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 (j-value ¼ 0.34). The intraobserver j-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 j-value ¼ 0.50) was observed (P ¼ 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.
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 1week 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.Waldenstrom's macroglobulinemia (WM) is a B-cell disorder characterized primarily by bone marrow infiltration with lymphoplasmacytic cells along with demonstration of an IgM monoclonal gammopathy (1). This condition is considered to be lymphoplasmacytic lymphoma as defined by the REAL and WHO classification systems (2, 3). Despite advances in therapy, WM remains incurable. As such, novel therapeutic agents are needed for the treatment of WM.One class of therapeutics that has been successfully used in patients with WM are monoclonal antibodies. Both rituximab and alemtuzumab have been evaluated in WM as single agents with major response rates of 30% to 40%, whereas the combination of rituximab with chemotherapy has resulted in response rates of 70% to 90% (4). With the attainment of higher response rates with chemo-antibody therapy, considerably more short-term and long-term toxicities have been reported (4, 5). In an effort to augment monoclonal antibody responses in WM patients while averting short-term and longterm chemotherapy-induced toxicities, we have sought the development of immunomodulatory agents for combination with rituximab. Thalidomide and its more potent immunomodulatory derivative lenalidomide augment antibodydependent cell-mediated cytotoxicity (5). Moreover, these agents also lead to expansion of natural killer cells, which serve as important effector cells for rituximab activity in patients with indolent non-Hodgkin's lymphoma (6 -9). As a follow-up to these findings, we recently performed a clinical trial exploring the ...
Background and Objectives. Few therapeutic options are presently available for patients with multiple myeloma (MM) who relapse after autologous or allogeneic stem cell transplantation, or for patients who are refractory to conventional chemotherapy and not eligible for salvage high‐dose therapy. Thalidomide, a glutamic acid derivative with anti‐angiogenic properties, has been recently proposed as an effective therapy for patients with advanced refractory disease. The aim of this study was to evaluate the activity of thalidomide in a large series of MM patients. Design and Methods. From October 1999 to January 2001, 65 patients (46 males/19 females) from 8 Italian institutions were treated with thalidomide. Twenty‐six patients had relapsed after autologous stem cell transplantation, either single (n = 12) or double (n= 12); 38 patients had shown disease progression after greater than or equal to 2 lines of conventional chemotherapy, 2 patients had relapsed after allotransplant, one single patient had not received previous treatment. Sixty‐one (93.8%) patients were in stage 111, median beta2 microglobulin was 2.9 mg/L, and median bone marrow plasma cell infiltration was 50%. Thalidomide was initially administered at a dose of 100 mg/day; if well tolerated, the dose was to be increased serially by 200 mg every other week to a maximum of 800 mg/day. Results. The median administered dose of thalidomide was 400 mg/day. WHO grade> II toxic effects were constipation (52%), lethargy (34%), skin rash (11%), peripheral neuropathy (14%) and leukopenia (3%). Sixty patients are presently evaluable for response; of these, 17 (28.3%) showed greater than or equal to 50% reduction in serum or urinary M protein concentration and 11 (18.3%) showed greater than or equal to 25% tumor reduction, for a total response rate averaging 46.6%. After a median of 8 months' follow‐up, 15/28 patients are alive and progression‐free (at 2 to 16 months), 12 patients have relapsed, and 1 patient died of pulmonary edema while still in partial remission. Among pre‐treatment variables that were analyzed for their potential relationship with tumor response, only the concentration of vascular endothelial growth factor (VEGF) in the conditioned media obtained upon culture of bone marrow plasma cells was statistically significant. Plasma cells from patients who responded favorably to thalidomide secreted a significantly lower amount of VEGF than plasma cells from resistant patients (126.45 ± 165 pg/mL vs 227.11 ± 70 pg/mL, p = 0.04). Interpretation and Conclusions. These data confirm that thalidomide is active in patients with advanced relapsed/ refractory MM and represent the basis for ongoing clinical trials aimed at testing the role of this drug as front line therapy for newly diagnosed disease.
Thalidomide enhances rituximab-mediated, antibody-dependent, cell-mediated cytotoxicity. We therefore conducted a phase 2 study using thalidomide and rituximab in symptomatic Walden-strom 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. Thalido-mide in combination with rituximab is active and produces long-term responses in WM. Lower doses of thalidomide (ie, < 200 mg/day) should be considered given the high frequency of treatment-related neuropathy in this patient population. This trial is registered at www. clinicaltrials.gov as #NCT00142116. (Blood. 2008;112:4452-4457) Introduction Monoclonal antibodies have been successfully used to treat patients with B-cell malignancies, including Waldenstrom macroglobu-linemia (WM). Most of these efforts have focused on the use of rituximab, a chimeric human IgG 1 monoclonal antibody, which targets CD20, which is widely expressed in WM. 1,2 Studies using standard-dose rituximab therapy have demonstrated activity in WM, with overall response rates of 27% to 35% and median durations of response from 8 to 27 months. 2-7 More recently, the use of extended schedule rituximab has been evaluated wherein patients received 8 infusions of rituximab (375 mg/m 2 per week) at weeks 1 to 4 and 12 to 16. Overall response rates of 44% to 48% were observed in these studies, with median durations of response from 16 to 29 months. 8,9 Among WM patients receiving rituximab as monotherapy, lower response rates have been observed in those patients with high serum IgM (6000 mg/dL) and beta-2 microglobulin (B 2 M; 3.0 mg/L) levels, as well as homozygous expression of phenylalanine at amino acid position 158 on CD16 (FcRIIIA-158). 8-10 Studies combining rituximab with chemotherapy have also been explored in WM. 11 The combination of nucleoside analogs plus rituximab has yielded major response rates of 70% to 90%, 12-15 whereas the combinations of CHOP-R (cyclophosphamide, adria-mycin, vincristine, prednisone, rituximab) or DC-R (dexametha-sone, cyclophosphamide, rituximab) have resulted in response rates of 80% to 90%. 16-18 Median time to progression (TTP) in excess of 3 years has been reported with these combinations. Although these combinations have produced more impressive responses, greater toxi...
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