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Biomedical subjects

A B Deisseroth

Publications and source records attributed to A B Deisseroth.

At least 145 records · Page 8Linked to original sources
PubMed1986

High-dose cisplatin in hypertonic saline: reduced toxicity of a modified dose schedule and correlation with plasma pharmacokinetics. A Northern California Oncology Group Pilot Study in non-small-cell lung cancer.

Although increased efficacy has been described with a five-day schedule of high-dose cisplatin (CDDP) in hypertonic saline, severe myelosuppression and cumulative neurotoxicity have limited the usefulness of this therapy. In order to evaluate a possible dose-response relationship in non-small-cell lung cancer (NSCLC), 17 patients with metastatic disease were treated with a modified dose schedule delivering the same total dose (200 mg/m2) in a divided day 1 and 8 schedule. During a pilot study, a total of 47 cycles of therapy were administered, with a median of three cycles per patient and a median total cumulative dose of 600 mg/m2. Nine of 17 patients received at least 600 mg/m2. While nephrotoxicity was similar to previous reports of the five-day schedule, the incidence and severity of myelosuppression and peripheral neuropathy were markedly reduced. Using this modified schedule, severe myelosuppression did not occur. Clinically severe peripheral neuropathy developed in only one patient (6%). The overall response rate was 47% (eight of 17 patients). Plasma platinum pharmacokinetics during five cycles of the modified day 1 and 8 schedule were compared with pharmacokinetics of the five-day schedule. Accumulation of plasma ultrafiltrate platinum occurred in the five-day schedule, but not in the day 1 and 8 schedule. This difference in pharmacokinetics is one possible explanation for the reduced toxicity of this modified schedule. Although the degree of activity seen in this pilot study is encouraging, the efficacy of high-dose CDDP in NSCLC remains to be defined. In view of reduced myelosuppression and neurotoxicity, further trials with this modified schedule are indicated.

Adult↗
PubMed1985

The hematopoietic toxicity of regional radiation therapy. Correlations for combined modality therapy with systemic chemotherapy.

Using circulating granulocyte-monocyte precursor colony-forming units in culture (CFUc) numbers as a probe along with standard blood count (CBC), the authors have quantitatively examined the hematopoietic toxicity of conventionally fractionated radiation therapy (RT) when combined with concurrent systemic chemotherapy or when used alone. Among 20 patients with limited stage small cell lung cancer receiving systemic chemotherapy with cyclophosphamide, CCNU, and methotrexate, the addition of involved field chest RT resulted in increased hematopoietic toxicity as judged by increased need for platelet transfusion (P less than 0.05) and decreased frequency of measurable CFUc (P less than 0.04). Among 22 patients receiving regional radiotherapy alone consistent hematopoietic toxicity was also observed. This toxicity, although generally of only mild to moderate clinical significance, was detected earlier and to a greater degree in patients who required radiation to larger treatment volumes, who had significant amounts of bone marrow in the port, and who had a high percentage of cardiac output flowing through the port. These data suggest that the hematopoietic toxicity of regional radiotherapy may be additive to that of concurrent systemic chemotherapy and may occur more promptly and to a greater degree when treatment volumes are larger or incorporate increased amounts of marrow volume or cardiac output.

Adolescent↗
PubMed1985

Ultrafiltrate and total platinum in plasma and cerebrospinal fluid in a patient with neuroblastoma.

Ultrafiltrate and total plasma and cerebrospinal fluid (CSF) platinum concentrations were examined in a patient with neuroblastoma following a 2-hour infusion of 120 mg/m2 of cisplatin. Total plasma platinum was 93.4% bound, while the ultrafiltrate of plasma accounted for the remaining 6.6%. The CSF ultrafiltrate resulted in equivalent concentrations of platinum to total CSF platinum. CSF concentrations were 2.9% of the total plasma platinum and 43.5% of the ultrafiltrate plasma platinum 2 hours after the end of the infusion.

Brain Neoplasms↗
PubMed1984

Clinical trials with Staphylococcus aureus and protein A in the treatment of malignant disease.

Perfusion of plasma from tumor-bearing animals over Staphylococcus aureus with membrane-bound protein A has resulted in significant tumor shrinkage. Similar therapy has now been given to 16 patients by three methods. No tumor responses have been observed. Five patients were treated with perfusion over fixed and killed S. aureus Cowan I. Cardiovascular and respiratory toxicity was excessive and appeared to be related to volume and rate of plasma infused. Eight patients were treated with perfusion of autologous plasmas over protein A-collodion-charcoal. Doses of plasma ranged from 50 to 450 ml. No toxicity was noted. Three patients have been treated with perfusion over protein A-silica. Toxicity in two resembled that seen in the S. aureus trials, although it was not as severe. We conclude that the toxicity of this therapy can be life-threatening, and human trials should be undertaken with caution.

Humans↗
PubMed1983

Treatment of poor prognosis nonseminomatous testicular cancer with a "high-dose" platinum combination chemotherapy regimen.

A new intensive four drug combination chemotherapy regimen, termed PVeBV, consisting of cis-platinum, vinblastine, bleomycin, and VP-16, was administered to six previously untreated patients with poor prognosis advanced nonseminomatous testicular cancer and to four patients who had relapsed on primary platinum based regimens. The cis-platinum was administered in 250 ml of 3% saline at twice the dose (40 mg/m2 IV days 1-5 every three weeks) used in other treatment schedules. All six previously untreated patients achieved a complete remission. Four achieved a complete remission with three cycles of PVeBV while the other two patients achieved a complete remission with an additional cycle of cisplatinum and VP-16 at 200 mg/m2 IV X five followed by autologous bone marrow infusion. All four relapsed patients responded to PVeBV (two complete remissions and two partial remissions). There were no deaths associated with PVeBV therapy; however, myelosuppression was severe. There has been no renal toxicity (other than hypomagnesemia) observed with 35 cycles of high-dose platinum therapy in previously untreated patients. These results indicate that PVeBV is a promising chemotherapy regimen for the treatment of poor prognosis testicular cancer patients. Furthermore, it appears that cis-platinum can be administered at higher doses than previously used without an increase in renal toxicity if administered in hypertonic saline. The high-dose cis-platinum schedule, as used in PVeBV, warrants evaluation in other tumors which respond to standard-dose platinum therapy.

Antineoplastic Agents↗
PubMed1983

Acquired alpha-thalassemia in preleukemia is due to decreased expression of all four alpha-globin genes.

A somatic mutation(s), acquired during the evolution of preleukemia in a 75-year-old Caucasian male of North European origin, resulted in a marked decrease in alpha-globin mRNA. The small amount of alpha-globin mRNA present in bone marrow cells was normally processed, had a normal (alpha 1/alpha 2)-globin mRNA ratio, and was translated normally. No detectable zeta-globin mRNA was found. The alpha- and zeta-globin genes were both hypomethylated and restriction endonuclease maps of the alpha- and zeta-globin genes were comparable in the patient's marrow and fibroblast DNA. The data are most consistent with the acquisition of a mutation(s) that resulted in decreased expression of all four alpha-globin genes.

Aged↗
PubMed1983

Changes in the translational activity of polyadenylated messenger RNA of HL60 promyelocytic leukemia cells associated with myeloid or macrophage differentiation.

In order to characterize the events which commit the HL60 human promyelocytic leukemia cell line to differentiate into macrophages or mature myeloid cells, we have analyzed the in vitro [35S]methionine-labeled translational products obtained from polyadenylated messenger RNA of the HL60 cells before and after exposure to: (a) dimethylformamide (DMF), an inducer of myeloid differentiation; (b) 12-O-tetradecanylphorbol-13-acetate (TPA), an inducer of macrophage differentiation; or (c) a combination of the two inducers. Exposure of the HL60 cells to either TPA or DMF results in decreases in the relative abundancy of translational products with molecular weights of 20,000, 17,000, and 15,000. Exposure of the HL60 cells so as to generate macrophage differentiation results in elevations of translational products with molecular weights of 60,000, 47,000, 42,000, 32,000, 27,000, 14,000, and 12,300, while DMF-induced myeloid differentiation is associated with increases in the abundancy of translational products with molecular weights of 60,000, 42,000, 35,000, 32,000, 27,000, 13,000 and 12,300. The addition of the macrophage inducer TPA to HL60 cells previously exposed to the myeloid inducer DMF results in changes in the relative abundance of several translational products, yielding a pattern which differs quantitatively from that obtained from cells treated with DMF or TPA alone. These changes in the relative abundancies of the HL60 translational products suggest that the steady state levels of several different populations of mRNA or the ability of these mRNAs to be translated are being modified during the induction of myeloid or macrophage differentiation in the HL60 promyelocytic leukemia cell line.

Actins↗
PubMed1983

Prognostic indicators of tumor response to Staphylococcus aureus Cowan strain I plasma perfusion.

Ten tumor-bearing dogs were treated with passage of autologous plasma over fixed Staphylococcus aureus Cowan strain I. Five similar dogs were treated identically except for the exposure to S. aureus. These animals have been assessed to identify positive and negative prognostic variables for response. Nonresponder treated animals had significantly larger chest wall tumor bulk than did the responder and control groups (P less than .01). Responder animals had fewer initial circulating immune complexes than did the nonresponders, though each group had similar reductions in immune complexes with therapy. Nonresponder animals had smaller volumes of plasma processed per kilogram of body weight per procedure than did controls (P = .016), whereas responder and control animals had similar volumes processed per kilogram of body weight per procedure (P = .84). These data suggest that the response observed in our original series was significantly related to the larger amount of plasma treated per procedure and suggest that a factor may be eluted from the S. aureus cartridge that mediates this response.

Adenocarcinoma↗
PubMed1981

Lethal pulmonary reactions associated with the combined use of amphotericin B and leukocyte transfusions.

Amphotericin B is used increasingly in high-risk patients with profound neutropenia and suspected sepsis. We have observed serious pulmonary reactions characterized by acute dyspnea, hypoxemia, and interstitial infiltrates on chest films in patients receiving amphotericin B and leukocyte transfusions. We reviewed 6 1/2 years of experience at the National Institutes of Health to determine whether this combination was associated with pulmonary toxicity not characteristic of either therapy alone. Amphotericin was used during 22 of 57 leukocyte-transfusion courses. Acute respiratory deterioration occurred during 14 (64 per cent) of these courses but in only two (6 per cent) of 35 courses without amphotericin (P less than 0.01). In seven cases, respiratory deterioration began during or immediately after amphotericin infusion, and it contributed to death in five patients. Diffuse intraalveolar hemorrhage was found when lung biopsy or autopsy was performed. Acute respiratory deterioration was not observed in comparably neutropenic patients given amphotericin but not leukocyte transfusions during the same period. It was mot common when amphotericin was begun with or after institution of daily leukocyte transfusions. Leukocyte transfusions may cause changes in the lungs that amplify the acute toxicity of amphotericin, thereby permitting severe pulmonary reactions.

Adolescent↗
PubMed1981

Identification of a population of bipotent stem cells in the HL60 human promyelocytic leukemia cell line.

HL60, the human promyelocytic leukemia cell line, consists of cells that resemble promyelocytes but are transformed into more mature myeloid forms (polymorphonuclear leukocytes) that express most of the functional characteristics of terminally differentiated myeloid forms when incubated in the presence of dimethyl formamide (HCONMe(2)). When HL60 cells are exposed to the phorbol diester 12-O-tetradecanoylphorbol 13-acetate [phorbol 12-myristate 13-acetate (PMA)], they shift from suspension to adherent on the surface of the tissue culture vessel, assume the appearance of macrophages, and acquire macrophage-associated surface markers, the enzyme-nonspecific esterase, the isozyme acid phosphatase, and the myeloid-specific esterase. Although data from other laboratories suggest that HL60 consists of stem cells that are bipotent with respect to myeloid or macrophage differentiation, unequivocal proof of bipotency or evidence that ruled out the presence of two different types of stem cells, each committed to different lines of hematopoietic differentiation, has been lacking. To resolve these two alternatives, we have developed a cloned population of HL60 cells and studied the properties of these cells when exposed to inducers of myeloid (HCONMe(2)) or macrophage (PMA) differentiation. After 120 hr of incubation with HCONMe(2), 95% of the cells acquire myeloid markers and lack specific macrophage markers, whereas the reverse is true in the presence of PMA, clearly establishing that HL60 is able to commit itself to the development of two different programs of hematopoietic differentiation. Moreover, the commitment to macrophage differentiation is irreversible after 6 hr of incubation in PMA whereas development of the myeloid program requires continuous exposure of the cells to HCONMe(2). Commitment of HL60 to macrophage differentiation by PMA is not affected by subsequent addition of HCONMe(2), whereas HCONMe(2)-induced myeloid differentiation is overridden by exposure of the cells to PMA. These data suggest that the HL60 cell may provide a model system for studying the process that generates several classes of precursor cells, each committed to different lines of hematopoietic differentiation, as well as the process that mediates the maturation of these committed precursor cells to their terminally differentiated state.

Cell Differentiation↗
PubMed1981

Cyclophosphamide treatment expands the circulating hematopoietic stem cell pool in dogs.

Increased numbers of circulating granulocyte-monocyte precursor cells (CFUc) have been observed in the peripheral blood of man after antineoplastic chemotherapy. We have developed a canine model to study the biologic significance of this phenomenon for hematopoietic reconstitution following hematopoietically lethal exposure to total body irradiation (TBI). After cyclophosphamide administration, a 16-fold expansion of circulating CFUc numbers was observed during the period of rapid leukocyte recovery that occurred after the chemotherapy-induced leukocyte nadir. We had previously noted this association between leukocyte recovery and CFUc expansion in our human studies. After 900 rad TBI hematopoietic reconstitution was attempted with autologous, cryopreserved collections of peripheral blood mononuclear cells obtained either at times of post-cyclophosphamide CFUc expansion (group A, 14 dogs) or without CFUc expansion (group B, 12 dogs). Asd compared to group B collections, group A collections contained 11-fold more CFUc and were 12.5-fold more potent in fostering hematopoietic recovery after TBI. These results suggest that the expansion of CFUc numbers we observed was accompanied by a similar expansion of more primitive hematopoietic stem cell numbers. We conclude that chemotherapy-induced expansion of circulating CFUc numbers appears to be of substantial import in effecting hematopoietic reconstitution--an observation that may be of significance for further studies of autologous hematopoietic reconstitution in man.

Animals↗
PubMed1981

Amplification of circulating granulocyte-monocyte stem cell numbers following chemotherapy in patients with extensive small cell carcinoma of the lung.

Circulating numbers of committed granulocyte-monocyte hematopoietic stem cells (CFUc) were measured in the peripheral blood of 20 patients with extensive-stage small cell lung carcinoma during induction chemotherapy. All patients received cyclophosphamide, doxorubicin, VP16-213, and vincristine. CFUc measurements were made either weekly or twice weekly. As leukocytes declined following chemotherapy, circulating CFUc numbers also declined. However, as leukocytes recovered from their nadir levels, circulating CFUc numbers per mononuclear cell and per ml of whole blood became substantially expanded in 19 and 17, respectively, of the 20 patients studied. Per mononuclear cell, the median CFUc expansion was 7.9-fold, and the highest expansion seen was 157-fold. Per mol of blood, the median CFUc expansion was 6.7-fold, and the highest expansion seen was 46-fold. The magnitude of the amplification, its occurrence in 85 to 95% of patients studied, and its association with leukocyte recovery strongly suggest that appropriately timed collections of peripheral blood mononuclear cells obtained during leukocyte recovery from nonablative chemotherapy could be used to provide hematopoietic stem cells in numbers sufficient to effect hematopoietic reconstitution after subsequent marrow-ablative therapy.

Adult↗
PubMed1981

Suppression of transfusion-related alloimmunization in intensively treated cancer patients.

A retrospective review of HLA antibody testing and transfusion records of 100 cancer patients who required extensive platelet support revealed that 27 of 100 patients exhibited positive HLA antibody tests; only 13 remained positive on repetitive examination, while 88% of aplastic anemia patients so tested were positive. Sixty-five patients with leukemia, 16 with Ewing's sarcoma, and 19 with recurrent undifferentiated lymphoma were studied. Each patient received at least 10 U of platelets (mean of 72). HLA antibodies were detected in 31% (20/65) of the leukemias, 12% (2/16) of the Ewing's, and 26% (5/19) of the lymphoma patients. Fourteen of the 27 patients who developed antibodies became antibody negative again within 2 mo and remained so. There were no significant differences in quantity of platelet transfusions between antibody-negative patients and alloimmunized patients. A smaller group (n = 8) of aplastic anemia patients followed at the NCl exhibited a frequency of alloimmunization of 88% (7/8) after a mean of 44 U of platelets were transfused. Granulocyte transfusions given therapeutically for granulocytopenia and documented infection did not appear to influence HLA antibody formation. These data indicate that significant immunosuppression occurs in intensively treated cancer patients, as measured by their ability to from antibodies to HLA antigens expressed on the surface of transfused platelets.

Anemia, Aplastic↗