First report of pulmonary large cell neuroendocrine carcinoma treated with stereotactic body radiation therapy.

INTRODUCTION: Pulmonary large-cell neuroendocrine carcinoma (LCNEC) is a very rare disease, comprising approximately 3% of lung cancers. Even for Stage I disease, recurrence after resection is common, with a poor five-year overall survival. We present the first report of stereotactic body radiotherapy (SBRT) for pulmonary LCNEC. METHODS: A 54-year-old woman with a left upper lobe pulmonary nodule underwent a wedge resection with thoracoscopic mediastinal lymph node dissection, revealing a 2.3 cm pT1b N0 LCNEC. Approximately one year later, surveillance imaging demonstrated a new left upper lobe PET-avid nodule, resulting in completion left upper lobectomy revealing LCNEC, with 0/6 involved lymph nodes and negative staging studies. The patient subsequently chose surveillance over adjuvant chemotherapy; unfortunately 23 months later imaging revealed an enlarging 0.7 cm nodule adjacent to the previous resection site, despite the patient remaining in good health (KPS = 90). Subsequent restaging demonstrated no evidence of metastatic disease. Due to the morbidity of a third operation in this region, and based on the safety of SBRT for Stage I non small-cell lung cancer, the consensus decision from our thoracic oncology team was to proceed with SBRT as preferred management for presumptive second recurrence of LCNEC. The patient shortly thereafter underwent SBRT (50 Gy in 10 Gy/fraction) to this new nodule, 41 months following initial LCNEC diagnosis. RESULTS: Four months following SBRT, the patient remains in excellent clinical condition (KPS 90), with no evidence of disease spread on surveillance studies. The nodule itself demonstrated no evidence of growth following SBRT. CONCLUSIONS: This first report of SBRT for pulmonary LCNEC demonstrates that SBRT is a feasible modality for this rare disease. A multidisciplinary thoracic oncology approach involving medical oncology, thoracic surgery, radiation oncology and pulmonology is strongly recommended to ensure proper patient selection for receipt of SBRT.

Atypical ductal hyperplasia: interobserver and intraobserver variability.

Interobserver reproducibility in the diagnosis of benign intraductal proliferative lesions has been poor. The aims of the study were to investigate the inter- and intraobserver variability and the impact of the addition of an immunostain for high- and low-molecular weight keratins on the variability. Nine pathologists reviewed 81 cases of breast proliferative lesions in three stages and assigned each of the lesions to one of the following three diagnoses: usual ductal hyperplasia, atypical ductal hyperplasia and ductal carcinoma in situ. Hematoxylin and eosin slides and corresponding slides stained with ADH-5 cocktail (cytokeratins (CK) 5, 14. 7, 18 and p63) by immunohistochemistry were evaluated. Concordance was evaluated at each stage of the study. The interobserver agreement among the nine pathologists for diagnosing the 81 proliferative breast lesions was fair (κ-value=0.34). The intraobserver κ-value ranged from 0.56 to 0.88 (moderate to strong). Complete agreement among nine pathologists was achieved in only nine (11%) cases, at least eight agreed in 20 (25%) cases and seven or more agreed in 38 (47%) cases. Following immunohistochemical stain, a significant improvement in the interobserver concordance (overall κ-value=0.50) was observed (P=0.015). There was a significant reduction in the total number of atypical ductal hyperplasia diagnosis made by nine pathologists after the use of ADH-5 immunostain. Atypical ductal hyperplasia still remains a diagnostic dilemma with wide variation in both inter- and intraobserver reproducibility among pathologists. The addition of an immunohistochemical stain led to a significant improvement in the concordance rate. More importantly, there was an 8% decrease in the number of lesions classified as atypical ductal hyperplasia in favor of usual hyperplasia; in clinical practice, this could lead to a decrease in the number of surgeries carried out for intraductal proliferative lesions.

Lenalidomide and rituximab in Waldenstrom's macroglobulinemia.

PURPOSE: Thalidomide and its more potent immunomodulatory derivative lenalidomide enhance rituximab-mediated antibody-dependent cell-mediated cytotoxicity. We therefore evaluated lenalidomide and rituximab in symptomatic Waldenstrom's macroglobulinemia (WM) patients naive to either agent. EXPERIMENTAL DESIGN: Intended therapy consisted of 48 weeks of lenalidomide (25 mg/d for 3 weeks and then 1 week off) along with rituximab (375 mg/m(2)/wk) dosed on weeks 2 to 5 and 13 to 16. Sixteen patients were enrolled, 12 of whom were previously untreated. RESULTS: Unexpectedly, we observed an acute decrease in hematocrit in 13 of 16 patients (median hematocrit decrease, 4.8%), which was attributable to lenalidomide patients and which led to cessation of further enrollment on this study. Lenalidomide-related anemia was observed even at doses as low as 5 mg/d and occurred in the absence of hemolysis or other cytopenias. The overall response and major response (<50% decrease in serum IgM) rates were 50% and 25%, respectively, on an intent-to-treat basis. With a median follow-up of 31.3 months, 4 of 8 responding patients have progressed with a median time to progression of 18.9 months. CONCLUSION: Lenalidomide produces unexpected but clinically significant acute anemia in patients with WM. In comparison with our previous study with thalidomide and rituximab in an analogous patient population, the responses achieved in WM patients with lenalidomide and rituximab appear less favorable.

Thalidomide and rituximab in Waldenstrom macroglobulinemia.

Thalidomide enhances rituximab-mediated, antibody-dependent, cell-mediated cytotoxicity. We therefore conducted a phase 2 study using thalidomide and rituximab in symptomatic Waldenstrom macroglobulinemia (WM) patients naive to either agent. Intended therapy consisted of daily thalidomide (200 mg for 2 weeks, then 400 mg for 50 weeks) and rituximab (375 mg/m(2) per week) dosed on weeks 2 to 5 and 13 to 16. Twenty-five patients were enrolled, 20 of whom were untreated. Responses were complete response (n = 1), partial response (n = 15), and major response (n = 2), for overall and major response rate of 72% and 64%, respectively, on an intent-to-treat basis. Median serum IgM decreased from 3670 to 1590 mg/dL (P < .001), whereas median hematocrit rose from 33.0% to 37.6% (P = .004) at best response. Median time to progression for responders was 38 months. Peripheral neuropathy to thalidomide was the most common adverse event. Among 11 patients experiencing grade 2 or greater neuropathy, 10 resolved to grade 1 or less at a median of 6.7 months. Thalidomide in combination with rituximab is active and produces long-term responses in WM. Lower doses of thalidomide (ie,