Phase I study of a third-generation selective estrogen receptor modulator, LY353381.HCL, in metastatic breast cancer.

PURPOSE: We conducted this phase I trial to determine the safety and toxicity profile of LY353381.HCl-a novel, potent, third-generation selective estrogen receptor modulator (SERM)-because this benzothiophene derivative demonstrated an SERM profile in preclinical studies. PATIENTS AND METHODS: We studied 32 patients with recurrent or metastatic breast cancer. Patients were treated in four cohorts with oral daily doses of 10, 20, 50, and 100 mg. Pharmacokinetic sampling was performed during the first 72 hours following the first dose on day 1 and during the 24 hours after the day 57 dose. Eligibility criteria included Eastern Cooperative Oncology Group performance status of 0 to 2; no significant major organ dysfunction; and at least 3 weeks elapsed since most recent hormonal therapy, chemotherapy, and estrogen replacement therapy. RESULTS: The median patient age was 56 years (range, 30 years to 76 years). The median number of prior chemotherapies for metastatic disease was one (range, zero to four), while the median number of prior hormone regimens for metastatic disease was two (range, zero to five). Receptor status was estrogen receptor (ER) positive and progesterone receptor (PR) positive, 19 patients; ER positive and PR negative, eight patients; ER positive and PR unknown, two patients; and ER and PR unknown, three patients. Dose-limiting toxicity was not observed. Treatment was well tolerated with mild to moderate hot flashes in 18 of 32 patients (56%) at all dose levels. Transvaginal ultrasound performed at baseline and after 12 weeks of treatment showed no endometrial thickening. Of the 32 patients evaluable for response, six patients had stable disease for at least 6 months with a median duration of 7.7 months (range, 6.2 months to 33.8 months). The pharmacokinetics of LY353381.HCl were generally linear with respect to time and studied dose range. CONCLUSION: As predicted in preclinical testing, daily oral LY353381.HCl is safe, is well tolerated at all tested dose levels, and may be clinically beneficial in patients with extensively pretreated metastatic breast cancer. Further studies with LY353381 to evaluate the efficacy in patients with or without prior exposure to tamoxifen and fewer overall prior regimens are under way.

Potential role of hematopoietic stem cell transplantation in children with secondary acute lymphocytic leukemia.

Secondary acute lymphocytic leukemias (ALL) are uncommon events in the pediatric patient population. There are few detailed reports on the laboratory characteristics and clinical course of patients with secondary lymphocytic leukemia. Historically, these patients have had a poor outcome. We report two patients treated at one institution who developed treatment-related secondary ALL. Both patients underwent hematopoietic stem cell transplantation, one with a compatible unrelated donor cord blood unit and one with an HLA-matched sibling donor bone marrow. One of the two patients survives disease-free 3 years after transplantation.

Calcium channel blockade inhibits platelet activating factor production by human umbilical vein endothelial cells.

An increase in intracellular calcium level is an important signal in the regulation of cellular responses under normal and pathological conditions. Because two key enzymes in the synthetic pathway of platelet activating factor (PAF), phospholipase A2 and acetyltransferase, are calcium dependent, we hypothesized that calcium channel blockade may inhibit agonist-induced PAF synthesis. Primary cultures of human umbilical vein endothelial cells (EC), pre-incubated with [3H]acetate, were exposed to thrombin (5 U/mL) and PAF production was quantitated by incorporation of radiolabel into the EC lipid fraction co-migrating with exogenous PAF in thin-layer chromatography. The effect of pre-incubation with calcium channel blockers (verapamil, diltiazem, 10(-4) M) or buffer was determined. Results (triplicate experiments, * P less than 0.05 vs buffer, P less than 0.05 vs thrombin) demonstrate that pre-incubation with calcium channel blocker markedly inhibits thrombin-induced PAF production (verapamil:buffer 273 +/- 122, thrombin 10,735 +/- 1524*, thrombin + verapamil 178 +/- 91 cpm/plate; diltiazem:buffer 1097 +/- 581, thrombin 15,283 +/- 2661*, thrombin + diltiazem 280 +/- 56 cpm/plate). The effect of diltiazem was dose-dependent (% inhibition: 10(-7) M, 46%; 10(-5) M, 60%; 10(-4) M, 98%). Diltiazem also inhibited bradykinin (10(-8) M) induced PAF synthesis. In calcium-free medium or in the presence of LaCl3 (10(-3) M), the PAF response of EC to thrombin was blunted (buffer 582 +/- 360, thrombin 5394 +/- 1069, thrombin + calcium free medium 1055 +/- 571, thrombin + LaCl3 1271 +/- 58 cpm/plate). We conclude that calcium channel blockers prevent agonist-induced PAF synthesis, possibly by preventing cellular calcium influx and activation of PAF synthetic enzymes. We speculate that this mechanism may underlie, at least in part, the beneficial effect of calcium channel blockade under various pathological conditions.

A phase II study of gemcitabine plus carboplatin in platinum-sensitive, recurrent ovarian carcinoma.

OBJECTIVES: Gemcitabine and carboplatin each have demonstrated effectiveness without increased neurotoxicity in pretreated patients with ovarian cancer. We evaluated the efficacy and safety of gemcitabine plus carboplatin in patients with recurrent ovarian cancer in a multicenter phase II study. METHODS: Women with histologically proven measurable or evaluable epithelial ovarian cancer (any FIGO) who relapsed > or =6 months after discontinuation of first-line, platinum-containing therapy received gemcitabine 1000 mg/m(2) on days 1 and 8 and carboplatin AUC 4 on day 1 (after gemcitabine) every 21 days for up to six cycles. RESULTS: Of the 40 enrolled/evaluable patients, 6 (15%) had complete response and 19 (47.5%) had partial response (PR), including one patient with PR in nonmeasurable disease (PRNM), for an overall response rate of 62.5% (95% CI, 45.8-77.3%). The median duration of response was 7.8 months (95% CI, 6.7-10.0), the median time to progressive disease was 9.6 months (95% CI, 8.5-11.0), and the median time to treatment failure was 9.3 months (95% CI, 8.2-10.4). The main grade 3/4 toxicities were neutropenia (78% of patients), leukopenia (30%), thrombocytopenia (18%), and anemia (15%); no grade 4 nonhematologic toxicities occurred, and grade 3 nonhematologic toxicities were mild. CONCLUSIONS: The combination of gemcitabine and carboplatin is active and feasible in platinum-sensitive patients with recurrent ovarian cancer. This regimen is undergoing further evaluation in a large phase III trial.

Activation of the mitogen-activated protein kinase pathway is involved in and sufficient for megakaryocytic differentiation of CMK cells.

Activation of the mitogen-activated protein (MAP) kinase pathway has been associated with both cell proliferation and differentiation. Constitutively activated forms of Mek (MAP kinase/Erk kinase) and Erk (MAP kinase) have been previously shown capable of inducing differentiation or proliferation in nonhematopoietic cells. To specifically examine the role of Erk activation in megakaryocytic growth and development, we activated the MAP kinase pathway by the transfection of constitutively activated Mek or Erk cDNA into a human megakaryoblastic cell line, CMK, by electroporation. The CMK transfectant clones that expressed constitutively activated Mek or Erk showed morphologic changes of differentiation. Transfected cells also showed expression of mature megakaryocytic cell surface markers. The MAP kinase pathway was also activated by treatment of the hematopoietic cells with a cytokine that activates Erk. The treatment of CMK cells with stem cell factor (SCF ) caused MAP kinase activation and induced differentiation by the expression of mature megakaryocytic cell surface markers. The effects of the SCF treatment were inhibited by pretreatment with a specific inhibitor of the MAP kinase pathway, PD98059. In this report, we conclude that activation of the MAP kinase pathway was both necessary and sufficient to induce differentiation in this megakaryoblastic cell line.

Gemcitabine as first-line therapy in patients with metastatic breast cancer: a phase II trial.

OBJECTIVES: This phase II study was conducted to evaluate the efficacy and safety of gemcitabine in patients with metastatic breast cancer (MBC). METHODS: Women with histologically or cytologically confirmed bidimensionally measurable MBC not amendable to curative surgery or radiation were eligible. Prior chemotherapy for metastatic disease was not permitted. Patients received gemcitabine 1,200 mg/m(2) on days 1, 8 and 15 for 3 weeks every 28 days for a maximum of 8 cycles. RESULTS: Thirty-nine patients, with a median age of 58 years, were enrolled. The overall response rate for the 35 evaluable patients was 37.1% (95% confidence interval [CI], 21.5-55.1%), with 2 complete responses and 11 partial responses. Median time to progression and survival were 5.1 months (95% CI, 3.5-8.8 months) and 21.1 months (95% CI, 11.0-26.9 months), respectively. Chemotherapy was well tolerated, with a median of 4 cycles completed. Grade 4 toxicities were 1 infection and 1 abnormal pulmonary function. Grade 3 neutropenia and thrombocytopenia occurred in 30.3% and 6.3% of patients, respectively. The most common grade 3 non-hematologic toxicity was nausea/vomiting (10.3%). Five of 21 patients had improved Karnofsky performance status (KPS) scores. CONCLUSION: Single-agent gemcitabine is active and well tolerated as first-line treatment in patients with MBC.

Three new exon 10 glucose-6-phosphate dehydrogenase mutations.

Three previously undescribed mutations of the glucose-6-phosphate dehydrogenase (G6PD) gene have been documented in patients with hereditary non-spherocytic hemolytic anemia (HNSHA). In none of the cases have we been able to obtain a sufficient volume of blood to characterize the residual enzyme biochemically. "G6PD Calvo Mackenna" was due to an A-->G transition in cDNA nucleotide 1138 creating an Aat II site and resulting in a substitution of valine for isoleucine at amino acid 380. "G6PD Riley" was due to a T-->C transition at cDNA nucleotide 1139 also changing the 380 isoleucine, in this case to a threonine. "G6PD Wisconsin" was due to an C-->G transversion in cDNA nucleotide 1177, destroying a Aci I site and resulting in a substitution of glycine for arginine at amino acid 393. All of these mutations were in exon 10, where mutations that cause HNSHA appear to be clustered. We present a list of the 83 mutations of G6PD that have been documented to the end of April, 1995.

Extranodal spread of anaplastic large cell (CD30+) lymphoma presenting as a cutaneous perivascular infiltrate.

Cutaneous lesions of anaplastic large cell (CD30+) lymphoma (ALCL) typically present as solitary or multiple ulcerated nodules. This tumor is histologically characterized by a diffuse dermal and sometimes subcutaneous infiltrate composed of bizarre, pleomorphic, neoplastic cells that may be occasionally multinucleated. We report a case of extranodal spread of ALCL to the skin in a 2 1/2-year-old boy presenting as a widespread papular eruption that on biopsy showed lymphoma restricted to the perivascular and periadnexal dermis.