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Biomedical subjects

D H Johnson

Publications and source records attributed to D H Johnson.

At least 181 records · Page 10Linked to original sources
PubMed1993

Bioavailability of low-dose oral etoposide.

PURPOSE: To determine the bioavailability of oral etoposide capsules administered at doses of 100 mg and 400 mg. PATIENTS AND METHODS: The bioavailability of oral etoposide was determined by measuring the area under the etoposide plasma concentration versus time curve (AUC) following intravenous (IV) etoposide administration and comparing that value to the AUC achieved following an oral dose administered 1 day later to the same patient. The bioavailability of a 100-mg oral dose of etoposide was measured on 16 occasions in 11 patients. The bioavailability of a 400-mg dose was determined on 12 occasions in six patients. RESULTS: The mean (+/- SD) bioavailability following a 100-mg dose of oral etoposide was 76% +/- 22%, which was significantly greater (P < .01) than the mean bioavailability of 48% +/- 18% following a 400-mg oral dose. The coefficient of variation in oral etoposide bioavailability was significant: 29% with a 100-mg oral dose and 37% with a 400-mg dose. CONCLUSION: Bioavailability of a 100-mg oral etoposide dose is greater than suggested in the package insert from Bristol Laboratories (Evansville, IN). Comparable oral etoposide doses are not uniformly twice that of an IV dose, as suggested by the package insert, but will depend on the final oral dose administered. Bioavailability is better at lower oral etoposide doses. This study confirms the wide interpatient and intrapatient variability in oral etoposide bioavailability.

Administration, Oral↗
PubMed1993

Alternating chemotherapy and twice-daily thoracic radiotherapy in limited-stage small-cell lung cancer: a pilot study of the Eastern Cooperative Oncology Group.

PURPOSE: This pilot study was undertaken to determine the efficacy and feasibility of alternating cisplatin and etoposide with multiple daily fractions of thoracic radiotherapy (TRT) in patients with limited-stage small-cell lung cancer (SCLC). PATIENTS AND METHODS: Thirty-four SCLC patients received four courses of cisplatin (30 mg/m2/d x 3) plus etoposide (120 mg/m2/d x 3) (PE) every 3 weeks. TRT was administered twice daily (1.5 Gy per fraction) for 5 consecutive days in the week after cycles 1, 2, and 3 of chemotherapy (total TRT dose, 45 Gy). Patients who achieved a complete response (CR) received one course of late-intensification (LI) treatment consisting of cyclophosphamide (4 g/m2) and etoposide (900 mg/m2). Prophylactic cranial irradiation (PCI) was optional. RESULTS: Nineteen of 32 assessable patients achieved a CR (59%) and 12 had a partial response (38%), for an overall response rate of 97% (95% confidence interval [CI], 84% to 99%). Median survival was 18 months, while 2-year progression-free survival was 47%. Leukopenia < or = 1,000/microL occurred in 12% of induction treatment cycles. Severe esophagitis was uncommon. Pulmonary fibrosis that was asymptomatic or minimally symptomatic was observed in eight patients (25%). There was one episode of adult respiratory distress syndrome (ARDS) during LI chemotherapy. Life-threatening neutropenia (< or = 500/microL) developed in all patients who underwent LI chemotherapy, with a median duration of 10 days (range, 8 to 19). Two patients died of sepsis during LI chemotherapy. CONCLUSION: Alternating PE and TRT as performed in this trial is an effective brief induction regimen for limited-stage SCLC. However, this particular regimen did not appear to be substantially different in terms of efficacy or toxicity compared with regimens using concurrent chemotherapy and standard-fraction TRT. LI chemotherapy was associated with unacceptable toxicity and did not appear to have a favorable impact on survival.

Aged↗
PubMed1993

Effective therapy for poor-prognosis non-Hodgkin's lymphoma with 8 weeks of high-dose-intensity combination chemotherapy.

PURPOSE: Despite substantial advances in the treatment of aggressive non-Hodgkin's lymphoma, therapeutic results with conventional regimens remain poor in some subsets of patients. In an attempt to improve the prognosis of such patients we used an 8-week, multidrug chemotherapy regimen of high dose-intensity. PATIENTS AND METHODS: Between April 1986 and April 1991, 70 patients with advanced intermediate- or high-grade non-Hodgkin's lymphoma were treated. The median age was 41 years (range, 18 to 69). Fifty-one patients (73%) had stage IV disease; 37 (53%) were Shipp's category 3; 17 (24%) had small noncleaved-cell lymphoma; 35 (50%) had Eastern Cooperative Oncology Group (ECOG) performance status > or = 2; 24 (34%) had two or more extranodal sites involved; and 17 (24%) had bone marrow involvement. The 8-week regimen included cyclophosphamide, etoposide, doxorubicin, vincristine, bleomycin, methotrexate with leucovorin rescue, and prednisone. RESULTS: Sixty-two of 70 patients completed the regimen as planned. Fifty-seven patients (81%) obtained a complete response (CR) and the actuarial 5-year failure-free survival rate is 52%. Thirty-seven patients remain alive and disease-free a median of 35 months (range, 7 to 68) after therapy. Adverse prognostic factors included age more than 50 years, bone marrow involvement, and serum lactic dehydrogenase (LDH) more than 500 IU/L (normal range, 125 to 250). Myelosuppression was responsible for most of the treatment-related toxicity. Severe leukopenia (< 1,000/microL) occurred in all patients and lasted a median of 9 days. Seven patients (10%) died of myelosuppression-related complications; five of these patients were older than 60 years. CONCLUSION: This brief but intensive therapy was effective in treating poor-prognosis patients with non-Hodgkin's lymphoma. With this therapy, patients with small noncleaved-cell lymphoma or Shipp's category 3 disease had treatment outcome similar to the group as a whole. This therapy was not well tolerated by patients older than 60 years, and should not be given to this subgroup. Verification of these results in a randomized trial setting is indicated.

Adolescent↗
PubMed1993

Combination chemotherapy with or without thoracic radiotherapy in limited-stage small-cell lung cancer: a randomized trial of the Southeastern Cancer Study Group.

PURPOSE: The primary objective of this randomized prospective study was to compare the survival of limited-stage small-cell lung cancer (SCLC) patients treated with chemotherapy alone or chemotherapy plus thoracic radiotherapy (TRT). A secondary objective was to determine the effect of consolidation chemotherapy on survival. PATIENTS AND METHODS: This multiinstitutional phase III study included 386 patients with limited-stage SCLC. All patients received cyclophosphamide 1,000 mg/m2, doxorubicin 40 mg/m2, and vincristine 1 mg/m2 (CAV) every 3 weeks for six cycles. Irradiated patients received 30 Gy in 10 fractions during weeks 1 and 2 of chemotherapy. Fifteen Gy in five fractions was administered during week 7 (total dose, 45 Gy). Following CAV, responding patients were randomized to receive two cycles of consolidation chemotherapy (cisplatin 20 mg/m2/d for 4 days plus etoposide 100 mg/m2/d for 4 days) or observation. RESULTS: Complete (46% and 38%; P = .14) and overall response rates (67% and 64%; P = .58) were not statistically significantly different. Although not significantly different, median (14.4 v 12.8 months) and 2-year survival (33% v 23.5%) rates favored the irradiated patients. Grade 4 hematologic toxicity was greater in irradiated patients (60% and 39%; P < .001). Patients given consolidation chemotherapy experienced superior median (21.1 v 13.2 months; P = .028) and 2-year survival (44% v 26%; P = .028) rates. CONCLUSION: The concurrent use of TRT and CAV chemotherapy as administered in this study failed to improve the survival of limited-stage SCLC patients compared with CAV alone. Life-threatening hematologic toxicities were more frequent with combined-modality therapy. The survival of limited-stage patients treated with CAV (with or without TRT) was improved with two cycles of cisplatin and etoposide consolidation therapy. Whether similar survival results could be achieved with cisplatin and etoposide alone requires additional study.

Adult↗
PubMed1993

Treatment of the elderly patient with small-cell lung cancer.

The population of the United States is gradually aging. Within a generation, over 20 percent of the population will be > 65 years of age. Since cancer is a disease of older persons, the incidence of malignancies of all types is expected to increase during the coming decades. In general, since older patients appear to tolerate chemotherapy less well than their younger counterparts, strategies that lessen toxicity and yet maintain efficacy are desperately needed. Recently, the use of single-agent oral etoposide has been shown to be an effective palliative therapy for older patients with small-cell lung cancer. Future studies will need to focus on the unique requirements of older patients in order to improve therapy in these individuals.

Aged↗
PubMed1993

Investigation of new agents in small-cell lung cancer.

The identification of new agents active against small-cell lung cancer (SCLC) remains a high priority for clinical investigators. Recently, 2 very different approaches have been used to evaluate new agents in this disease. Some groups have opted to test new agents in previously untreated patients with extensive-stage SCLC, and the second approach is to continue to test new agents only in previously treated patients. Regardless of which method is used, it appears that new-agent activity can be assessed in either previously treated or untreated SCLC patients without compromising the therapeutic gains of the past 2 decades, provided proper patient selection guidelines are employed.

Carcinoma, Small Cell↗
PubMed1993

Ethacrynic acid: outflow effects and toxicity in human trabecular meshwork in perfusion organ culture.

The effect of ethacrynic acid, a potential outflow agent for the treatment of glaucoma, was studied in a series of 25 pairs of human eyes in perfusion organ culture. Concentrations varied from 0.01 mM to 2.4 mM and were used in single or repetitive doses. Intraocular pressure was continuously recorded for up to two weeks after exposure. Eyes were then fixed and the meshwork examined histologically. Ethacrynic acid in single doses of 0.05 mM, 0.3 mM, and 0.6 mM increased facility of outflow at least 40% when compared with fellow control eyes. The duration of effect was approximately 18 hours, during which time the intraocular pressure gradually returned to baseline. Histologic examination revealed dose related effects on the trabecular cells, ranging from clumping of nuclear chromatin in some eyes to cellular swelling, disruption of cytoplasmic membranes, and cell necrosis in other eyes at concentrations of 0.1 mM and higher. No recovery or reversal of these changes was noted with time, even two weeks after a single exposure to the drug. Although ethacrynic acid is effective in temporarily lowering intraocular pressure in the human eye, a low therapeutic index may limit its clinical usefulness.

Adult↗
PubMed1993

A case study of a coordinated care program: development and implementation of Fort Sill's Catchment Area Management Project.

One of the Department of Defense's initiatives to contain costs of the Civilian Health and Medical Program of the Uniformed Services is the Catchment Area Management (CAM) Demonstration Project. CAM's fundamental coordinated care concept is to contain the military's health care costs by granting the military treatment facility (MTF) commander full clinical and fiscal responsibility for the health care of all beneficiaries within the MTF's catchment area. This article describes the CAM Demonstration Project at Fort Sill during its developmental and implementation phase from June 1989 to April 1991. The six operational goals of the CAM Project are identified and discussed. Additionally, nine essential lessons learned are briefly reviewed.

Catchment Area, Health↗
PubMed1992

A meta-analysis of thoracic radiotherapy for small-cell lung cancer.

BACKGROUND: In spite of 16 randomized trials conducted during the past 15 years, the effect of thoracic radiotherapy on the survival of patients with limited small-cell lung cancer remains controversial. The majority of these trials did not have enough statistical power to detect a difference in survival of 5 to 10 percent at five years. This meta-analysis was designed to evaluate the hypothesis that thoracic radiotherapy contributes to a moderate increase in overall survival in limited small-cell lung cancer. METHODS: We collected individual data on all patients enrolled before December 1988 in randomized trials comparing chemotherapy alone with chemotherapy combined with thoracic radiotherapy. Trials that included only patients with extensive disease were excluded. RESULTS: The meta-analysis included 13 trials and 2140 patients with limited disease. A total of 433 patients with extensive disease were excluded. Overall, 1862 of 2103 patients who could be evaluated died; the median follow-up period for the surviving patients was 43 months. The relative risk of death in the combined-therapy group as compared with the chemotherapy group was 0.86 (95 percent confidence interval, 0.78 to 0.94; P = 0.001), corresponding to a 14 percent reduction in the mortality rate. The benefit in terms of overall survival at three years (+/- SD) was 5.4 +/- 1.4 percent. Indirect comparison of early with late radiotherapy and of sequential with non-sequential radiotherapy did not reveal any optimal time for treatment. There was a trend toward a larger reduction in mortality among younger patients: the relative risk of death in the combined-therapy as compared with the chemotherapy group ranged from 0.72 for patients less than 55 years old (95 percent confidence interval, 0.56 to 0.93) to 1.07 (0.70 to 1.64) for patients over 70. CONCLUSIONS: Thoracic radiotherapy moderately improves survival in patients with limited small-cell lung cancer who are treated with combination chemotherapy. Identification of the optimal combination of chemotherapy and radiotherapy will require further trials.

Age Factors↗
PubMed1992

A phase II trial of cisplatin and prolonged administration of oral etoposide in extensive-stage small cell lung cancer.

Etoposide is a schedule-dependent agent with greater activity against small cell lung cancer (SCLC) when a given dose is administered over several days compared with a 1-day administration of the same dose. In an attempt to capitalize on the schedule dependency of etoposide, 22 previously untreated extensive-stage SCLC patients were given cisplatin (100 mg/m2 on day 1) plus 21 days of low-dose, oral etoposide (50 mg/m2/d). Chemotherapy was repeated every 28 days for four cycles. Complete blood counts were monitored weekly, and etoposide was discontinued if either the leukocyte or platelet count dropped below 2000/microliters or 75,000/microliters, respectively. All 22 patients were evaluable for response; 18 had either a complete (9%) or partial response (73%), an overall response rate of 82% (95% confidence interval, 62% to 93%). The median response duration was 7 months, and the median survival was 9.9 months (range, 1 to 17+ months). Sixteen (73%) patients received all planned cycles of etoposide. In Cycle 1 of chemotherapy, the median leukocyte nadir was 2700/microliters (range, 100 to 6300/microliters), and median platelet nadir was 180,000/microliters (range, 51,000 to 397,000/microliters). Life-threatening leukopenia (less than 1000/microliters) was rare (3 of 74 cycles). There were three treatment-related deaths, only one of which was associated with neutropenia. One patient had mild renal insufficiency that resolved after discontinuation of therapy. Alopecia was observed in all patients, but other nonhematologic toxicities were uncommon. A randomized study is necessary to determine if this schedule of cisplatin and etoposide administration is superior to more standard methods. However, these data do not indicate a major survival benefit will be derived from increasing the duration of etoposide administration when used in combination with cisplatin given every 28 days.

Administration, Oral↗
PubMed1992

Changes in PETCO2 and pulmonary blood flow after bronchial occlusion in dogs.

The use of PETCO2 in detecting accidental bronchial intubation was investigated. The PETCO2 was measured in six mongrel dogs after occluding the left mainstem bronchus in three conditions; pentobarbital anaesthesia, 0.8% halothane insufflation together with pentobarbital anaesthesia, and simultaneous left pulmonary artery and bronchial airway occlusion with intravenous pentobarbital anaesthesia. An external flow probe measured left pulmonary artery blood flow. The PETCO2 decreased after bronchial occlusion during pentobarbital (35 +/- 3 vs 30 +/- 5 mmHg) and halothane-pentobarbital (30 +/- 6 vs 25 +/- 6 mmHg) conditions (P less than 0.05). However, within three minutes of bronchial occlusion, the values of PETCO2 had returned to their pre-occlusion values. After five minutes of bronchial occlusion pulmonary artery blood flow in the non-ventilated lung decreased (P less than 0.05) during pentobarbital (770 +/- 533 ml.min-1 vs 575 +/- 306 ml.min-1) and halothane-pentobarbital (495 +/- 127 ml.min-1 vs 387 +/- 178 ml.min-1) conditions. Simultaneous bronchial and pulmonary artery occlusion prevented any changes in PETCO2. It was concluded that accidental one-lung ventilation results in small and transient decreases in PETCO2. A redistribution of blood flow from the non-ventilated to ventilated lung occurs which restores PETCO2 to the original values observed with two-lung ventilation.

Airway Obstruction↗
PubMed1992

Function-based modeling of binaural processing: interaural phase.

The intent of function-based modeling is to predict from theoretical considerations the input/output characteristics of a neuron if it were to perform a specific signal processing task within a sensory system. In this study, the sensory task is localization within the horizontal plane of a sustained low-frequency tone using interaural phase cues alone. The stimulus is assumed to be represented by primary-like discharge patterns from each ear. These patterns serve as the input to a system whose task is to extract the information needed to determine azimuthal angle. The optimal system resembles the classic Jeffress model, but differs from it in important details. In particular, the Jeffress model is shown to be a sub-optimal approximation in that it ignores the characteristic frequency of the inputs. The physical realization of either model by a structure resembling currently known MSO anatomy and innervation is discussed.

Acoustic Stimulation↗
PubMed1992

Excitatory/inhibitory interaction in the LSO revealed by point process modeling.

We studied lateral superior olivary (LSO) unit responses to binaural tone-bursts using a general point process approach. We show that inhibition of the ipsilaterally elicited response by contralateral stimulation cannot be modeled simply as a reduction of the ipsilateral input. Statistical analyses reveal that inhibition operates by scaling the intensity of the point process describing the ipsilateral response. In some cases the scaling process has secondary effects: Binaurally elicited discharges produce bimodal interspike interval histograms from units that produce unimodal interval histograms under monaural stimulation. We present a specific point process model that describes the scaling process and successfully replicates the observed responses to monaural and binaural stimulation of the three types of LSO units: slow choppers, fast choppers, and bimodal units. We interpret scaling as a shunting inhibitory process in these LSO neurons. By relating scaling magnitude to interaural level difference, we demonstrate the spatial sensitivity of LSO units.

Acoustic Stimulation↗
PubMed1992

Microdissection of a human marker chromosome reveals its origin and a new family of centromeric repetitive DNA.

A series of procedures including chromosome microdissection, sequence-independent PCR, Southern-blot-hybrid-selection-cloning and sequencing of microdissected DNA-library members were used to analyze DNA from a familial marker chromosome centromere and to determine the origin of the marker chromosome in the case of a live-born, tetraploid human infant. A new family of repetitive DNA, termed sn5 satellite, was sequenced and characterized by DNA hybridization. The sn5 satellite family appears to be primate-specific and shows a chromosome-specific distribution which parallels that of alpha satellite suprachromosomal family 2. This suprachromosomal classification is based on sequence similarity of centromeric alpha satellite DNA within particular groups of chromosomes. It has been postulated that the similarity of alphoid sequences within each of the three suprachromosomal families results from homologous exchanges between nonhomologous chromosomes within each family. The parallel distribution of sn5 satellite sequences at the centromeres of chromosomes of alphoid suprachromosomal family 2 suggests that homologous exchanges between non-homologous chromosomes may be the basis of simultaneous chromosome-specific sequence conservation for multiple centromeric satellite DNA families.

Base Sequence↗
PubMed1992

Staging lung carcinoma with a Tc-99m labeled monoclonal antibody.

Thirty-three patients with biopsy-proven lung cancer and a total of 150 lesions diagnosed by conventional staging procedures were imaged using a Tc-99m labeled monoclonal Fab fragment of an IgG2B murine monoclonal antibody (MoAb) (NR-LU-10, NeoRx Corporation). Immunoscintigraphy demonstrated 100% of primary and 78% of metastatic lesions. MoAb imaging detected 88% of lesions in 12 small cell lung cancer (SCLC) patients and 77% of lesions in 21 non-small cell lung cancer (NSCLC) patients. Based on initial evaluation by other methods, 29 sites of MoAb activity were not associated with evidence of disease. Eleven of these were subsequently shown to represent sites of metastases; 18 remain unconfirmed. Four of ten patients studied with limited NSCLC had eight unsuspected lesions on MoAb imaging. Confirmation of unsuspected lesions in two patients altered initial clinical staging, and surgical therapy was abandoned. This study demonstrates that Tc-99m labeled NR-LU-10 can accurately stage patients with lung cancer.

Carcinoma, Non-Small-Cell Lung↗
PubMed1992

Prolonged administration of oral etoposide plus cisplatin in extensive stage small cell lung cancer.

Etoposide is a highly schedule-dependent agent. We previously reported that a 21-day schedule of oral etoposide had good activity in small cell lung cancer (SCLC). The current phase II study was designed to test the combination of 21-day oral etoposide with cisplatin in hopes of capitalizing on etoposide's schedule dependency. Sixteen extensive stage SCLC patients were treated with cisplatin 100 mg/m2 day 1 plus 21 days of low-dose oral etoposide 50 mg/m2/day. Chemotherapy was repeated every 28 days for 4 cycles. Blood counts were monitored weekly, and etoposide was discontinued if the leukocyte or platelet count dropped below 2.0 x 10(9)/l or 75 x 10(9)/l, respectively. Fifteen of 16 patients were evaluable for response; 13 achieved either a complete (13%) or partial response (73%), for an overall response rate of 86% (95% confidence interval, 62-93%). Median response duration was approximately 7 months; median survival was not reached. Thirteen patients (81%) received all the planned cycles of chemotherapy. In cycle 1 of chemotherapy, the median leukocyte nadir was 2.8 x 10(9)/l (range, 0.1-6.3 x 10(9)/l; median platelet nadir was 180 x 10(9)/l (range, 51-397 x 10(9)/l). Life-threatening leukopenia (less than 1.0 x 10(9)/l) was unusual (2 of 58 cycles). There was 1 treatment-related death. One patient developed mild renal insufficiency that resolved after therapy. Nonhematologic toxicities were uncommon, but alopecia occurred in all patients. These data do not suggest that a major survival benefit will be derived for patients with extensive stage SCLC by increasing the duration of etoposide administration when used in combination with cisplatin. A randomized study is needed to determine if this long-term schedule of etoposide plus cisplatin is superior to the standard schedule of etoposide plus cisplatin.

Antineoplastic Combined Chemotherapy Protocols↗