Phase II study of mitoxantrone and 5-azacytidine for accelerated and blast crisis of chronic myelogenous leukemia: a study of the Eastern Cooperative Oncology Group.

A total of 40 evaluable patients were treated for blastic crisis of chronic myelogenous leukemia with mitoxantrone, 12 mg/m2 per day for three days and 5-azacytidine 150 mg/m2 per day for 5 days. Toxicity was primarily hematologic and was manageable. The overall response rate was 23%, including five complete responders, two partial responders, and two with hematologic improvement. Cytogenetic and immunophenotypic characterization of the leukemia was performed on all patients with aspirable bone marrow, and these results were correlated with response and survival, but did not have predictive value once the patient was in blastic crisis. Only initial platelet count (p = 0.02), hemoglobin (p = 0.03), and lower white blood cell count (p = 0.09) were somewhat predictive of response. Lack of hepatic involvement (p = 0.05), lower white blood cell count (0.05), and higher platelet count (p = 0.02) were predictive of prolonged survival. Although response did not strongly correlate with survival, one third of responders were alive at one year. This regimen produces results similar to those of other recently published regimens in this disease. Earlier intervention and more effective therapy is necessary in these patients.

Escalating doses of sequential methotrexate and 5-fluorouracil, doxorubicin, and vincristine for the treatment of metastatic breast cancer.

Antitumor efficacy of sequential methotrexate, 5-fluorouracil, and mid-cycle doxorubicin regimens has been established in advanced gastric cancer. Based on similar theoretical kinetic considerations, we treated 15 women with metastatic breast cancer with a five-drug nonalkylating agent regimen. Six of 14 evaluable patients had an objective response. Three patients achieved a complete remission (duration 9, 14, 19+ months), and 3 attained a partial remission (duration 2, 3, 6 months). Hematologic toxicity was significant, with 8 patients developing moderate to severe (ECOG grade 3 or 4) toxicity. Although significant antitumor activity with this nonalkylating agent regimen was observed, hematologic toxicity was considerable and limits the usefulness of this regimen in its present schedule.

CT guided interstitial therapy of pancreatic carcinoma.

We describe the use of percutaneous CT guidance for localization and placement of 192Ir sources into a patient with pancreatic carcinoma. We have shown the feasibility of this procedure and the lack of complications which are probably due to minimal damage to tissue involved. Computed tomography is ideally suited for percutaneous implantation because it provides the most accurate method for needle placement within the abdomen.

Alternating sequential combination chemotherapy in the management of advanced Hodgkin's disease. A Southeastern Cancer Study Group trial.

The Southeastern Cancer Study Group has explored the use of alternating sequential combination chemotherapy in advanced Hodgkin's disease. Two hundred twelve evaluable patients were randomly assigned to treatment with the six-drug combination, BCNU, cyclophosphamide, vinblastine, procarbazine, prednisone, and bleomycin (BCVPP-Bleo) or with the same drugs alternating in monthly cycles with doxorubicin, dacarbazine, and bleomycin. Both regimens produced complete response rates of approximately 73%. The duration of remission and survival were similar for the two treatment regimens. Although our sequence of combinations does not rigorously meet the criteria for "non-cross-resistant" our results do not lend support to the hypothesis that alternating sequential non-cross-resistant drug combinations improves the outcome in advanced Hodgkin's disease.

General principles of the evaluation and therapy of anemias.

The etiologic explanation of an anemia is important for the most effective therapy of that anemia. This may also define an underlying disease process. The etiology of the anemia can be achieved by appropriate use of the history, physical examination, and laboratory data. This information may be used to clarify the anemia, define a diagnosis, and direct appropriate therapy.

Iron overload disorders: natural history, pathogenesis, diagnosis, and therapy.

Hemochromatosis is a syndrome which, when fully expressed, is manifested by melanoderma , diabetes mellitus, and liver cirrhosis, with iron overload involving parenchymal and reticuloendothelial cells in many organ systems. This clinical presentation may arise as a consequence of either hereditary or acquired abnormalities of iron overload, although the mechanisms are quite different. In hereditary hemochromatosis (also known as primary, or idiopathic, hemochromatosis), increased intestinal iron absorption leads to excessive accumulations of iron, throughout the body, particularly in parenchymal cells. In secondary forms of iron overload including transfusional hemosiderosis, alcoholic cirrhosis, thalassemia, sideroblastic anemia, and porphyria cutanea tarda, iron accumulates in the reticuloendothelial system initially, but with increasing amounts of total body iron, excessive iron deposits eventually accumulate in parenchymal cells throughout the body producing a picture indistinguishable from hereditary hemochromatosis. In this article, the course, prognosis, and therapy of iron overload will be reviewed in detail. Clinical and experimental data concerning the pathogenesis of the different forms of iron overload will be examined critically. In particular, information relating to possible abnormalities of reticuloendothelial function, intestinal mucosal iron transport, and alterations in serum and tissue isoferritin patterns in hereditary hemochromatosis will be analyzed, and possible directions for future research will be suggested. The mode of inheritance and linkage with the major histocompatibility (HLA) complex will be discussed. Theories on the pathogenesis of tissue damage by excess iron will be evaluated. Methods for measuring the extent of iron overload in clinical practice will be described, including measurements of serum iron, serum ferritin, iron absorption, cobalt excretion, desferrioxamine excretion, liver biopsy and tissue iron determinations, and HLA typing. Finally, unresolved problems in the understanding of the disease process, diagnosis, and therapy will be delineated.

Thoracic and elective brain irradiation with concomitant or delayed multiagent chemotherapy in the treatment of localized small cell carcinoma of the lung: a randomized prospective study by the Southeastern Cancer Study Group.

A prospective randomized study was carried out to compare the effectiveness of concomitant or delayed multiagent chemotherapy combined with irradiation to the primary tumor and regional lymph nodes and to the brain in a group of 70 patients with histologically proven small cell undifferentiated carcinoma of the lung. Complete and partial response in both groups was comparable, and the overall survival was comparable. However, relapse-free survival was significantly higher in patients receiving concomitant chemotherapy and irradiation in comparison with the radiotherapy alone group. Disease-free survival was higher in the concomitant chemotherapy-radiotherapy patients, although survival was not significantly modified, probably because of suboptimal chemotherapy. The initial intrathoracic failure rate was 40.7% inthe concomitant chemotherapy-irradiation group, compared with 53.8% in the radiotherapy-alone patients. None of the patients receiving delayed chemotherapy following the radiotherapy recurrence showed significant tumor response to the drugs. The incidence of distant metastasis was slightly lower in the chemotherapy groups. Brain metastases were noted in 7% of the patients in both groups. Increased intrathoracic recurrences were noted in patients with lower doses of irradiation. Nine of 13 patients treated with inadequate portals developed intrathoracic recurrences in comparison to 13 of 40 treated with adequate irradiation fields. The study emphasizes the need for intensive chemotherapy and adequate radiation therapy to improve survival of patients with small cell undifferentiated carcinoma of the lung. Additional trials are necessary to assess the role of each modality in the management of these patients.

Multiple myeloma in young men. Clinical course and electron microscopic studies of bone marrow plasma cells.

Two cases of multiple myeloma in young men are described. Electron microscopic characteristics of the bone marrow plasma cells are presented. Multiple myeloma is unusual in the young, and when onset in male patients occurs between the ages of 15 and 25 years, the clinical course is more mild and survival longer, even though response to chemotherapy is limited.

Eosinophilopoietin. A circulating low molecular weight peptide-like substance which stimulates the production of eosinophils in mice.

In earlier studies, methods were developed to raise specific antibodies in rabbits against purified suspensions of mouse or human eosinophils. On administration of antieosinophil serum (AES) to mice, the mature eosinophils in tissues, peripheral blood, and bone marrow were depleted, while the immature eosinophil pool in the bone marrow was observed to proliferate. The current investigations explore the generation of eosinophilopoietic factors during AES-induced eosinophilopenia. Mice received three injections of AES, one every other day. As the peripheral eosinophil counts started to recover after the last AES injection, the serum was collected and transferred to normal animals. Within 2 days the recipients showed an increase in peripheral blood as well as in bone marrow eosinophils. The rise in bone marrow eosinophils was due to newly formed cells as evidenced by increased uptake of [(3)H]thymidine. The generation of eosinophilopoietic activity was specifically related to depletion of eosinophils but not neutrophils. The eosinophilopoietic activity was: (a) dependent on the volume of serum transferred, (b) lost on dialysis, and (c) largely heat labile. The activity eluted as a low molecular weight substance on G-25 Sephadex and was digested by pronase but not by trypsin. Active fractions collected from G-25 columns were not chemotactic for the eosinophils in vitro. Thus, specific depletion of mature eosinophils generates a low molecular weight peptide which stimulates eosinophilopoiesis in vivo. It is suggested that this substance be named eosinophilopoietin.

Central nervous system involvement in mycosis fungoides: pre mortem diagnosis by light and electron microsocopic study of the spinal fluid.

Involvement of the brain, spinal cord, peripheral nerves, meninges, and cerebrospinal pathways in mycosis fungoides manifests itself, clinically, as an obscure neurologic disturbance, occurring in patients with cutaneous manifestations of that disorder. Neurologic expressions of this particular cutaneous lymphoma are infrequently reported, in spite of the fact that many patients dying in the course of mycosis fungoides have pathologically demonstrable central nervous system, peripheral nervous system, and meningeal involvement. We report here a patient who incurred devastating neurologic illness as one of the initial features of the course of systemic dissemination of mycosis fungoides. Death occurred nine years after the onset of cutaneous illness. In this instance, cerebrospinal fluid cytologic studies established the diagnosis of nervous system involvement. Mycosis fungoides cells shed into the cerebrospinal fluid were studied by special techniques of light and electron microscopy. Brain scan abnormalities were present, which were clinically correlative with foci of brain involvement. The initial response of patient's nervous system illness to therapy was gratifying but unsustained, and she went on to fatal brain and multiple organ involvement with disseminated mycosis fungoides. The techniques of spinal fluid cytologic diagnosis, confirmatory of the etiology of disease in this case, may have practical appications in the diagnosis of otherwise obscure neurologic disorders.

A computer-based method for the quantification of leukocyte chemotaxis.

A computerized method for the counting of polymorphonuclear leukocytes (PMN's) on chemotactic membranes is described. Through the use of an optical scanner-computer accurate objective quantification is obtained which is similar to the results generated by visual tabulation of the same membranes. Futhermore, the electronic quantification method is both less time consuming and highly reproducible.

Delayed cerebrovascular consequences of therapeutic radiation. A clinicopathologic study of a stroke associated with radiation-related carotid arteriopathy.

A young woman, successfully treated for Hodgkin's disease with radiation and MOPP chemotherapy, incurred a devastating stroke months after radiation therapy to the neck and other areas. There was no premonitory clinical history of cerebrovascular attacks. Autopsy showed unilateral thrombotic occlusion of the internal carotid artery unassociated with neoplastic or fibrotic annular constriction of the vessel. There was medial thickening and fibroblastic proliferation within the carotid artery. Areas of focal elastic membrane degeneration involved the cervical portions of the carotid. Thrombus was organized to the damaged vessel wall and was propagated into the intracranial vessels. Aneurysm formation and arterial hemorrhages were absent. These vascular changes occurred in an area of extensive radiation (7200 rads). Pathoanatomical studies in this patient indicate that radiation-induced vascular changes were associated with a "delayed" stroke.

Hemochromatosis. Pathophysiologic and genetic considerations.

The clinical, genetic, and pathologic findings, and the pertinent case histories in two families with idiopathic hemochromatosis are presented. These studies support the view that idiopathic hemochromatosis is a disease inherited in at least two ways. In one of these families, inheritance appeared to occur in an autosomal recessive manner, whereas in the other, autosomal dominant expression seemed evident. Evidence that an inability of the reticuloendothelial cells to handle iron may play a major role in the pathogenesis of hemochromatosis is presented. The early age of onset and poorer prognosis associated with the recessive inheritance suggest that the defect in reticuloendothelial cell function present in such cases is different from or more severe than those associated with dominant inheritance.