A practical tool for estimating subsurface LNAPL distributions and transmissivity using current and historical fluid levels in groundwater wells: Effects of entrapped and residual LNAPL.

A model is presented to account for elevation-dependent residual and entrapped LNAPL above and below, respectively, the water-saturated zone when predicting subsurface LNAPL specific volume (fluid volume per unit area) and transmissivity from current and historic fluid levels in wells. Physically-based free, residual, and entrapped LNAPL saturation distributions and LNAPL relative permeabilities are integrated over a vertical slice of the subsurface to yield the LNAPL specific volumes and transmissivity. The model accounts for effects of fluctuating water tables. Hypothetical predictions are given for different porous media (loamy sand and clay loam), fluid levels in wells, and historic water-table fluctuations. It is shown the elevation range from the LNAPL-water interface in a well to the upper elevation where the free LNAPL saturation approaches zero is the same for a given LNAPL thickness in a well regardless of porous media type. Further, the LNAPL transmissivity is largely dependent on current fluid levels in wells and not historic levels. Results from the model can aid developing successful LNAPL remediation strategies and improving the design and operation of remedial activities. Results of the model also can aid in accessing the LNAPL recovery technology endpoint, based on the predicted transmissivity.

A constitutive model for air-NAPL-water flow in the vadose zone accounting for immobile, non-occluded (residual) NAPL in strongly water-wet porous media.

A hysteretic constitutive model describing relations among relative permeabilities, saturations, and pressures in fluid systems consisting of air, nonaqueous-phase liquid (NAPL), and water is modified to account for NAPL that is postulated to be immobile in small pores and pore wedges and as films or lenses on water surfaces. A direct outcome of the model is prediction of the NAPL saturation that remains in the vadose zone after long drainage periods (residual NAPL). Using the modified model, water and NAPL (free, entrapped by water, and residual) saturations can be predicted from the capillary pressures and the water and total-liquid saturation-path histories. Relations between relative permeabilities and saturations are modified to account for the residual NAPL by adjusting the limits of integration in the integral expression used for predicting the NAPL relative permeability. When all of the NAPL is either residual or entrapped (i.e., no free NAPL), then the NAPL relative permeability will be zero. We model residual NAPL using concepts similar to those used to model residual water. As an initial test of the constitutive model, we compare predictions to published measurements of residual NAPL. Furthermore, we present results using the modified constitutive theory for a scenario involving NAPL imbibition and drainage.

A practical model for mobile, residual, and entrapped NAPL in water-wet porous media.

Flow of nonvolatile nonaqueous phase liquid (NAPL) and aqueous phases that account for mobile, entrapped, and residual NAPL in variably saturated water-wet porous media is modeled and compared against results from detailed laboratory experiments. Residual saturation formation in the vadose zone is a process that is often ignored in multifluid flow simulators, which might cause an overestimation of the volume of NAPL that reaches the ground water. Mobile NAPL is defined as being continuous in the pore space and flows under a pressure gradient or gravitational body force. Entrapped NAPL is defined as being occluded by the aqueous phase, occurring as immobile ganglia surrounded by aqueous phase in the pore space and formed when NAPL is replaced by the aqueous phase. Residual NAPL is defined as immobile, nonwater entrapped NAPL that does not drain from the pore spaces and is conceptualized as being either continuous or discontinuous. Free NAPL comprises mobile and residual NAPL. The numerical model is formulated on mass conservation equations for oil and water, transported via NAPL and aqueous phases through variably saturated porous media. To account for phase transitions, a primary variable switching scheme is implemented for the oil-mass conservation equation over three phase conditions: (1) aqueous or aqueous-gas with dissolved oil, (2) aqueous or aqueous-gas with entrapped NAPL, and (3) aqueous or aqueous gas with free NAPL. Two laboratory-scale column experiments are modeled to verify the numerical model. Comparisons between the numerical simulations and experiments demonstrate the necessity to include the residual NAPL formation process in multifluid flow simulators.

A constitutive model for air-NAPL-water flow in the vadose zone accounting for immobile, non-occluded (residual) NAPL in strongly water-wet porous media.

A hysteretic constitutive model describing relations among relative permeabilities, saturations, and pressures in fluid systems consisting of air, nonaqueous-phase liquid (NAPL), and water is modified to account for NAPL that is postulated to be immobile in small pores and pore wedges and as films or lenses on water surfaces. A direct outcome of the model is prediction of the NAPL saturation that remains in the vadose zone after long drainage periods (residual NAPL). Using the modified model, water and NAPL (free, entrapped by water, and residual) saturations can be predicted from the capillary pressures and the water and total-liquid saturation-path histories. Relations between relative permeabilities and saturations are modified to account for the residual NAPL by adjusting the limits of integration in the integral expression used for predicting the NAPL relative permeability. When all of the NAPL is either residual or entrapped (i.e., no free NAPL), then the NAPL relative permeability will be zero. We model residual NAPL using concepts similar to those used to model residual water. As an initial test of the constitutive model, we compare predictions to published measurements of residual NAPL. Furthermore, we present results using the modified constitutive theory for a scenario involving NAPL imbibition and drainage.

Flow behavior and residual saturation formation of liquid carbon tetrachloride in unsaturated heterogeneous porous media.

The formation of residual, discontinuous nonaqueous phase liquids (NAPLs) in the vadose zone is a process that is not well understood. To obtain data that can be used to study the development of a residual NAPL saturation in the vadose zone and to test current corresponding models, detailed transient experiments were conducted in intermediate-scale columns and flow cell. The column experiments were conducted to determine residual carbon tetrachloride (CCl(4)) saturations of two sands and to evaluate the effect of CCl(4) vapors on the water distribution. In the intermediate-scale flow cell experiment, a rectangular zone of the fine-grained sand was packed in an otherwise medium-grained matrix. A limited amount of CCl(4) was injected from a small source and allowed to redistribute until a pseudo steady state situation had developed. A dual-energy gamma radiation system was used to determine fluid saturations at numerous locations. The experiments clearly demonstrated the formation of residual CCl(4) saturations in both sands. Simulations with an established multifluid flow simulator show the shortcomings of current relative permeability-saturation-capillary pressure (k-S-P) models. The results indicate that nonspreading behavior of NAPLs should be implemented in simulators to account for the formation of residual saturations.

The addition of interferon or high dose cyclophosphamide to standard chemotherapy in the treatment of patients with multiple myeloma: phase III Eastern Cooperative Oncology Group Clinical Trial EST 9486.

BACKGROUND: Interferon (IFN) has demonstrated activity in the treatment of patients with multiple myeloma. A previous Eastern Cooperative Oncology Group (ECOG) study suggested that the rates of complete response (CR) and survival were increased with a regimen that alternated IFN with chemotherapy. The current study was designed to evaluate the effect of adding alternating cycles of IFN or early intensification with high dose cyclophosphamide (HiCy) to the VBMCP regimen for the treatment of multiple myeloma patients. METHODS: From February 1988 to May 1992, the ECOG entered previously untreated patients with active multiple myeloma on a study in which they were randomized to VBMCP (vincristine 1.2 mg/m(2) administered intravenously [i.v.] on Day 1, BCNU 20 mg/m(2) i.v. on Day 1, melphalan 8 mg/m(2) administered orally [p.o.] on Days 1-4, cyclophosphamide 400 mg/m(2) i.v. on Day 1, and prednisone 40 mg/m(2) p.o. on Days 1-7; 5-week cycles) or VBMCP + rIFN(alpha2), the latter given at 5 Mu/m(2) 3 times a week starting on Day 22 of each 6-week cycle after 2 initial cycles of VBMCP. Patients younger than 70 years were also randomized to a third treatment that substituted cyclophosphamide 600 mg/m(2) i.v. on Days 1-4 and prednisone 100 mg/m(2) p.o. on Days 1-4 for cycles 3 and 5 of VBMCP (VBMCP + HiCy). Treatment was continued for 2 years. RESULTS: Of the 653 patients entered, 628 were eligible for the study. All were evaluated for response. With median follow-up for surviving patients of 54 months, the median survival duration was 42 months-1 year longer than usually reported for melphalan combined with prednisone. A comparison of the three regimens revealed no significant difference in the rates of survival or objective response (OR). However, CRs were increased among patients treated with VBMCP + rIFN(alpha2) compared with VBMCP alone (18% vs. 10%, P = 0.03). Patients treated with VBMCP + rIFN(alpha2) had a longer response duration than patients treated with VBMCP alone (30 vs. 25 months, P = 0.035). There was a greater response rate with the IFN regimen among elderly patients (OR and CR = 67% and 31%, respectively) and patients with immunoglobulin A (IgA) myeloma (OR and CR = 83% and 29%, respectively). Severe infections were seen as often with VBMCP as with VBMCP + rIFN(alpha2) (13% vs. 15%), but they were more frequent with VBMCP + HiCy (25%). CONCLUSIONS: VBMCP + rIFN(alpha2) yields a higher rate of CR and a longer response duration than VBMCP alone but appears to make no difference in the rates of overall response or survival compared with VBMCP or VBMCP + HiCy. The superior ability of VBMCP + rIFN(alpha2) induction therapy to produce CR and more durable responses, as well as its activity in older patients and in those with IgA myeloma, suggest that this therapy has important biologic activity in myeloma and merits further clinical investigation.

An aggressive high dose cyclophosphamide and prednisone regimen for advanced multiple myeloma.

There is strong evidence that corticosteroids contribute to the objective and subjective response rate observed following treatment with several cytotoxic chemotherapy agents, and that there is a dose response effect for treatment of multiple myeloma with alkylating agents. Therefore, the Eastern Cooperative Oncology Group (ECOG) studied cyclophosphamide 600 mg/M2 given for four consecutive days intravenously combined with prednisone 100 mg orally daily in 57 patients who had progressed following or failed to respond to standard doses of these drugs. Forty eight patients met the eligibility criteria for evaluation of response and toxicity. Fourteen patients (29%) had an objective response (OR) and an additional 2 (4%) had a subjective response (SR) only. The median duration of objective response was 3.1 months and estimated median survival was 8.6 months. These results are identical to our prior experience with high dose cyclophosphamide alone. The addition of prednisone does not appear to enhance results either through increased remissions or greater survival. Therefore, this study indicates that the preferred form of high dose cyclophosphamide for multiple myeloma is as a single agent given in intravenous four day courses.

Timed-sequential high-dose cyclophosphamide and vincristine in the treatment of multiple myeloma.

BACKGROUND: This study was designed to examine the efficacy and toxicity of high-dose cyclophosphamide (CY), and to evaluate the potential added effect of vincristine (VCR) given at a theoretic time of malignant cell stimulation in a group of patients with multiple myeloma, refractory to or relapsing after, treatment with standard doses of chemotherapy. METHODS: Patients were randomly assigned to receive CY 2400 mg per M2 as a single-day dose and VCR 1.4 mg per M2 given on Day 1 or Day 9 after the CY. RESULTS: There were 108 cases suitable for analysis. No difference in objective response (17.6%, 23.5%), subjective response, remission duration, or survival was observed in the two treatment arms. CONCLUSIONS: The authors conclude that a single, high dose of cyclophosphamide is more toxic and provides equal or less response than the equivalent dose given over 4 consecutive days and that no improved effect was detected using timed-sequential therapy with VCR.

OCIS: 15 years' experience with patient-centered computing.

In the mid-1970s, the medical and administrative staff of the Oncology Center at Johns Hopkins Hospital recognized a need for a computer-based clinical decision-support system that organized patients' information according to the care continuum, rather than as a series of event-specific data. This is especially important in cancer patients, because of the long periods in which they receive complex medical treatment and the enormous amounts of data generated by extremely ill patients with multiple interrelated diseases. During development of the Oncology Clinical Information System (OCIS), it became apparent that administrative services, research systems, ancillary functions (such as drug and blood product ordering), and financial processes should be integrated with the basic patient-oriented database. With the structured approach used in applications development, new modules were added as the need for additional functions arose. The system has since been moved to a modern network environment with the capacity for client-server processing.

A large private university hospital system. The Johns Hopkins Oncology Center.

Clinical trials are a major commitment for a university-based comprehensive cancer center. In 1992, The Johns Hopkins Hospital registered 3508 new patients with cancer and, from this large population, 2880 patients were entered in clinical trials (many patients participated in more than one protocol). The Oncology Center, one of many departments at Johns Hopkins that conducts clinical research, participates in phase I and II new drug trials, phase III comparative studies, and, increasingly, in epidemiologic and prevention research. This calls for much broader participation by community hospitals and for many more patients who normally would not come to Johns Hopkins for their care. There are more than 100 protocols available from the Eastern Cooperative Oncology Group, but Johns Hopkins may participate in no more than 20 at any given time. Thus, every research facility must be selective about the trials in which it participates, given the finite number of hours, dollars, and resources available to carry out these programs. The institution provides safeguards to protect the interest of the patient. These include review and annual overseeing of the concept, design, and specifics of the proposed study. The pharmacy and nursing staff play an important role in control of chemotherapy distribution and use. Patients and physicians, however, must understand the questions the study is asking and agree that they are worth answering. There are problems in motivation; information; costs to the patient, hospital, insurers, and the physician; the concept of the placebo; and informed consent. Clinical research is the most ethical way to test drugs, radiation therapy, surgical procedures, or other new treatments. The clinical trial must meet rigorous criteria of design, conduct, and analysis. The patient must understand the issues and be a volunteer. We must make every effort to help patients and physicians get information about clinical trials and to participate if they choose.

Preparation of substituted N-phenyl-4-aryl-2-pyrimidinamines as mediator release inhibitors.

The role of immunologically released mediators, such as histamine, leukotrienes, and platelet-activating factor, is well-established for asthma and other allergic disorders. Developing therapeutic agents which would block mediator release from mast cells and other relevant cell types would provide a rational approach to asthma therapy. Using human basophil as a screen, a series of 4-aryl-2-(phenylamino)pyrimidines was found which inhibited mediator release. These compounds were prepared by condensing acetyl heterocycles with dimethylformamide dimethyl acetal to form enaminones which are cyclized with aryl guanidines to give pyrimidines. After examining a large number of analogs, N-[3-(1H-imidazol-1-yl)phenyl]-4-(2-pyridinyl)-2- pyrimidinamine (1-27) was chosen for toxicological evaluation.

AUTRES--the Johns Hopkins Hospital automated resume.

The Johns Hopkins Hospital has developed AUTRES, an electronic discharge summary. This computer generated report was designed to provide improved continuity in the care of patients by offering a legible, standardized summary of the events of hospitalization. It can be sent by mail, FAX, or electronically (computer-to-computer) to the next care giver who will see the patient. It is available from any network attached terminal at the hospital and School of Medicine to support re-admission to the hospital, treatment in the emergency room, or outpatient visits. AUTRES first ran in fully supported production serving the Department of Medicine in 1988. Re-engineered to take advantage of cooperative processing, it has been implemented in Neurology, Internal Medicine, Obstetrics and Gynecology and Pediatrics, with plans for phased installation in the remaining clinical departments of The Johns Hopkins Hospital.

A computer workstation for clinical medicine.

New computer tools for physicians, nurses, and the medical care team will become common in the 1990s. This paper describes a clinical workstation (CWS) development project that uses new technology that moves the technical support for medical decision making from the computer room to the nursing station. Collection, processing, and display of clinical information including patient identification, laboratory, and radiology results and current medications are carried out in the environment of a multi-windowed computer workstation. Easy access to automated medical literature databases from the workstation is also provided. This pilot project has successfully demonstrated a CWS operating on an acute general neurology and neurosurgical inpatient nursing unit and a critical care unit at The Johns Hopkins Hospital.

N-azamonobactams. 2. Synthesis of some N-iminoacetic acid and N-glycyl analogues.

The synthesis of the title compounds has been accomplished. The N-iminoacetic acid analogues (12a and 12b) containing the aminothiazole type side chain exhibited good in vitro antibacterial activity against Gram-negative organisms. The corresponding N-glycyl derivative (17) was not active.

Primary lymphoma in the salivary glands: report of five cases and review of the literature.

The finding of a lymphoma in a major salivary gland could mean one of two things: either it is part of a disseminated process, or it is the first clinicopathologic evidence of lymphoma. In the latter instance, whether the disease originated in the glandular stroma itself or in a paraglandular lymph node and then invaded the stroma, the lymphoma is defined as primary, as long as there is no detectable disease outside the salivary gland. Five cases of primary salivary gland lymphomas are described. All had a complete clinical staging including chest x-ray, bilateral bone marrow biopsy, liver-spleen scan, bilateral pedal lymphangiography and/or abdominal CT scan. There was no evidence of lymphoma outside the gland in any of the patients described; hence, these can be labeled as primary lymphomas of the salivary gland. Review of the literature suggests that this presentation of the disease is extremely rare. Although 324 cases of salivary gland lymphomas have been described in the literature, only six may be considered primary by our criteria. The remaining patients were either not adequately staged or had documented evidence of disease elsewhere at the time of diagnosis. The diagnosis of primary salivary gland lymphoma should not be made unless complete staging is performed.

The effects of distance from primary treatment centers on survival among patients with multiple myeloma.

Twenty-one comprehensive cancer centers participated in a national reporting system of common data items, recording information on all patients seen between 1977 and 1982. There were 240,531 patients who had data abstracted. This report describes 1,479 patients with multiple myeloma. Parameters that may effect the type of treatment given during the initial episode of therapy in the center and the effect of these characteristics on survival were studied. In the univariate analysis, age, treatment, and distance traveled to the center were statistically associated with survival. In a multivariate analysis adjusting for potentially confounding covariates, blacks survive better than whites and the effects of sex and socioeconomic status (SES) on survival approach significance. Survival consistently improved with increasing distance traveled to treatment centers. This may be a serious confounding variable in assessing the results by both single and multiinstitution clinical trials.

Contribution of prednisone to the effectiveness of hexamethylmelamine in multiple myeloma.

The Eastern Cooperative Oncology Group evaluated hexamethylmelamine in 89 patients with advanced refractory or relapsing multiple myeloma. Hexamethylmelamine was initially used as a single agent administered orally at 200 mg/m2/day for the first 3 weeks of each 4-week cycle. When this regimen proved to be ineffective, it was modified first by increasing the dose of hexamethylmelamine to 280 mg/m2/day and subsequently by adding prednisone at 75 mg for the first 7 days of each 28-day cycle. None of the 39 patients receiving hexamethylmelamine without prednisone had an objective response, while two patients had minimal objective improvement (25%-50% decrease in M protein with symptomatic improvement). Only 14% of these patients had objective or symptomatic response or both. In contrast, patients treated with hexamethylmelamine plus prednisone had a 22% objective response rate, with another 14% showing lesser degrees of objective improvement. Fifty-one percent of the patients treated with this regimen had either objective or symptomatic improvement or both. Severe (grade 3) toxicity was seen in nearly two-thirds of the patients on the higher-dose hexamethylmelamine regimens compared with 37% of the patients receiving low-dose hexamethylmelamine; however, in most instances this represented rapidly reversible cytopenias. Because all but one of the patients responding to hexamethylmelamine plus prednisone had experienced previous treatment failure on regimens containing prednisone in similar dose and schedules, it is unlikely that the responses are due to prednisone alone. Instead, this study suggests that the activity of hexamethylmelamine in multiple myeloma is dependent on the concomitant administration of prednisone and that the combination regimen appears to be synergistic.

Imidazo[1,5-d][1,2,4]triazines as potential antiasthma agents.

By using inhibition of histamine release from antigen-challenged, sensitized human basophils as a means of identifying a potentially prophylactic drug for the treatment of asthma, a series of substituted imidazo[1,5-d][1,2,4]triazines were found, which were active. These compounds were prepared by treating imidazolecarboxaldehydes with excess Grignard agent and then oxidizing the resulting alcohols to ketones with Jones reagent. Pyrolysis of a mixture of ketone and methyl carbazate at 200 degrees C in diphenyl ether produced the desired imidazo[1,5-d][1,2,4]triazines. Those compounds with the greatest basophil activity were tested for in vivo activity in the mouse passive cutaneous anaphylaxis (PCA) and the guinea pig passive anaphylaxis tests. The best compounds, 1-ethyl-8-methyl-6-propylimidazo[1,5-d][1,2,4]triazin-4(3H)- one (4-17) and 1,8-dimethyl-6-propylimidazo[1,5-d][1,2,4]triazin-4-(3H)-one (4-16) were chosen for further study.