Phase II study of 13-cis-retinoic acid plus interferon-alpha 2a in heavily pretreated squamous carcinoma of the cervix.

The combination of 13-cis-retinoic acid (13-cRA) and interferon (IFN)-alpha 2a has been reported to be highly active in previously untreated squamous carcinoma of the cervix. In this phase II study, 13-cRA was given at a dose of 1 mg/kg/day and IFN-alpha 2a was given subcutaneously at a dose of 3 million units/m2/day. Thirteen of 14 patients enrolled in this study are evaluable for response and toxicity. There were no complete or partial responses. Ten patients had progressive disease and the remaining three had stable disease. Principle toxicities were fatigue, nausea, and vomiting. This regimen appears cross-resistant with radiotherapy and/or platinum-based cytotoxic therapy in heavily pretreated patients with squamous carcinoma of the cervix.

Phase I study of adozelesin (U-73,975) in patients with solid tumors.

During a phase I clinical and pharmacologic trial, 26 patients with refractory solid tumors were treated with increasing doses of adozelesin by brief intravenous infusion every 3 weeks. Overall, adozelesin was well tolerated. The dose-limiting toxicity was myelosuppression, mainly thrombocytopenia and leukopenia. Nonhematologic toxicity was generally mild, with fatigue (36%), local reaction at the infusion site (24%), nausea or vomiting (20%) and hypersensitivity reaction (16%) being the most common adverse effects. There were no objective clinical responses. The maximally tolerated dose on this schedule was 188 micrograms/m2 with the recommended phase II starting dose being 150 micrograms/m2 on an every 3 week schedule. Adozelesin merits broad investigation at the phase II level.

Functional characteristics of in vivo induced neutrophils after differentiation therapy of acute promyelocytic leukemia with all-trans-retinoic acid.

The authors describe the functional capabilities of in vivo induced neutrophils from a patient with acute promyelocytic leukemia (French-American-British M3v) treated with differentiation therapy using all-trans-retinoic acid (45 mg.m-2.day-1). The induced neutrophils from the leukemic clone appeared in the blood 7 days after therapy. Normal neutrophils, presumably derived from nonclonal normal hematopoiesis, appeared 15 days after the initiation of therapy. The induced neutrophils were separated from normal neutrophils by density gradient centrifugation. Their origin was established by fluorescence in situ hybridization. The induced neutrophils were morphologically atypical but stained for myeloperoxidase (Sudan black B) and AS-D chloroacetate esterase and were negative for alpha-naphthyl butyrate esterase. Induced neutrophils were functionally mature, showing nitroblue tetrazolium reduction in 72% of the cells compared with 84% in the normal neutrophil fraction. Both the rate and total killing of Staphylococcus aureus (American Type Culture Collection Strain 25923) were normal in both neutrophil fractions. Random locomotion was equivalent and within the normal reference range in both fractions; however, using the under-agarose technique, induced neutrophils showed a minor chemotactic defect in response to both n-formyl-methionyl-leucyl-phenylalanine (score 292, normal 338-868) and complement-derived chemotactic factors (score 420, normal 457-1408). At autopsy, induced neutrophils infiltrated necrotic myocardial tissue, suggesting a normal response to inflammatory stimuli.

Leukoerythroblastic anemia in metastatic prostate cancer. Clinical and prognostic significance in patients with hormone-refractory disease.

BACKGROUND: The clinical and prognostic significance of leukoerythroblastic anemia (LKEA) in patients with metastatic prostate cancer and, in general, patients with disseminated solid tumors is poorly understood. Therefore, the authors studied a population of patients with metastatic prostate cancer refractory to hormonal therapy to assess the incidence, clinical features, and prognostic implications of LKEA. METHODS: The medical records of 106 patients with hormone-refractory prostate cancer metastatic to bone seen at the Tucson Veterans Affairs Medical Center between 1985 and 1991 were reviewed retrospectively. The clinical and laboratory data, number of packed erythrocyte transfusions required, and length of survival from the time of diagnosis of hormone-refractory disease until last follow-up visit or death were investigated in 91 identified patients. RESULTS: Twenty-six of 91 patients (28.6%) were found to have LKEA. LKEA developed before or at the time of diagnosis of hormone-refractory disease in 8 patients and after diagnosis of hormone-refractory disease in 18 patients. The presence of LKEA was associated with significantly lower hemoglobin levels and platelet (Plt) counts and significantly higher total bilirubin, lactic dehydrogenase (LDH), and alkaline phosphatase values (P < 0.05). Leukopenia (< 4.0 x 10(9)/l leukocytes), thrombocytopenia (< 150 x 10(9)/l Plt), elevated LDH levels (> 220 U/l), and laboratory evidence of disseminated intravascular coagulation (DIC) were more common in patients with LKEA than in those without LKEA (P < 0.01). Microangiopathic hemolysis was seen in only 2 of 91 patients (2.1%). Patients with LKEA had significantly greater transfusion requirements compared with patients without LKEA (P < 0.0001), but the median survival length was not significantly different (9 months versus 11 months, respectively). The presence of DIC and LDH levels of 500 U/l or greater in patients with LKEA was associated with a poor prognosis. CONCLUSIONS: LKEA is a relatively common finding in patients with hormone-refractory metastatic prostate cancer and is associated with greater transfusion requirements. Its presence, however, does not affect survival significantly.

Solitary cerebellar metastasis from transitional cell carcinoma of bladder.

Brain metastasis from transitional cell carcinoma of the bladder is unusual, occurring most often in the presence of widespread systemic metastases. We report on a patient who presented with an isolated cerebellar metastasis and recurrent carcinoma of the bladder, after treatment with local excision and intravesical thiotepa. Further evaluation failed to demonstrate other distant metastases. Excision of the cerebellar lesion revealed transitional cell carcinoma identical to the original bladder tumor. In a review of the literature, we found reports of two similar patients in whom a solitary cerebellar lesion was the first sign of metastasis from carcinoma of the bladder; neither patient had evidence of other distant metastases, and neither previously had received systemic chemotherapy. These observations indicate that central nervous system metastasis from carcinoma of the bladder, while rare, should be considered in the differential diagnosis of solitary intracerebellar lesions in such patients.

Predominance of chromosome 5 deletions in myeloid neoplasia associated with solid tumors managed by surgical excision.

To assess potential differences in genetic predisposition to myeloid neoplasia, we evaluated the karyotypes and reviewed results of cytogenetic studies on bone marrow specimens from six patients with myelodysplastic syndrome, or acute myeloid leukemia, and a history of solid tumor managed solely by surgical resection. Structural or numerical deletions of chromosome 5 were identified in each of four patients with abnormal marrow karyotypes. Constitutional karyotypes were normal in two patients studied with clonal marrow chromosome abnormalities. Review of previously reported cases of myeloid neoplasia following resection of solid tumors disclosed a preponderance of chromosome 5 deletions. Predisposition to specific chromosome loss may influence genetic expression of disease in solid tumor patients developing hematologic malignancy.

Myelodysplastic transformation of polycythemia vera: case report and review of the literature.

We report a case of refractory anemia with excess blasts (RAEB) developing in a 67-year old man with a history of polycythemia vera; results of cytogenetic and immunophenotyping studies are described. In this report the clinical, cytogenetic and hematologic features of myelodysplasia complicating polycythemia vera are reviewed. Results of immunophenotyping and cytogenetic studies, and the preponderance of cases developing after myelosuppressive therapy suggest that in the majority of cases myelodysplasia is treatment-related.