A phase II clinical and pharmacodynamic study of E7070 in patients with metastatic, recurrent, or refractory squamous cell carcinoma of the head and neck: modulation of retinoblastoma protein phosphorylation by a novel chloroindolyl sulfonamide cell cycle inhibitor.

PURPOSE: E7070 is a synthetic sulfonamide cell cycle inhibitor that induces hypophosphorylation of the retinoblastoma (Rb) protein and G(1) arrest in vitro. This Phase II study was conducted to explore the efficacy, safety, and pharmacodynamics of E7070 in squamous cell carcinoma of the head and neck (SCCHN). EXPERIMENTAL DESIGN: Patients with metastatic, recurrent, or refractory SCCHN, treated with no more than one prior therapy for recurrent disease, received E7070 at 700 mg/m(2) over 1 h every 3 weeks. Pre- and posttreatment tumor fine needle aspirates were subjected to immunohistochemistry with a panel of phospho-specific anti-Rb antibodies. End points included progression-free survival, response rate and duration, overall survival, toxicity profile, and inhibition of Rb phosphorylation. RESULTS: Because none of the first 15 patients achieved progression-free survival > 4 months, the early stopping rule was invoked. Eleven patients had oropharyngeal cancer and 12 were male. Median age was 59 years (range, 49-73 years). Thirty-nine cycles of E7070 were delivered (median, 2.6 cycles/patient; range, 1-5 cycles). Six patients had stable disease after 2 cycles and 2 patients each subsequently received 1, 2, and 3 additional cycles, respectively, before experiencing progression. Immunohistochemistry of tumor cell aspirates from 3 patients demonstrated reduced Rb phosphorylation posttreatment. CONCLUSIONS: At this dose and schedule, E7070 is unlikely to be superior over single-agent chemotherapy in SCCHN. However, the data suggest that cdk activity can be inhibited in tumor cells, resulting in posttreatment modulation of Rb phosphorylation. In the absence of cytotoxicity, more frequent administration of E7070 may be required to sustain Rb hypophosphorylation and cytostatic growth arrest.

Metastatic mammary carcinomas with endocrine features: potential diagnostic pitfalls.

Mammary carcinomas with endocrine differentiation (MCED) are an uncommon subtype of breast carcinomas that are morphologically indistinguishable from low-grade endocrine neoplasms arising in other organs. Aspirates of MCED yield relatively monotonous cells with eccentrically placed nuclei containing characteristic "salt and pepper" chromatin. In the breast, these features represent MCED. In extramammary sites, the differential is more extensive, and diagnosing MCED metastases to the lung, a common location for primary and metastatic endocrine tumors, can be a challenging task, with significant clinical implications. Although primary MCED have been described extensively in the cytology literature, secondary pulmonary MCED have not been reported to the best of our knowledge. We report three cases of MCED metastatic to the lung and present the cytological and immunohistochemical features.

Combined fludarabine and rituximab for low grade lymphoma and chronic lymphocytic leukemia.

As both fludarabine and rituximab are active against indolent lymphoproliferative disorders, we have studied the combination of fludarabine and rituximab in patients with low-grade lymphoma and chronic lymphocytic leukemia (CLL) in phase I/II fashion. Of 33 patients enrolled, 21(63.6%) had low-grade lymphoma and 12 (36.4%) had CLL. They received fludarabine 30 mg/m2 on days 1-4 and rituximab 125, 250 or 375 mg/m2 on day 5 at intervals of 28 days to a maximum of 8 cycles. Three patients were removed from the study because of rituximab-associated anaphylaxis and four because of prolonged hematopoietic toxicity. Toxicity and responsiveness did not differ at the different dose levels of rituximab. For 29 evaluable patients, responses were seen in 82.8% and complete responses in 34.5%. Of 7 responding patients not referred for stem cell transplantation, 6 remain in complete remission at a median follow-up of 16 months (range 4-30 months). Of 13 previously untreated patients, all responded and 46.2% had a complete response. Of 16 previously treated patients, 68.5% responded and 25% had a complete response. The combination of fludarabine and rituximab has major activity and acceptable toxicity in patients with low-grade lymphoma and CLL.

Prognostic value of miR-375 and miR-214-3p in early stage oral squamous cell carcinoma.

MicroRNAs (miRs) control cell growth, apoptosis and differentiation, and thus play a key role in carcinogenesis. Identification of a set of miRs that demonstrate differential expression in oral squamous cell carcinoma (OSCC) patients with poor prognosis has potential for utility as a prognostic marker. A retrospective study of miR expression was conducted in 20 tissue samples from early stage (Stages I & II) OSCC patients with known clinical outcome (10 from those who had 5-year disease free survival and 10 who died of disease within 5 years) using genome-wide deep sequencing analysis. The promising miR candidates were then validated in 80 tissue samples using quantitative real-time PCR (qRT-PCR). The deep sequencing and qRT-PCR analysis identified two promising miRs, miR-375 and miR-214-3p. Combining the two miRs as a panel with age and gender had a predictive value for the area under the curve (AUC) of 0.932, with a sensitivity of 87.5% and a specificity of 87.2% (p<0.0001) to identify patients with poor prognosis. A miR-based prognostic risk score model was constructed, which included the miR-214-3p, miR-375, age and gender, each weighed by relative contribution. The risk score model was able to identify high-risk individuals who had significantly shorter time to relapse (p<0.001) and time to death (p<0.001). The model consisting of a two-miR panel with age and gender may be useful in prognostication of early stage OSCC patients, which can aid in identifying patients with poor prognosis who will benefit from a subsequent aggressive treatment regimen.