Biomedical subjects

D H Johnson

Publications and source records attributed to D H Johnson.

At least 217 records · Page 12Linked to original sources

PubMed1991

Chronic oral etoposide.

Etoposide is an important drug that has been recently incorporated with other agents in the curative treatment of patients with advanced neoplasms, including germ cell tumors, non-Hodgkin's lymphomas (NHL), and small cell lung cancer (SCLC). Etoposide demonstrates remarkable schedule dependency. A randomized comparison has shown an impressive survival difference for patients with extensive SCLC receiving a 5-day course versus those receiving a 1-day course. Because of these and previous clinical and laboratory data, etoposide is now given intravenously or orally in a 3-day to 5-day schedule. It is generally accepted that approximately 50% of the orally administered drug is absorbed. The authors have initiated several etoposide studies using an extended administration schedule, believing that a prolonged schedule may be superior to the standard 3-day to 5-day schedule. This was initially tested in a Phase I study. Results showed that etoposide (50 mg/m2/d) given over 21 days was feasible and was associated with only moderate toxicity. Several Phase II studies have been completed or are nearing completion, including studies in patients with SCLC, NHL, germ cell tumors, soft tissue sarcoma, renal carcinoma, and ovarian carcinoma. Responses have been seen in all of these groups, particularly in patients with SCLC, lymphoma, and germ cell tumors. In these groups we saw responses in patients who were clearly resistant to etoposide plus cisplatin given in a standard schedule or in some patients who were resistant to high-dose etoposide with bone marrow transplantation. Investigators at Indiana University Medical Center who studied oral etoposide in a similar fashion in patients with advanced germ cell tumors and SCLC achieved results similar to those reported here. The authors have initiated a number of combination chemotherapy programs using the chronic oral form of etoposide. These include patients with SCLC, non-small cell lung cancer, and elderly patients with high-grade and intermediate forms of NHL. In addition, chronic intravenous oral etoposide is being used in salvage approaches for patients with acute myelocytic leukemia and recurrent resistant intermediate-grade and high-grade NHL. Preliminary pharmacokinetic data suggest that a 50-mg/m2 oral dose is highly bioavailable (91% to 96%). Therefore, during a prolonged oral course at 50 mg/m2, many patients maintain a minimum plasma concentration of 1 microgram/ml. Further studies of multiple dose or continuous infusion etoposide to maintain a potentially critical plasma level are in progress. Etoposide administered in this way could represent a "new" drug because many of its features are different, and its activity spectrum may be broader.

Drug Administration Schedule↗

PubMed1991

The role of etoposide in the treatment of poorly differentiated carcinoma of unknown primary site.

Patients with poorly differentiated carcinoma (PDC) or poorly differentiated adenocarcinoma (PDA) of unknown primary site comprise 25% to 35% of the patients with carcinoma of unknown primary site. Some of these patients have neoplasms that are highly responsive to combination chemotherapy, and a minority have potentially curable tumors. Between 1978 and 1982, 68 patients were treated with combination chemotherapy (most received cisplatin, vinblastine, and bleomycin [PVB] with or without doxorubicin). Thirty-eight patients (56%) responded to treatment, with 15 (22%) complete responder (CR) and 9 (13%) long-term, disease-free survivors. Since that time, we have incorporated etoposide into the treatment of these patients because of its synergism with cisplatin and its great activity against several other neoplasms, including germ cell tumors. Seventeen patients with PDC of unknown primary site received salvage therapy with etoposide and cisplatin after failing PVB. Ten of these patients had partial responses (PR), with a median response duration of 5 months (range, 2 to 12 months). Thirty-two previously untreated patients with PDC received etoposide and cisplatin combinations as initial treatment. Eighteen of 30 evaluable patients (60%) responded to therapy, and 11 patients (37%) had CR. Seven patients remain disease-free 39 to 63 months after the completion of therapy. Etoposide is an active drug in the treatment of PDC of unknown primary site. Preliminary results indicate that initial treatment with etoposide and cisplatin combinations produces results equivalent to or superior to those achieved with PVB.

Adenocarcinoma↗

PubMed1991

A comparison of hexamethylmelamine (altretamine), cyclophosphamide, doxorubicin, and cisplatin (H-CAP) vs. cyclophosphamide, doxorubicin, and cisplatin (CAP) in advanced ovarian cancer.

We retrospectively compared the results of treatment with hexamethylmelamine (HMM), cyclophosphamide, doxorubicin, and cisplatin (H-CAP) to treatment results using cyclophosphamide, doxorubicin, and cisplatin (CAP) in patients with advanced ovarian cancer. The treatments were identical in dosage and schedule with the exception of the addition of HMM to one regimen. Fifty-five patients treated with H-CAP between August 1977 and March 1980 were compared with a subsequent group of 22 patients who received CAP between October 1984 and October 1987. Following 6 months of therapy, patients were restaged either with second-look laparotomy or with clinical restaging. Fifty-three of 55 patients (96%) and 14/21 (67%) patients had objective responses to H-CAP and CAP respectively (p = 0.001). The pathologic complete response rate as determined by second-look laparotomy was higher in the patients who received H-CAP (35% vs. 19%). The median survival of patients receiving H-CAP is 47 months compared to 21 months for the CAP patients. In limited residual disease patients (maximum tumor diameter less than or equal to 3 cm), the median survival also favored the H-CAP treatment (101 months vs. 21 months, p = 0.002). The median time to progression was greater in patients receiving H-CAP vs. those receiving CAP (67 months vs. 16 months, p = 0.045). Treatment-related toxicity was similar for the two regimens. These findings suggest that the addition of HMM to CAP chemotherapy prolongs the median survival for patients with limited residual disease advanced ovarian cancer.

Altretamine↗

PubMed1991

Mitoxantrone, fluorouracil, and high-dose leucovorin: an effective, well-tolerated regimen for metastatic breast cancer.

Between September 1988 and August 1990, we treated 35 women with metastatic breast cancer with a novel regimen containing mitoxantrone, fluorouracil (5-FU), and high-dose leucovorin. This regimen was designed to take full advantage of the favorable toxicity profiles of these agents while maintaining a high level of activity. All patients had received previous chemotherapy (adjuvant only, 15 patients; at least one metastatic regimen, 20 patients). Seven patients had received previous doxorubicin, but none within 6 months of study entry. Of 31 assessable patients, 20 (65%) had objective responses (two complete, 18 partial), with a median response duration of 6 months (range, 3 to 16+ months). Four patients with bone metastases (abnormal bone scan only) and pain were not considered assessable by strict response criteria; two of these patients had sustained symptomatic relief for 6 and 8 months, respectively. Myelosuppression was the most frequent toxicity but was mild in most patients; only four hospitalizations for fever and neutropenia were required (2% of courses). No severe thrombocytopenia occurred and no RBC transfusions were required. Alopecia, mucositis, and nausea/vomiting were uncommon and were not severe in any patient. The combination of mitoxantrone, 5-FU, and high-dose leucovorin is well tolerated and active as a first- or second-line treatment for metastatic breast cancer. Comparison with other standard regimens for breast cancer is indicated.

Adult↗

PubMed1991

Poorly differentiated carcinoma of unknown primary site: clinical usefulness of immunoperoxidase staining.

To assess the clinical utility of immunoperoxidase tumor-cell staining in patients with poorly differentiated carcinoma of unknown primary site, we performed a battery of stains on tumors from 87 patients treated between August 1978 and April 1983. Poorly differentiated carcinoma or poorly differentiated adenocarcinoma was diagnosed on the basis of light microscopic examination, and all patients were treated before the technology of immunoperoxidase staining was routinely used. Therefore, results of immunoperoxidase staining can be correlated with clinical outcome in this group of similarly treated patients with a long median follow-up. Immunoperoxidase staining confirmed the diagnosis of poorly differentiated carcinoma in 49 patients (56%) and yielded other diagnoses in 14 patients (16%): melanoma, eight; lymphoma, four; prostatic carcinoma, one; and yolk sac carcinoma, one. In 24 patients (28%) the immunoperoxidase staining pattern was inconclusive; electron microscopy was usually helpful in clarifying the diagnosis in these patients. Seventy-five patients (86%) received combination chemotherapy with a cisplatin-based regimen, and 24 patients (28%) had a complete response. Nine of these patients were later given specific diagnoses by immunoperoxidase staining (lymphoma, four; melanoma, four; yolk sac tumor, one). All patients with an immunoperoxidase diagnosis of lymphoma also had clinical features compatible with lymphoma and are long-term survivors. Patients with immunoperoxidase features suggesting melanoma were surprisingly responsive to chemotherapy, with three of seven complete responses and two long-term survivors. Patients with melanoma diagnosed by immunoperoxidase staining should not be excluded from a trial of cisplatin-based therapy. Immunoperoxidase staining is useful in the routine evaluation of metastatic poorly differentiated carcinoma of unknown primary site, as it can occasionally suggest the lineage of the tumor and have specific therapeutic implications.

Adenocarcinoma↗

PubMed1991

Effective treatment of small-noncleaved-cell lymphoma with high-intensity, brief-duration chemotherapy.

Small-noncleaved-cell (SNC) lymphoma is a high-grade, biologically aggressive neoplasm notable for poor response to therapy, high relapse rate, and less than a 20% long-term survival. We treated 20 patients with SNC lymphoma with a novel chemotherapeutic regimen using intensive doses of chemotherapy at frequent intervals in the inpatient setting. All patients were previously untreated. Sixteen patients (80%) had stage IV disease. Most patients (95%) had at least one other characteristic associated with poor prognosis (bulky [greater than 10 cm] disease, multiple extranodal sites, poor performance status), and 85% had two or more characteristics associated with poor prognosis. Seventeen patients (85%) achieved a complete response (CR) to therapy, including all three patients with human immunodeficiency virus (HIV)-associated disease. There have been three relapses, all occurring less than 18 months after treatment, and two of three relapses occurred in patients who were unable to complete therapy. At a median follow-up of 29 months, 13 patients (65%) remain disease-free; the calculated 5-year actuarial disease-free survival is 60%. Toxicity, chiefly myelosuppression, was severe but manageable. There were two treatment-related deaths, both in elderly patients with poor performance status and advanced-stage disease. These data suggest that such a dose-intensive approach improves the response and survival of patients with SNC lymphoma.

Adult↗

PubMed1991

Effects of halothane on hypoxic pulmonary vasoconstriction in canine atelectasis.

We studied the interactions of atelectasis and halothane on hypoxic pulmonary vasoconstriction using an isolated canine lobe. We divided pulmonary vascular resistance into arterial, venous, and middle segmental resistances by a vascular occlusion technique. We found that middle segmental resistance significantly increased (P less than 0.05) from 0.016 +/- 0.007 cm H2O.mL-1.min-1 during normoxic ventilation to 0.06 +/- 0.007 cm H2O.mL-1.min-1 during hypoxic ventilation. We then produced sublobar atelectasis by introducing 4.5-mm steel ball bearings into the lobar bronchus, which resulted in a significant increase (P less than 0.05) of middle segmental resistance to 0.046 +/- 0.014 cm H2O.mL-1.min-1 during normoxic ventilation and a further significant increase (P less than 0.05) to 0.084 +/- 0.02 cm H2O.mL-1.min-1 during hypoxic ventilation. Ventilation with 2.0% halothane but not 0.5% halothane prevented the increases in middle segmental resistance observed with either atelectasis or hypoxic ventilation. Values of arterial and venous segmental resistances were not similarly affected. We conclude that sublobar atelectasis increases pulmonary vascular resistance by stimulating hypoxic pulmonary vasoconstriction. Both halothane and hypoxia primarily act upon the middle vascular segment, but their effects are in opposite directions and, in the former instance, are concentration-dependent.

Analysis of Variance↗

PubMed1991

Staging and prognostic factors in nonseminomatous testicular cancer.

Staging of nonseminomatous testicular cancers, as with other tumors, renders important prognostic information and is necessary for making appropriate treatment recommendations. There is no universally accepted staging system for testis cancer, however. Despite the lack of uniformity, most of the staging systems in use today are capable of segregating patients into a "good-risk" or "poor-risk" category. The former group experiences cure less frequently and are appropriate candidates for investigational treatment. Tumor bulk is the most important prognostic factor in virtually all staging systems.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1990

A novel RNA helicase gene tightly linked to the Triplo-lethal locus of Drosophila.

The Triplo-lethal (Tpl) locus of Drosophila is the only known locus which is lethal when present in three copies rather than the normal two. After recovering a hybrid-dysgenesis-induced mutation of Tpl we used a rapid combination of transposon tagging, chromosome microdissection and PCR to clone the P element that had transposed into the Tpl region. That P element is located within the gene for a new and unique member of the RNA helicase family. This new helicase differs from all others known by having glycine-rich repeats at both the amino and carboxyl termini. Curiously, genetic analysis shows that the P element inserted into this gene is not responsible for the Tpl mutant phenotype. We present possible explanations for these findings.

Amino Acid Sequence↗

PubMed1990

Thoracic radiotherapy does not prolong survival in patients with locally advanced, unresectable non-small cell lung cancer.

STUDY OBJECTIVE: To compare the survival of patients with locally advanced non-small cell lung cancer treated with single-agent vindesine, thoracic radiotherapy, or both treatment modalities. DESIGN: Randomized, prospective, phase III trial. SETTING: Multi-institutional, university-based national cooperative oncology group. PATIENTS: The study included 319 patients with locally advanced, unresectable non-small cell lung cancer who had no evidence of extrathoracic metastases. All patients were ambulatory and had measurable disease. Some patients could not have surgery because of coexisting medical conditions. INTERVENTION: Patients were randomly assigned to receive vindesine, 3 mg/m2 body surface area weekly; standard thoracic radiotherapy, 60 Gy over 6 weeks; or both vindesine and thoracic radiotherapy. Vindesine was administered for 6 weeks and then every other week to patients who had no disease progression. Patients who developed progressive disease while receiving vindesine or radiotherapy alone were crossed over to radiotherapy or vindesine, respectively. Response assessment took place at week 6. RESULTS: The overall response rate was superior in the radiotherapy arms (radiotherapy alone, 30%; radiotherapy plus vindesine, 34%; vindesine alone, 10%; P = 0.001). However, with a minimum follow-up of 42 months, no improvement in survival has been seen with radiotherapy. The median survival was 8.6 months for patients receiving radiotherapy alone, 9.4 months for those receiving radiotherapy plus vindesine, and 10.1 months for those receiving vindesine (P = 0.58). Radiotherapy also failed to improve long-term survival. The 5-year survivals were 3%, 3%, and 1%, respectively (P = 0.56). CONCLUSION: Patients with non-small cell lung cancer who have inoperable, nonmetastatic disease gain no clinically meaningful survival advantage with immediate thoracic irradiation, even when modern megavoltage radiation therapy techniques and equipment are used.

Adenocarcinoma↗

PubMed1990

An evaluation of combination 5-fluorouracil and spirogermanium in the treatment of advanced colorectal carcinoma.

Seventeen patients with advanced colorectal carcinoma were treated with a combination of 5-fluorouracil and spirogermanium, a recently developed azaspiran-germanium compound remarkable for its lack of hematologic, gastrointestinal, renal or hepatic toxicity. Response to treatment and the incidence and severity of toxicity were evaluated. No patient achieved a complete response; there were three partial responses. Toxicity was unexpectedly frequent and severe; one patient was removed from study early due to intractable diarrhea, and there were two toxic deaths, both attributable to neutropenia and sepsis. Significant toxicity occurred in all seventeen patients, including three instances of Grade 3 or 4 hematologic toxicity. Given the low response rate and high incidence of life-threatening toxicity, we do not recommend further evaluation of this schedule of 5-fluorouracil and spirogermanium in the treatment of colorectal carcinoma.

Adult↗

PubMed1990

The filtration characteristics of the aqueous outflow system.

To determine the filtration characteristics of the aqueous outflow system, microspheres (0.18 micron -1.1 micron) were perfused through enucleated human and bovine eyes. The microspheres were smaller than morphologically determined flow dimensions, and yet a significant fraction of all sizes of microspheres were captured. The bovine (calf) aqueous outflow system was found to be a far more efficient filter than was the human outflow system. Combining the experimental results with morphological observations and theoretical calculations leads to the conclusion that 'sticky wall' interactions are responsible for much of the microsphere capture, and that the site of filtration may be distinct from the site of flow resistance. Consequently, the dimension of the sites generating flow resistance cannot be determined from filtration studies.

Animals↗

PubMed1990

Vasodilators do not abolish pulmonary vascular critical closing pressure.

To examine whether the critical closing pressure (Pcrit) of the pulmonary vasculature is dependent upon vasomotor tone, we measured Pcrit in six dog lobes before and after the administration of vasodilators. We evaluated the pressure-flow (P-Q) relationship in zone 2 flow conditions in situ perfused dog lobe (control period). We calculated Pcrit as the mean extrapolated zero-flow pressure intercepts for the P-Q relationship. We also used arterial and venous occlusions under zone 3 conditions to partition pulmonary vascular resistance into arterial, middle and venous segment resistances. We then repeated all measurements following administration of papaverine (150 micrograms/ml) and sodium nitroprusside (200 micrograms/min) into the venous reservoir (vasodilator period). Resistance in all three vascular segments was significantly reduced during vasodilator conditions. Pcrit decreased from 3.68 +/- 0.76 cm H2O to 2.53 +/- 0.92 cm H2O during control and vasodilator periods respectively (P less than 0.05). The slopes of the P-Q relationships were similar during both conditions. Our data support a model in which vasomotor tone normally sets Pcrit but in which the pulmonary vasculature can exhibit the phenomenon of critical closure even with vasomotor tone pharmacologically ablated.

Animals↗

PubMed1990

New chronic gastric cannula for feeding ethanol liquid diet to young and old rats.

Fifty-eight male Fischer-344 rats ages 5 and 23 mo were fed a liquid diet containing ethanol for 6 wk by means of a newly designed chronic gastric cannula that permitted maximum allowable freedom with minimum stress. Rats were weaned onto the Lieber-DeCarli diet and fed 10 mL three times daily by bolus injection. With or without ethanol, the minimum daily intake of calories necessary to maintain body weight was determined to be approximately 150-160 kcal/kg/day for the young adult rats and 120-125 kcal/kg/day for the aged animals.

Age Factors↗

PubMed1990

Chronic daily administration of oral etoposide in refractory lymphoma.

In a phase II study, 25 patients with previously treated lymphoma received oral etoposide for 21 consecutive days. All patients were considered incurable with standard therapy. Etoposide was administered at 50 mg/m2 per day: courses were repeated every 28-35 days, depending on myelosuppression. 15 patients (60%) had partial responses (95% CI 41-77%), while 10 patients had no response. Median time to disease progression was 5 months (range 2-13 months). Oral etoposide was active against indolent and aggressive (intermediate and high grade) lymphomas; however, median time to progression was only 3 months in aggressive lymphoma compared with 8 months in indolent lymphoma. Myelosuppression was the major side-effect; 7 patients (28%) had a leucocyte nadir below 1000/microliters during the first course, and 11 patients required dose reduction during subsequent courses due to unacceptable leukopenia. All patients had total alopecia, but other side-effects were uncommon. These results highlight the importance of schedule in the administration of etoposide.

Administration, Oral↗

PubMed1990

Function-based modeling of binaural processing: interaural level.

The function-based modeling approach applies optimal estimation theory to sensory phenomena for determining how relevant sensory parameters are extracted from stimuli and how the characteristics of the resulting optimal processing system compare with those of the sensory system. This approach is applied to the neural system involved in the binaural localization of sustained high-frequency sound sources: the lateral superior olive (LSO) of the cat. The sufficient statistic produced by the optimal processor is shown to be related to the interaural level difference. This level difference is processed optimally when the inputs are excitatory from one ear and inhibitory from the opposite ear. Response characteristics of LSO single units are remarkably similar, thereby strongly supporting the notion that LSO units are intimately involved in high-frequency binaural hearing. Optimal processor theory is also used to assess lateralization performance when the hearing thresholds of the two ears differ.

Algorithms↗

PubMed1990

Rate fluctuations and fractional power-law noise recorded from cells in the lower auditory pathway of the cat.

The noise properties of the sequence of action potentials recorded from adult-cat auditory nerve fibers and lateral superior olivary units have been investigated under various stimulus conditions. Large fluctuations exhibited by the spike rate, and spike clusters evident in the pulse-number distribution, both indicate an unusual underlying sequence of neural events. We present results demonstrating that (i) the firing rate calculated with different averaging times can exhibit self-similar behavior; (ii) the pulse-number distribution remains irregular even for large numbers of samples; (iii) the spike-number variance-to-mean ratio increases with the counting time T in fractional power-law fashion for sufficiently large T; and (iv) the exponent in the power law generally depends on the stimulus level. The results obtained in our laboratories support the notion that all auditory-nerve and LSO units exhibit fractal neural firing patterns, as indicated earlier by Teich (IEEE Trans. Biomed. Eng. 36, 150-160, 1989).

Action Potentials↗

PubMed1990

Molecular cloning of DNA from specific chromosomal regions by microdissection and sequence-independent amplification of DNA.

A method that permits the in vitro amplification and cloning of DNA dissected from specific regions of a chromosome and does not require prior knowledge of the DNA sequence is described. DNA from several different chromosomal loci in the Drosophila melanogaster genome has been isolated by this method. Although the procedure was developed to permit the isolation of DNA sequences from serial sections of a single microdissected polytene chromosome, it should be useful for obtaining DNA clones from specific regions of the nonpolytene chromosomes of other organisms as well.

Animals↗