Biomedical subjects
M B Garnick
Publications and source records attributed to M B Garnick.
Prostate cancer: screening, diagnosis, and management.
OBJECTIVE: To provide physicians with a review of diagnosis, screening, staging evaluation, treatment options, prognosis, psychosocial issues, economic considerations, and future research directions in the management of patients with all stages of prostate cancer. DATA SOURCES: A MEDLINE search of articles relating to the diagnosis, staging, screening, surgery, radiation therapy, medical management, and research in prostate cancer. Emphasis on information reported from government- and nongovernment-sponsored large cooperative trials, consensus development conferences, and proceedings of prostate cancer organ site workshops. STUDY SELECTION: Results of randomized treatment trials and consensus summary statements are reported where long-term results (> 5 years follow-up) are available for localized prostate cancer treatment and where survival outcomes are available for metastatic disease treatment. DATA SYNTHESIS: Both qualitative and quantitative data are reported. Information on staging, management, and prognosis of localized prostate cancer is based on studies that are predominantly nonrandomized, include heterogeneous patient groups, and often use differing outcome measures. Information on management of metastatic prostate cancer is more quantitative and includes side effects of treatment and survival results obtained from randomized, prospective, multi-institutional studies. CONCLUSIONS: Despite the increase in prostate cancer incidence and detection, substantial controversy still exists about the advisability and effectiveness of screening programs, the most appropriate staging evaluation, and the optimal management of patients with all stages of prostate cancer. Although randomized, prospective studies attempt to address some of these issues, physicians must appreciate inherent ambiguities involved in recommending staging and treatment choices.
Long-term followup of 150 patients with testicular cancer treated at a single institution.
Between 1977 and 1988, 150 patients with disseminated primary testicular germ cell tumors were treated with cisplatin, vinblastine and bleomycin. Of the 150 patients 90 (60%) achieved a complete response to chemotherapy. An additional 33 patients achieved a complete response after removal of residual masses following chemotherapy. Thus, 123 of 150 patients (82%) achieved a disease-free status following chemotherapy with or without an operation. After a median followup of 49 months the estimated long-term probability of remaining without failure and of surviving is 77%. With this data base a multivariate analysis of prognostic factors determined the Indiana University staging system to be highly predictive. Other staging systems proved to be less useful. The subset of patients with minimal and moderate disease by Indiana staging containing mature teratoma in the orchiectomy specimen has a particularly excellent prognosis (99% actuarial survival) with chemotherapy.
Effects of recombinant human macrophage colony-stimulating factor on plasma cholesterol levels.
Recombinant human macrophage colony-stimulating factor (rhM-CSF) is a hematopoietic growth factor that stimulates the growth, differentiation, proliferation, and activation of cells of the monocyte/macrophage lineage. rhM-CSF was administered to rabbits and nonhuman primates to evaluate effects on cholesterol homeostasis. Decreases in plasma cholesterol concentrations were observed during rhM-CSF administration. The observed mean (+/- SD) decreases over a range of doses in nonhuman primates receiving rhM-CSF by continuous intravenous infusion (CIVI) or intravenous bolus (IVB) injection were approximately 16% +/- 8% and 43% +/- 10%, respectively. Low-density lipoprotein (LDL) cholesterol levels decreased 55% +/- 9% from pretreatment baseline values in the animals receiving rhM-CSF by IVB. Normocholesterolemic New Zealand white rabbits receiving rhM-CSF over a range of doses by CIVI showed a decrease from baseline in total cholesterol of approximately 28% +/- 17%, with LDL cholesterol levels decreasing by approximately 72% +/- 33%, while high-density lipoprotein levels showed variable changes, including increased values. A decrease of 36% +/- 26% in total plasma cholesterol was observed in Watanabe Heritable Hyperlipidemic rabbits receiving rhM-CSF by CIVI for 7 days. This decrease was attributable almost entirely to decreases in LDL cholesterol, which fell approximately 34% +/- 24% from baseline. Although the mechanism of this cholesterol-lowering effect is unknown, these results strongly suggest that rhM-CSF may provide a novel treatment for hypercholesterolemia and may be useful in investigations into the mechanisms of cholesterol homeostasis and atherogenesis.
CT and pathologic predictive features of residual mass histologic findings after chemotherapy for nonseminomatous germ cell tumors: can residual malignancy or teratoma be excluded?
Forty-eight patients with disseminated nonseminomatous germ cell tumors were studied retrospectively to determine whether initial pathologic features and pre- and post-chemotherapy computed tomographic (CT) features could be used to exclude malignancy or teratoma in residual masses that were excised after chemotherapy. Neither CT findings (residual mass size, attenuation, and degree of shrinkage during chemotherapy) nor type of primary testicular tumor cell was significantly correlated with malignancy or teratoma versus necrosis in residual masses. No significant correlation was demonstrated between the combined features of (a) the absence of teratoma in a histologic specimen of the primary testicular tumor and (b) greater than 90% shrinkage of masses during chemotherapy and the absence of malignancy or teratoma in residual masses as suggested in the literature. Of nine patients with both of these findings, two had malignancy and two had teratoma. Radiographic and pathologic features cannot be used to reliably exclude malignancy or teratoma in residual abdominal masses after chemotherapy for nonseminomatous testicular cancer.
The role of recombinant human erythropoietin in the management of anemia associated with acquired immunodeficiency syndrome.
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Clinical applications of recombinant macrophage-colony stimulating factor (rhM-CSF).
rhM-CSF has diverse in vitro and in vivo hematologic and metabolic effects. Clinical trials with this new biopharmaceutical are now in progress and early results have confirmed preclinical findings. The major demonstrated effects of rhM-CSF include an increase in number and activation of monocytes and macrophages, the ability to enhance antibody-dependent cellular cytotoxicity, enhancement of macrophage microbial phagocytic and killing activity, cholesterol lowering, and platelet lowering. The range of potential indications for the use of rhM-CSF makes the further clinical development of this molecule both a challenge and an opportunity. Investigation of combination therapies with other cytokines or monoclonal antibodies will be an important aspect of future investigations.
Effects of parenteral recombinant human macrophage colony-stimulating factor on monocyte number, phenotype, and antitumor cytotoxicity in nonhuman primates.
Recombinant human macrophage colony-stimulating factor (rhM-CSF) was given to cynomolgus monkeys by continuous intravenous infusion or subcutaneous injection, at a dose of 50 to 100 micrograms/kg/d in repetitive 14-day cycles. Starting within 24 to 48 hours of initiation of rhM-CSF, there was a progressive increase in the number of circulating monocytes, from a baseline of 811 +/- 253 cells/microL to a peak of 3,495 +/- 712 cells/microL on day 5 to 7. Many of these cells were large, granular, and extensively vacuolated. The expanded cell population expressed HLA-DR, LFA3, CD11b (904), and CD14 (MY4), and was 77% CD16 (FcRIII) positive by two-color cytofluorometry. In functional assays, fresh monocytes showed little cytotoxicity against cultured human melanoma cells (SKMel-1), with or without prior rhM-CSF treatment. However, after 3 days of in vitro culture in rhM-CSF, monocytes from treated animals mediated efficient antibody-dependent cytotoxicity (ADCC) against SKMel-1 using the murine monoclonal antibody 3F8 (IgG3, anti-ganglioside GD2). Under the same conditions, monocytes from control animals showed little ADCC (17% versus 82%, P less than .05). Antitumor cytotoxicity in the absence of antibody was less efficient and was not significantly different between the two groups. There was a mild decrease in platelet count during rhM-CSF treatment, without clinical symptoms. No abnormalities of serum biochemical parameters were seen. We conclude that parenteral rhM-CSF increases the number of circulating monocytes in nonhuman primates, and that these monocytes mediate increased antitumor ADCC after a brief period of in vitro differentiation. This study has implications for the design of possible future clinical trials combining antitumor monoclonal antibodies and rhM-CSF.
Biology and management of bladder cancer.
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In vivo hematologic effects of recombinant human macrophage colony-stimulating factor.
Macrophage colony-stimulating factor (recombinant human M-CSF) given as a single intravenous injection to Lewis rats induces a dose-dependent peripheral monocytosis, neutrophilia, and lymphopenia. The monocytosis peaks at 28 to 32 hours with a seven- to eightfold increase in the number of circulating monocytes and promonocytes. The peripheral monocytosis is accompanied by a slight increase in marrow blasts, promonocytes, and monocytes. A monocytopenia reaching a nadir at 15 minutes precedes the monocytosis, suggesting that M-CSF activates circulating monocytes and causes intravascular margination. The M-CSF-induced neutrophilia and lymphopenia are relatively mild in magnitude, are observed between 2 and 16 hours after injection, and are no longer evident at later time-points. The monocytosis was at least partially inhibited by dexamethasone. M-CSF-induced monocytosis most likely reflects a direct effect of M-CSF on marrow monocyte precursor proliferation, maturation, and release, whereas the neutrophilia and lymphopenia may reflect indirect effects mediated by the known ability of M-CSF to cause the release of other cytokines.
Preclinical and clinical evaluation of recombinant human macrophage colony-stimulating factor (rhM-CSF).
The promise of hematopoietic growth factors is now being realized as clinical trials become more mature. The uses of granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor are now becoming more established in therapeutic applications of disease states. A variety of new hematopoietic growth factors is on the horizon, including recombinant human macrophage colony-stimulating factor (rhM-CSF), which has recently entered clinical trials after extensive preclinical testing. The diverse biological actions of rhM-CSF will provide novel ways of approaching various medical problems across the disciplines of hematology, oncology, infectious disease and cardiology.
Leuprolide therapy for prostate cancer. An association with scintigraphic "flare" on bone scan.
The scintigraphic "flare" phenomenon on bone imaging refers to an increase in intensity of tracer uptake in sites of bone metastases and/or the appearance of "new" lesions, which occur shortly after commencement of hormonal therapy or chemotherapy for breast, prostate, or lung cancer. In this study, we observed that scintigraphic flare can occur in patients with prostate cancer following treatment with the "hormone-like" luteinizing hormone releasing hormone analog, leuprolide acetate. Twenty-six patients with prostate cancer being treated with leuprolide acetate underwent serial bone scans at three-month intervals. Five (19.2%) of the 26 patients had findings consistent with a scintigraphic flare on bone scans obtained between three and six months after initiation of therapy. These scan findings should not be confused with progression of skeletal metastases.
Initial evaluation and response criteria for patients with superficial bladder cancer. Report of a workshop.
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Effects of interleukin-3 on hematopoietic recovery after 5-fluorouracil or cyclophosphamide treatment of cynomolgus primates.
Interleukin-3 (IL-3) is a hematopoietic growth factor that supports the growth of early hematopoietic progenitors in vitro. In vivo administration of recombinant human interleukin-3 (rhIL-3) to normal primates results in a modest and delayed leukocytosis secondary to increases in neutrophils, basophils, and eosinophils. We postulated that the effects of rhIL-3 might be more pronounced in hematologically stressed primates, and therefore administered rhIL-3 to primates after intensive myelosuppressive therapy. Primates received either cyclophosphamide (CPM) at 60 mg/kg or 5-fluorouracil (5-FU) at 75 mg/kg i.v. on two consecutive days. Subsequently, rhIL-3 was administered intravenously or subcutaneously at 20 micrograms/kg per d for 14 d. Compared to controls, all rhIL-3 treated primates experienced higher absolute neutrophil count (ANC) nadirs and dramatic decreases in the period of severe neutropenia (ANC less than 500) after myelosuppressive therapy. RhIL-3 administration resulted in a significant basophilia and eosinophilia, which resolved after discontinuation of the drug. RhIL-3 did not enhance erythroid recovery. Platelet recovery was earlier in rhIL-3-treated animals. However, variations in the platelet recovery observed in control animals, precluded accurate estimation of this effect or its significance. Our results indicate that the administration of rhIL-3 following intensive myelosuppressive therapy dramatically enhances myeloid recovery and ablates the predicted period of prolonged severe neutropenia.
Psychosocial factors, curative therapies, and behavioral outcomes. A comparison of testis cancer survivors and a control group of healthy men.
In a retrospective study of 223 testis cancer survivors and 120 controls matched sociodemographically, we examined the relative impact of sociodemographic and clinical factors on long-term outcomes in the areas of sexual function, relationships, employment, and mental outlook. For most of the survivors, testis cancer did not lead to unemployment (4.5%), divorce (6.8%), or disabling psychological problems. Multivariate analysis results confirm that cancer survivors report significantly more infertility and sexual performance distress, but not more desire distress, than the control group. Survivors' sexual impairment varied according to treatment received (and therefore histologic factors) and sociodemographic variables. Parental status (not having children) and education (college or less) independently predict infertility distress, whereas education and lower occupational level independently predicted sexual performance distress. Adjusting for socioeconomic status (SES), the men with advanced testis cancer who received chemotherapy and standard retroperitoneal lymph node dissection (RPLND) had significantly more infertility and performance distress than those men who received other treatments. Neither the treatment or SES variables predicted disrupted relationships or a deteriorated mental outlook. However, men with sexual impairment distress were more likely to report strained relationships and a pessimistic mental outlook. These findings have implications for treatment decisions and can be used to identify subgroups of survivors who could benefit from counseling and sexual rehabilitation services.
Nodular pneumonitis after cancer chemotherapy.
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Testicular cancer.
The management of testis cancer is continually changing. Since the introduction of curative chemotherapy for metastatic disease, the entire approach to early disease (stage I and stage II) is undergoing reevaluation. Individuals with favorable prognostic features can be offered, under detailed clinical protocols, orchiectomy followed by meticulous surveillance. Likewise, individuals with retroperitoneal disease may be offered retroperitoneal lymph node dissection initially or, alternatively, chemotherapy initially. The prognosis for individuals with metastatic disease is extremely favorable, with the majority of patients being cured with 9-12 weeks of combination chemotherapy. Major efforts are still underway to identify appropriate second-line or "salvage" regimens for individuals who are not cured with first-line chemotherapy. Likewise, the use of new modalities, such as bone marrow transplantation, and new drugs must be evaluated in appropriately designed, prospective studies. Such studies will continue to increase the cure rate of individuals with metastatic disease and enhance the prognosis for such high-risk populations of patients. This paper reviews basic aspects relating to histology, clinical staging, and approach to management for all stages of germ cell cancer of the testis.
Radiation therapy of seminoma: 17-year experience at the Joint Center for Radiation Therapy.
One hundred and sixteen patients with stage I and II primary testicular seminoma were treated at the Joint Center for Radiation Therapy (JCRT) between 1968 and 1984. Complete follow-up is available for 114 patients (98%) with a median follow-up time of 6 years. Actuarial relapse-free survival (RFS) and survival for the entire group at 10 years were 94 and 86%, respectively, with 27 patients still at risk beyond 10 years. Actuarial RFS and survival at 10 years by stage were 97 and 92% for stage I, 93 and 81% for stage IIa, 100 and 100% for stage IIb, but only 75 and 51% for stage IIc. The difference in actuarial survival between stage IIc patients and stage I, IIa and IIb patients was significant (p less than 0.01). These results indicate that radiation therapy is excellent treatment for stage I and II seminomas as long as the largest mass of disease is not greater than 5 cm (stage IIc). Patients with stage IIc seminoma are now treated with cisplatin-containing combination chemotherapy followed by radiation therapy to areas of bulk disease. Although the majority of patients with stage II disease in this series received mediastinal irradiation, this is no longer recommended at the JCRT.