodies to interferon-alpha 2b: results of comparative assays and clinical perspective.

Previous studies have reported a low (less than 3%) incidence of anti-interferon (IFN) serum neutralizing antibodies following treatment with IFN-alpha 2b. Since this result contrasts with a higher incidence reported with IFN-alpha 2a, the question has been raised whether differences in assay techniques and patient comparability rather than inherent differences in the molecules might account for the reported differences in antibody incidence. In this report two patient groups, 151 hairy cell leukemia (HCL) patients and 101 patients with other malignancies, who have received long-term dosing with IFN-alpha 2b, are reported. The sera of both groups were studied before, during and after treatment by various assay methodologies. Utilizing three assay techniques, a less than 3% overall incidence of serum antibody formation was confirmed in these retested samples. With over 575 samples tested in multiple assays, the radioimmunoassay, as utilized in prior reports, demonstrated 99% agreement with a bioassay. Therefore, prior speculation that the assay technique for IFN-alpha 2b might produce a high false-negative rate was disproven. Additionally, the clinical outcome of these patients also failed to demonstrate a pattern of clinical relapse. In summary, these new analyses confirm the low (less than 3%) incidence of neutralizing antibody development following treatment with IFN-alpha 2b and confirm that no high rates of clinical relapse have developed in patients treated with chronic long-term dosing. Assay methodology does not appear to be a likely explanation for the low incidence of antibody formation reported with IFN-alpha 2. Rather, the unique molecular structure and pharmaceutical formulation of IFN-alpha 2b remains the most likely explanation of its minimal antigenicity.

Comparison of finite-difference time-domain SAR calculations with measurements in a heterogeneous model of man.

A finite-difference time-domain technique was used to calculate the specific absorption rate (SAR) at various sites in a heterogeneous block model of man. The block model represented a close approximation to a full-scale heterogeneous phantom model. Both models were comprised of a skeleton, brain, lungs, and muscle. Measurements were conducted in the phantom model using an implantable electric-field probe and a computer-controlled data acquisition system. The calculation and measurement of SAR distributions were compared primarily in the head (including the neck) and chest. To obtain the necessary spatial resolution with the computer model, the head and neck were modeled with approximately 105,000 cells, while 86,000 cells were used to configure the chest. Planewave fields, polarized in the E orientation, were utilized to irradiate the models at an exposure frequency of 350 MHz. Reasonable correlation existed between the calculations and measurements.

Cost-benefit analysis of interferon alfa-2b in treatment of hairy cell leukemia.

The clinical benefits as well as the cost benefits of use of recombinant interferon (IFN) alfa-2b instead of conventional chemotherapy (primarily chlorambucil) for progressive hairy cell leukemia were assessed retrospectively on the basis of 12 months of clinical data from 128 patients treated with IFN alfa-2b. Data from 71 matched historical control patients who had received conventional treatment were used for survival analysis. Hematologic response (reversal of cytopenias) was achieved by 18% of the control patients versus 73% of the IFN-treated patients. This response was associated with virtual elimination of the need for transfusions and splenectomy as well as dramatic decreases in the frequency of fatal infections (22.5% vs. 1.6%) and the 12-month mortality rate (28% vs. 3.1%). Direct costs per patient per year for medical care (transfusions, antibiotic treatment, splenectomy, and chemotherapy) of those receiving IFN alfa-2b were 2.8-fold lower than costs for medical care of control patients ($5,027 vs. $14,046). Indirect costs, which reflect the present value of future earnings lost due to premature death, were 13.3-fold lower for IFN-treated patients than for control patients ($4,771 vs. $63,507). Our analysis demonstrates that IFN alfa-2b offers substantial clinical and cost advantages to patients with hairy cell leukemia and that the introduction of this therapy using novel biotechnology furthers the health care community's commitment to cost containment.

Minimal antigenicity of intron A in human recipients demonstrated by three analytical methods.

Antibodies to recombinant human interferon alpha 2b (Intron A) were detected in only a small number of 101 Intron A recipients. This group of cancer patients received Intron A for a mean treatment time of 4.3 months and were selected from disease categories in which subjects were expected to be immunocompetent. Three methods for the detection of antibodies were employed: (a) a bioassay measuring the neutralizing activity of the sera for the antiviral action of interferon alpha 2b, (b) a radioimmunological assay measuring the ability of the sera to prevent the detection of interferon alpha 2b by an immunoradiometric assay (IRMA), and (c) an enzyme-linked immunosorbent assay (ELISA) that measures the binding of immunoglobulins to interferon alpha 2b attached to a solid support. Three of the 101 patients developed neutralizing activity during treatment. Two of these exhibited low neutralizing titers of 1:6-1:9 and were unreactive in the IRMA and ELISA, while only one was positive by bioassay, IRMA, and ELISA. An additional seven patients were positive only in the ELISA. Six of these were borderline positive, i.e., the posttreatment:pretreatment ratio was less than or equal to 5. The results of this study confirm that Intron A is minimally antigenic in human subjects.

Treatment of epidemic Kaposi's sarcoma with a combination of interferon-alpha 2b and etoposide.

A prospective clinical trial of concomitant interferon-alpha 2b and etoposide was conducted in 24 previously untreated patients with epidemic Kaposi's sarcoma. Eight of 21 evaluable patients (38%) achieved either a complete response (1 patient) or a partial response (7 patients). None of the responders had a prior history of opportunistic infection. Hematologic toxicity was severe, and 8 patients developed an opportunistic infection. The combination of interferon-alpha 2b and etoposide has modest activity, but no additive or synergistic activity was evident in the dose and schedule utilized in this study. The exact role for interferon-alpha in epidemic Kaposi's sarcoma, both as a single agent and in combinations, remains to be determined.

Phase I trial of escalating dose doxorubicin administered concurrently with alpha 2-interferon.

The clinical use of alpha 2-interferon and doxorubicin is based on in vitro and preclinical in vivo observations of synergistic antitumor efficacy. To test this combination a Phase I clinical and pharmacokinetic study of the concurrent use of alpha 2-interferon and doxorubicin was initiated in patients with malignant solid tumors. Each 5-wk treatment cycle consisted of 3 wk of drug administration and 2 wk of rest. The alpha 2-interferon was administered s.c. at a constant dose of 10 million IU/m2 on Mondays, Wednesdays, and Fridays in all patients while the doxorubicin was administered weekly beginning with a dose of 5 mg/m2 and escalated to the maximum tolerated dose of 25 mg/m2. At least three evaluable patients were entered at each dose level, and no dose escalations were allowed within patients. The dose-limiting toxicities were granulocytopenia and thrombocytopenia. Hepatic enzyme elevations and systemic symptoms due to interferon occurred at all dose levels. None was severe or dose limiting, and all were reversible. These toxicity data suggest that the hepatotoxic effects of interferon do not enhance doxorubicin toxicity when given by this dose and schedule. Doxorubicin plasma levels were measured at each dose level. The recommended dose of doxorubicin is 25 mg/m2 per wk when administered with 10 million IU/m2 of interferon in this schedule. This schedule allows for the administration of a greater total dose of doxorubicin than has been achieved when given every 3 wk with the same dose and schedule of alpha 2-interferon in a parallel study.

Effect of ambient levels of power-line-frequency electric fields on a developing vertebrate.

Fertilized eggs of Gallus domesticus were exposed continuously during their 21-day incubation period to either 50- or 60-Hz sinusoidal electric fields at an average intensity of 10 Vrms/m. The exposure apparatus was housed in an environmental room maintained at 37 degrees C and 55-60% relative humidity (RH). Within 1.5 days after hatching, the chickens were removed from the apparatus and tested. The test consisted of examining the effect of 50- or 60-Hz electromagnetic fields at 15.9 Vrms/m and 73 nTrms (in a local geomagnetic field of 38 microT, 85 degrees N) on efflux of calcium ions from the chicken brain. For eggs exposed to 60-Hz electric fields during incubation, the chicken brains demonstrated a significant response to 50-Hz fields but not to 60-Hz fields, in agreement with the results from commercially incubated eggs [Blackman et al., 1985a]. In contrast, the brains from chicks exposed during incubation to 50-Hz fields were not affected by either 50- or 60-Hz fields. These results demonstrate that exposure of a developing organism to ambient power-line-frequency electric fields at levels typically found inside buildings can alter the response of brain tissue to field-induced calcium-ion efflux. The physiological significance of this finding has yet to be established.

The alpha interferons: clinical overview.

The clinical development of the recombinant alpha interferons has provided a prototype for the clinical development of biological compounds. With over 5,000 patients now treated with these compounds, some general principles have emerged that have wider implications for phase I-II strategies for testing other biologicals. There is a suggestion of dose-response relationships and a clearer picture of schedule dependence. The extent of tumor burden and identification of sensitive subtypes of patients also appear to be critical factors in evaluating the true potential activity of biological compounds. The toxicity profile of the alpha interferons is unusual. Fever and flu-like symptoms occur in all doses and schedules and are usually dose limiting. Somnolence and other CNS effects occur in a small percentage of patients. Hematologic toxicity occurs but is minimal at lower doses and is noncumulative and rapidly reversible at all doses. Gastrointestinal toxicity is mild. No other unusual or unexpected toxicities have been reported, and early reports of cardiovascular toxicity have not been confirmed in large trials. The use of these pioneer recombinant DNA products raised concerns about the potential development of antibodies and serum-neutralizing factors. Reports with small patient numbers confirmed the occasional development of serum-neutralizing activity to some alpha interferons. The significance of this neutralizing activity and the reasons for an apparent higher incidence of this phenomenon with some alpha interferon preparations remain to be determined. The full role of alpha interferon by itself or in combination with other available therapies will be resolved in coming years. This review presents current safety, efficacy, and neutralizing antibody data.

Interferons in oncology: current status and future directions.

The European School of Oncology has formed a study group to consider the present status of interferons in oncology. This position paper summarizes the discussions and conclusions of the first meeting of this study group.

A phase I clinical trial of recombinant DNA gamma interferon.

Recombinant gamma interferon (r-GIFN) demonstrates in vitro and in vivo characteristics that contrast with those of alpha and beta interferons. It has relatively weak antiviral properties, yet relatively potent immunomodulatory effects. A phase I trial was performed with r-GIFN (specific activity 2.6 X 10(6) IU/mg protein), administered as a continuous intravenous (IV) infusion over 24 hours for five days (Cl X 5) and repeated every 28 days. This schedule was chosen based on the short half-life of r-GIFN in animal systems and the in vitro augmentation of biologic effects with continuous exposure to interferons. Twenty-one patients with refractory solid tumors received 46 evaluable courses of therapy. The dose-limiting toxicities included fever, flu-like symptoms, cardiovascular toxicity, and neurotoxicity. The cardiovascular toxicity included hypotension and one episode of cardiac ischemia with chest pain. Neurotoxicity consisted of lethargy and confusion. These toxicities were reversible, and although dose-limiting, occurred sporadically throughout all dosage levels. Mild to moderately severe non-dose-limiting toxicities included nausea and vomiting, leukopenia, and liver function abnormalities. Other infrequent toxicities included hypocalcemia, diarrhea, constipation, and alopecia. The maximally tolerated dose of r-GIFN on this schedule is 0.5 X 10(6) IU/m2/d. Partial responses were seen in one patient with metastatic melanoma and in one patient with renal cell carcinoma. Toxicity and antitumor activity were seen at doses where interferon serum levels could not be detected by radioimmunoassay. In addition, the toxicity and antitumor activity seen were at much lower doses than previously described for shorter infusion schedules of other recombinant gamma interferon preparations. Differences in biologic activity of interferon preparations and/or differences in scheduling may account for this variability. Although this study defines a recommended phase II dose of r-GIFN based on the maximally tolerated dose, the optimal therapeutic index may exist at a lower dosage level.

Clinical overview of alpha interferon. Studies and future directions.

The clinical development of the alpha interferons has now progressed through initial Phase I and II trials into extensive controlled clinical trial designs. Alpha interferon has been a prototype of other biological agents that are now in clinical development. These agents operate through fundamentally different mechanisms of action than conventional chemotherapy and have produced a unique profile of side effects as well as response patterns. Time to response is generally longer than with chemotherapy, and dose-response and schedule-dependency questions continue to be explored for most tumor types. Although response rates have been low against most solid tumors when alpha interferon is used as a single agent, it has demonstrated a surprisingly wide range of efficacy in hematologic malignancies. These include tumors of presumed B-cell, T-cell, and myeloid lineages. In some diseases, e.g., hairy cell leukemia and chronic myelogenous leukemia, alpha interferon is broadly effective; it appears to considerably reduce or occasionally eliminate the malignant clone while normalizing the peripheral blood counts in most patients. In other diseases, alpha interferon appears destined to play a major role as part of combination therapy or in maintenance or consolidation therapy. In other disease settings, alpha interferon's role continues to be explored as part of combination therapy, adjuvant therapy, or as local-regional therapy. The full potential of alpha interferon as an antineoplastic agent will not be determined for many years. In this paper, the results from the first 5 years of widespread clinical testing are reviewed.