Phase I trial of dolastatin-10 (NSC 376128) in patients with advanced solid tumors.

Dolastatin-10 (dola-10) is a potent antimitotic peptide, isolated from the marine mollusk Dolabela auricularia, that inhibits tubulin polymerization. Preclinical studies of dola-10 have demonstrated activity against a variety of murine and human tumors in cell cultures and mice models. The purpose of this Phase I clinical trial was to characterize the maximum tolerated dose, pharmacokinetics, and biological effects of dola-10 in patients with advanced solid tumors. Escalating doses of dola-10 were administered as an i.v. bolus every 21 days, using a modified Fibonacci dose escalation schema. Pharmacokinetic studies were performed with the first treatment cycle. Neurological testing was performed on each patient prior to treatment with dola-10, at 6 weeks and at study termination. Thirty eligible patients received a total of 94 cycles (median, 2 cycles; maximum, 14 cycles) of dola-10 at doses ranging from 65 to 455 microg/m2. Dose-limiting toxicity of granulocytopenia was seen at 455 microg/m2 for minimally pretreated patients (two or fewer prior chemotherapy regimens) and 325 microg/m2 for heavily pretreated patients (more than two prior chemotherapy regimens). Nonhematological toxicity was generally mild. Local irritation at the drug injection site was mild and not dose dependent. Nine patients developed new or increased symptoms of mild peripheral sensory neuropathy that was not dose limiting. This toxicity was more frequent in patients with preexisting peripheral neuropathies. Pharmacokinetic studies demonstrated a rapid drug distribution with a prolonged plasma elimination phase (t 1/2z = 320 min). The area under the concentration-time curve increased in proportion to administered dose, whereas the clearance remained constant over the doses studied. Correlation analysis demonstrated a strong relationship between dola-10 area under the concentration-time curve values and decrease from baseline for leukocyte counts. In conclusion, dola-10 administered every 3 weeks as a peripheral i.v. bolus is well tolerated with dose-limiting toxicity of granulocytopenia. The maximum tolerated dose (and recommended Phase II starting dose) is 400 microg/m2 for patients with minimal prior treatment (two or fewer prior chemotherapy regimens) and 325 microg/m2 for patients who are heavily pretreated (more than two prior chemotherapy regimens).

Chemotherapy for advanced esthesioneuroblastoma: the Mayo Clinic experience.

OBJECTIVE: Esthesioneuroblastoma (olfactory neuroblastoma) is a rare neuroendocrine tumor that arises in the upper nasal cavity from the olfactory epithelium. Little information is available regarding the treatment of these tumors with chemotherapy in the advanced setting. A retrospective review of patients with recurrent esthesioneuroblastoma treated with chemotherapy between 1970 and 1995 at the Mayo Clinic was undertaken to gain more information regarding the efficacy of chemotherapy treatment for these patients. METHODS: Ten patients were identified using a computerized data base available at this institution. The clinical and pathological materials, when available, were reviewed, and each tumor reviewed was assigned a Hyams' grade. RESULTS: There were six men and four women, ranging in age from 22 to 74 years, all of whom had assessable Kadish Stage C disease at the time of chemotherapy treatment. The chemotherapy regimens and clinical follow-up varied during this 25-year time span. The only tumor regression resultant from chemotherapy was observed in patients with high-grade tumors. Two of four patients with high-grade tumors obtained regression from first-line, platinum-based chemotherapy, with a mean duration of regression of 9.3 months (range, 2-13 mo). Survival time from initial diagnosis was 139.5 months (range, 83-168 mo) in patients with low-grade tumors and 32.2 months (range, 5-84 mo) in patients with high-grade tumors. Survival from initial chemotherapy treatment was 44.5 months (range, 3-130 mo) in patients with low-grade tumors and 26.5 months (range, 2-67 mo) in patients with high-grade tumors. CONCLUSION: Hyams' grading of esthesioneuroblastoma tumors seems to be important in predicting response to chemotherapy. Despite sensitivity to platinum-based chemotherapy, patients with high-grade tumors in this series had a much more aggressive course than did those with lower-grade tumors. This series suggests that cisplatin-based chemotherapy is active in advanced, high-grade esthesioneuroblastoma and is a reasonable choice in the systemic treatment of these patients.

Detection of monoclonal plasma cells in the peripheral blood of patients with primary amyloidosis.

We evaluated the blood from 150 patients with primary AL-amyloidosis for circulating monoclonal plasma cells using a sensitive slide-based immunofluorescence technique. The percentage of monoclonal blood plasma cells (BPC) that were in S-phase was determined by the bromodeoxyuridine labelling index (BLI). Monoclonal BPC were detected in 16% (24/150) of patients. The median number of monoclonal BPC was 1 x 10(6)/l and 4.6% (7/150) of patients had a high number. The BLI was zero in all but three patients. This study demonstrates that monoclonal plasma cells circulate in the peripheral blood of patients with AL-amyloidosis.

Systemic mast cell disease associated with the hypereosinophilic syndrome.

Systemic mast cell disease (SMCD) is an uncommon disorder characterized by a proliferation of mast cells involving the bone marrow, spleen, liver, skin, and lymph nodes. Although rare, the association of SMCD and other hematologic disorders is well established. To our knowledge, however, no previously published reports have described SMCD associated with the hypereosinophilic syndrome (HES). Herein we describe two patients who had SMCD in association with HES. Both patients had evidence of cardiac eosinophilic involvement, and both responded to systemic therapy. SMCD is often associated with eosinophilia and may be associated with HES more frequently than is commonly appreciated. Because congestive heart failure is a major cause of morbidity in patients with HES, cardiac assessment in patients with eosinophilia and SMCD is important in order to identify those with eosinophilic organ involvement and treat them aggressively.