A phase II study of combined oral uracil and ftorafur with leucovorin for patients with squamous cell carcinoma of the head and neck.

BACKGROUND: The objective of this Phase II study was to define the response rate, safety profile, and toxicity of oral uracil and ftorafur (UFT) with leucovorin (UFT/LV) as a palliative treatment for patients with squamous cell carcinoma of the head and neck (SCCHN). METHODS: Patients with metastatic or recurrent SCCHN with an Eastern Cooperative Oncology Group performance status < 2 and adequate organ function were enrolled in an institutional review board-approved trial. Prior induction or adjuvant chemotherapy was permitted provided 6 months had elapsed since the last chemotherapy. Patients were treated with UFT 300 mg/m(2) per day and leucovorin 90 mg per day administered in three doses daily for 28 days followed by a 7-day break for a 35-day cycle. Planned intrapatient dose modifications were based on individual toxicity. Patients were removed from the study for progression of disease or unacceptable toxicity. RESULTS: One hundred six cycles of UFT/LV had been administered to 42 patients as of January 1, 2000. The most common toxicities, in descending order of incidence, were anemia, pain, fatigue, diarrhea, nausea, mucositis, and anorexia. Clinically significant toxicities attributable to UFT/ LV were primarily gastrointestinal. On an intent-to-treat basis, three patients (7%) achieved a complete response, and six patients (14%) achieved a partial response. The overall response rate was 21% (95% confidence interval, 10--37%). CONCLUSIONS: UFT/LV therapy is feasible in this patient population and is generally well tolerated. Response rates are similar to the rates expected with continuous-infusion 5-fluorouracil. UFT/LV should be studied further both alone and in combination therapy for patients with SCCHN.

Phase II trial of docetaxel, cisplatin, fluorouracil, and leucovorin as induction for squamous cell carcinoma of the head and neck.

PURPOSE: To evaluate the toxicity and efficacy of a 4-day regimen of docetaxel, cisplatin, fluorouracil, and leucovorin (TPFL4) in patients with locoregionally advanced squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: Thirty previously untreated patients with stage III or IV SCCHN and Eastern Cooperative Oncology Group functional status of 2 or less were treated with TPFL4. Postchemotherapy support included prophylactic growth factors and antibiotics. Patients who achieved a complete response (CR) or partial response (PR) to three cycles of TPFL4 received definitive twice-daily radiation therapy. The primary end points were toxicity and response to TPFL4. RESULTS: Eighty-five cycles were administered to 30 patients. The major acute toxicities to TPFL4 were mucositis and nausea. One patient died of neutropenic sepsis during therapy. Additional major toxicities were neutropenia, anorexia, nephropathy, neuropathy, and diarrhea. Fourteen percent of all cycles were associated with hospitalization for toxicity. The overall clinical response rate to TPFL4 was 93%, with 63% CRs and 30% PRs. Primary tumor site clinical and pathologic response rates were 93% and 68%, respectively. CONCLUSION: TPFL4 has an acceptable toxicity profile in good-performance-status patients. Modification of the 5-day TPFL regimen (TPFL5: shorter chemotherapy infusion time, earlier intervention with growth factors and antibiotics) led to fewer episodes of febrile neutropenia and hospitalization. Response rates to TPFL justify further evaluation of combinations of these agents in the context of formal clinical trials.

Clinical and pathologic characterization of mucosa-associated lymphoid tissue lymphoma of the head and neck.

Mucosa-associated lymphoid tissue (MALT) has recently been recognized as a possible site of origin for low-grade lymphomas of the B-cell type. Though relatively rare, these MALT lymphomas may arise within several sites in the head and neck, and often present diagnostic and therapeutic challenges. We review 4 cases of primary MALT lymphoma of the head and neck, treated with surgical excision (3 cases), irradiation (2 cases), and chemotherapy (1 case), to further characterize this new subtype of head and neck malignancy. The mean time from onset of symptoms to histologic diagnosis was 15 months. Fine needle aspiration identified an atypical lymphoid infiltrate in only 1 of 3 patients. Immunohistochemical analysis was essential in establishing the diagnosis of MALT lymphoma in all 4 of the cases, and demonstrated characteristic negative staining for CD3, CD5, and CD43, positive staining for CD20, and monotypic staining for either kappa or lambda light chain immunoglobulin markers. All patients achieved complete remission after primary therapy, and all remain free of disease with follow-up ranging from 6 to 54 months (mean 33 months). The diagnosis of MALT lymphoma should be considered in cases of atypical lymphoid infiltrates in the head and neck, and increased awareness coupled with detailed immunohistochemical analysis is essential to securing an accurate diagnosis. Clinical remission of MALT lymphoma may be achieved with several modalities, but further study will be required to determine the long-term response to treatment.

Human eosinophil Charcot-Leyden crystal protein: cloning and characterization of a lysophospholipase gene promoter.

The Charcot-Leyden crystal (CLC) protein is a lysophospholipase expressed exclusively by eosinophils and basophils. During eosinophilic differentiation of eosinophil-committed cell lines, CLC steady state mRNA levels increase significantly. This increased expression is transcriptionally regulated during butyrate induction of an eosinophilic subline (C15) of the promyelocytic leukemia cell line HL-60, as shown by nuclear run-on assays. The transcriptional start site of the CLC gene was identified 43 bp upstream of the 5' end of the longest available cDNA sequence. The gene encoding CLC protein was cloned from a chromosome 19-specific library and a fragment overlapping the transcriptional start site was isolated and sequenced. Plasmid constructs (in the pXP2 luciferase expression vector) containing 411 and 292 bp of genomic sequence upstream of the CLC transcriptional start site directed reporter gene expression in transient transfections of HL-60-C15 cells, as well as other myeloid (U937) and nonmyeloid (HeLa and RPMI 8402) cell lines. However, the differential expression of the two CLC promoter constructs in these cell lines suggests that the -292 to -411 bp region of the promoter may confer some specificity for expression in the eosinophil lineage. The CLC promoter sequence contains two consensus GATA binding sites, a purine-rich sequence that presents potential binding sites for PU.1, a member of the ets family of genes, as well as sequences described in other myeloid-specific promoters. This is the first demonstration of a functional eosinophil promoter that could serve as a model for identifying DNA elements and trans-activating factors that regulate gene expression during the commitment and differentiation of the eosinophil lineage.

Discordant disappearance of bioactive and immunoreactive parathyroid hormone after parathyroidectomy.

The disappearance of plasma PTH after parathyroidectomy was assessed in patients with primary hyperparathyroidism and normal renal function, chronic renal failure or restored renal function (after transplantation). Plasma PTH levels were determined by renal cytochemical bioassay and by midregion and carboxyl-terminal RIAs. Baseline PTH levels were lower in each patient when assessed by bioassay than when determined by RIA, and the rate of hormone disappearance was faster when determined by bioassay than when measured by RIA. This difference was accentuated in chronic renal failure due to prolongation of the disappearance rates of midregion and carboxyl-terminal immunoreactivity. The half-life of bioassayable hormone in patients with chronic renal failure was prolonged less than 2-fold compared to the half-life in patients with normal or restored renal function. The results emphasize the discordance between levels of bioactive and immunoreactive hormone regardless of renal function, demonstrate that this discordance is augmented after acute reduction in circulating hormone, and show that it is further increased when kidney function is impaired. The studies also implicate extrarenal mechanisms as a major factor in the clearance of bioactive hormone in established renal failure.