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Background: Several neoadjuvant trials have been conducted directed at treating triple negative breast cancer (TNBC) patients with platinum agents with pathologic complete response (pCR) rates ranging from 16%-32%. Eribulin mesylate, a nontaxane microtubule dynamics inhibitor with a novel mechanism of action, has clinical activity as monotherapy in breast cancer and other solid tumors. A recent phase I trial found that the combination of eribulin mesylate with carboplatin was well tolerated and showed activity in advanced solid tumors. The recommended dose for future trials was eribulin mesylate 1.1 mg/m2 and carboplatin AUC6. We proposed a neoadjuvant phase II trial with the combination of carboplatin and eribulin in patients with TNBC. Methods: 30 patients were enrolled between November 2011 and February 2013. Patients received eribulin at 1.4 mg/m2 (intravenously over 2-5 minutes) on days 1 and 8 followed by carboplatin AUC = 6 (intravenously over 30 minutes) on day 1 every 21 days for a total of 4 cycles. Definitive surgery was performed 3-8 weeks after completion of therapy. Our primary endpoint was to determine the pCR in TNBC patients treated with the combination of carboplatin and eribulin. Secondary objectives included determination of the clinical response rate, residual cancer burden (RCB), toxicity evaluation, in addition to correlative markers including TLE3, Smad3, cyclins/CDKs, and PIN1 and the Homologous Recombination Deficiency Assay (HRD). Results: There was an initial safety run-in to evaluate the appropriate dose of eribulin in the study population. After the 10th patient, the study was temporarily suspended; toxicity was assessed for the first 10 patients (cycle 1 only) to assess whether eribulin at 1.4mg/m2 or a dose reduction to 1.1 mg/m2 would be required for the remaining patients. Of the first 10 patients, only 2 of 10 experienced grade 3 or 4 neutropenia, and 0 of 10 patients experienced grade 3 or 4 peripheral neuropathy. Therefore, the study was continued for the remaining 20 patients with eribulin dosed at 1.4 mg/m2 and carboplatin AUC = 6. Thirty of the planned 30 patients have been enrolled to date. Of the 30 patients, 24 have completed therapy and 6 are currently on study. Of the 24 patients who have completed therapy, 11 have achieved a pCR (45.83%). As for clinical response rates, 5 have had stable disease (20.8%), 5 have had a complete response (20.8%), and 13 have had a partial response (54.2%). Final results will be presented at the time of the meeting including pCR, RCB, toxicity and correlative studies. The combination of eribulin and carboplatin was well tolerated with a predictable side effect profile. Of the 24 patients who have completed therapy, 8 (33%) required a dose reduction in eribulin for grade 3 or 4 neutropenia. One patient had neutropenic fever. There were no dose reductions for thrombocytopenia thus far. Correlative studies are in progress. Conclusion: The combination of carboplatin and eribulin in the neoadjuvant setting appears to be safe and efficacious in patients with TNBC. Statistical analysis on outcomes for the entire study population and correlative study results on pre- and post-treatment tissues are forthcoming. Future randomized clinical trials should evaluate further this regimen. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-14-14.

Because three-dimensional (3D) in vitro models are more accurate than 2D cell culture models and faster and cheaper than animal models, they have become a prospective trend in the biomedical and pharmaceutical fields, especially for personalized and targeted therapies. Because appropriate 3D models can be customized to mimic the in vivo microenvironment wherein various cell populations grow within an intricate but well organized extracellular matrix (ECM), they can accurately recapitulate physiological and pathophysiological progressions. The majority of cancers are carcinomas, which originate from epithelial cells, and dynamically interact with non-malignant cells including stromal cells (fibroblasts), vascular cells (endothelial cells and pericytes), immune cells (macrophages and mast cells), and the ECM. Employing a tumor monoclonal colony, tumor xenograft or patient cancer biopsy into an in vivo-like microenvironment, the native signaling pathways, cell-cell and cell-matrix interactions, and cell phenotypes are preserved and our fluorescent phenotypic 3D co-culture platforms can then accurately recapitulate the tumor in vivo scenario including tumor induced angiogenesis, tumor growth, and metastasis. In this paper, we describe a robust and standardized method to co-culture a tumor colony or biopsy with different cell populations, e.g., endothelial cells, immune cells, pericytes, etc. The procedures for recovering cells from the co-culture for molecular analyses, imaging, and analyzing are also described. We selected ECM solubilized extract derived from Engelbreth-Holm-Swam sarcoma cells. Because the 3D co-culture platforms can provide drug chemosensitivity data within 9 days that is equivalent to the results generated from mouse tumor xenograft models in 50 days, the 3D co-culture platforms are more accurate, efficient, and cost-effective and may replace animal models in the near future to predict drug efficacy, personalize therapies, prevent drug resistance, and improve the quality of life.

The inclusion of medically vulnerable population in research is required to improve population health. Ethnic Minorities are among the most medically underserved, and represent 40% of the US population. Hence, ethnic minority inclusion in biomedical research is essential to ensure optimal applicability and benefit of medical advancements. Informed by the Community Health Educator (CHE) program of the NCI-CRCHD and charged by our Cancer Center goal to reduce the burden of cancer within our Catchment area communities, we created and tested our Partnered for Inclusion and Access in Research (PAIR) model to increase community responsiveness and minority participation in our research. First, using a team science community engaged approach, our research institute – including basic, translational, clinical and population researchers – aligned with our clinical care, hospital component to form a common Community Advisory Council (CAC). The CAC enhances the integrated representation of the community’s voice within our research and practice. Our CAC, therefore, serves as a resource in reaching other community advisors for targeted research and community benefit programs. For example, our CAC facilitated the inclusion of African American, Chinese and Latino communities for our U01 project investigating breast cancer and the environment. Secondly, in collaboration with community partners including ACS, we are training community research navigators to broaden our reach, and increase community capacity to engage with researchers and participate in research, as well as address their pressing health concerns. Thirdly, we created a culturally and linguistically tailored brief video promoting Latino participation in clinical trials (CT), biospecimen studies (BB) and population research. This video is used in combination with direct referral to a research study with the intent of increasing awareness, acceptability, access and participation of Latinos in CT, BB and population research. Our report focusing on a BB study with Latinas, show that, to date a total of 372 women were accrued resulting in an 88% BB enrollment. Therefore, our community engaged, culturally and linguistically appropriate PAIR model demonstrates utility and effectiveness in engaging ethnic minorities and in particular Latinos in biomedical research. Future plans include continued, expanded face-to-face and technology platform dissemination of PAIR. Citation Format: Kimlin Ashing, Mayra Serrano, Steve Rosen, Marisela Huerta, Katty Nerio, Alejandro Fernandez, Lisa Dowd, Phyllis Clark, Lucy Young, Mary Ann Van Duyen, Precilla Belin. Using community team science: An advocacy engaged approach to recruit ethnic minorities in cancer research [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-052. doi:10.1158/1538-7445.AM2017-LB-052

Eleven patients with hematologic malignancies and two with aplastic anemia were treated using unmanipulated marrow and immunoselected CD34+ blood cells. Donors began G-CSF (10 microg/kg) injections 1 day after undergoing bone marrow harvest. Blood stem cells were collected on day 5 of G-CSF. Peripheral blood lymphocytes were depleted via CD34-positive selection. If, after marrow and blood harvest, less than 2.0 x 10(6) CD34 cells/kg were mobilized, leukapheresis was repeated on day 6. Median time to an absolute neutrophil count greater than 500 microl was day 10; transfusion-independent platelet count greater than 20,000/microl was day 13; average hospital discharge was day 14; and average inpatient hospital charges were 101,870 US dollars. Acute GVHD grade II occurred in five of 13 patients. No patient developed grade III or IV acute GVHD. At a median follow-up of 10 months, no patient has developed extensive chronic GVHD. Allografts of unmanipulated bone marrow supplemented with G-CSF-mobilized and CD34 immunoselected blood cells may prevent an increased risk of GVHD while preserving the rapid engraftment kinetics of peripheral blood. Supplementation of marrow with CD34 enriched blood cells appears to result in rapid engraftment, early hospital discharge, lower inpatient charges, decreased regimen-related toxicity, and no apparent increase in GVHD.

Peripheral blood or bone marrow cells of 15 patients with chronic lymphocytic leukemia (CLL) were separated on an albumin density gradient. In 5 of 5 CLL patients, the distribution of malignant B lymphocytes was similar across the gradient when blood and bone marrow were compared, but different from the distribution of cells from healthy volunteers. In 10 patients, B cell colony formation was measured in vitro from peripheral blood cells after gradient fractionation. Although most of the cells in all patients were found in fraction 4, the majority of B-lymphocyte colonies were found in light density fractions (1+2, 3) in patients with more advanced disease (Rai stages 3 or 4), and in heavier fractions (4, bottom) in patients with less advanced disease (Rai stages 0, 1 or 2). The density of CLL cells might provide a new prognostic marker in this disease.

Mantle cell lymphoma (MCL) exhibits considerable molecular heterogeneity and complexity, and is regarded as one of the most challenging lymphomas to treat. With increased understanding of the pathobiology of MCL, it is proposed that MCL is the result of 3 major converging factors, namely, deregulated cell cycle pathways, defects in DNA damage responses, and dysregulation of cell survival pathways. In the present era of targeted therapies, these biologic insights have resulted in the identification of several novel rational targets for therapeutic intervention in MCL that are undergoing active clinical testing. To date, there is no standard of care in MCL. Several approaches including conventional anthracycline-based therapies and intensive high-dose strategies with and without stem cell transplantation have failed to produce durable remissions for most patients. Moreover, considering the heterogeneity of MCL, it is increasingly being recognized that risk-adapted therapy might be a relevant therapeutic approach in this disease. At the first and second Global Workshops on Mantle Cell Lymphoma, questions addressing advances in the pathobiology of MCL, optimization of existing therapies, assessment of current data with novel therapeutic strategies, and the identification of molecular or phenotypic risk factors for utilization in risk-adapted therapies were discussed and will be summarized herein.

Mycosis fungoides (MF) and the Sézary syndrome (SS) are non-Hodgkin's lymphomas with a T-cell phenotype, which have cutaneous involvement as their predominant feature. These disorders are becoming more common, and the patients are frequently being referred to medical oncologists for assistance in management. The development of advanced laboratory techniques, such as molecular genetics and cell-surface phenotyping, has greatly enhanced our understanding of their pathogenesis and may lead to identification of responsible etiologic factors. A myriad of treatment options have been investigated including topical approaches, systemic chemotherapy, and external radiation. Currently, extensive trials are underway examining the potential benefits of agents such as the interferons, interleukin-2, monoclonal antibodies, the retinoids, 2-chlorodeoxyadenosine, and other novel biologic response modifiers or chemotherapeutics. Although all these therapies have benefit in phase II trials, few randomized comparative trials have been performed to identify optimal therapies. Performance of such trials should now become a priority.

Mycosis Fungoides and Sezary Syndrome are the most common types of cutaneous T-cell lymphomas. There is no current standard of care for Mycosis Fungoides/Sezary Syndrome, with a general tendency to rely on topical interventions for early disease delaying systemic, more toxic therapy until the development of extensive symptoms. Knowledge of the biological characteristics of this disease has allowed for the development of rational interventions and a significant advance in its treatment. Retinoids are active in Mycosis Fungoides/Sezary Syndrome with the newer rexinoids being available in topical and systemic forms. Interferon alpha remains one of the most active therapeutic agents for Mycosis Fungoides/Sezary Syndrome, especially in combination with other agents such as PUVA. The monoclonal antibody alemtuzumab leads to responses in at least half of patients with advanced disease with its side effect profile consisting mainly of immunosupression and infusion reactions. The recombinant IL2-diphteria toxin denileukin diftitox (Ontak) is active in this disease and appears to have a beneficial effect in symptoms relief and quality of life. Extracorporeal photochemotherapy as an immunostimulating intervention seems to be very effective in a subset of patients, but its availability is limited to less than a hundred centers worldwide. Experimental and less studied interventions include autologous and allogeneic peripheral stem cell transplantation, Interleukin-12, the histone-deacetylator depsipeptide and the synthetic deoxynucleotide CpG7909. Cutaneous T-cell lymphoma has served as a paradigm for the development of biological agents. Further knowledge of the signaling pathways in Mycosis Fungoides/Sezary Syndrome will allow for the development of more effective treatment strategies.

Cutaneous T-Cell Lymphomas (CTCL) represent a heterogeneous group of hematopoietic malignancies that account for 5-10% of Non-Hodgkin Lymphomas. The initial disease presentation is characterized by the infiltration of the skin by malignant clonal CD4+ lymphocytes that possess a mature memory helper T-cell phenotype. CTCL patients present in a spectrum of defined disease phenotypes, Mycosis Fungoides (MF) and Sézary Syndrome (SS) being the most common. Thus, it is not surprising that no underlying molecular basis for disease has been identified. Standard treatment protocols are designed to provide palliation, as no chemotherapeutic compound(s) has demonstrated increased long-term or disease-free survival. Currently, no curative therapy for CTCL exists. Our long-term goal is to gain a better understanding of the pathways governing CTCL cell survival and proliferation while identifying druggable targets for the development of new and more effective therapeutics. The principles of chemical biology, to discover and elucidate molecular pathways fundamental in cellular, developmental, and disease biology through synthetic organic chemistry, are readily applied to the field drug discovery. Using these methods, we have previously observed that inhibition of protein kinase C (PKC) β with the small molecule Enzastaurin (Enz), combined with inhibition of glycogen synthase kinase 3 (GSK3) with AR-A014418 (ARA), causes synergistic apoptosis in CTCL cell lines (Hut78 and H9) and patient cells. Further investigations have shown combined treatment with Enz and ARA increased β-catenin protein levels and that β-catenin downstream transcription activation negatively impacts CTCL viability. However, β-catenin alone is not sufficient to induce CTCL apoptosis. These data indicate there are additional mechanisms of cell death stimulated by the combined inhibition of PKC and GSK3. To identify the β-catenin independent targets of combined PKC and GSK3 inhibition, we have assayed drug-treatment induced changes in global gene expression through a microarray approach. We have identified transcripts that are significantly regulated after combined inhibition of PKC and GSK3 with Enz, ARA, and a combination of both small molecules. We are focusing our efforts on those targets and signaling pathways that are minimally regulated by each drug alone (or no change at all), but are dramatically impacted by the combination treatment to identify mechanisms of synergy. Using Gene Set Enrichment Analysis (GSEA), we noted enrichment in two pathways that are key to T-cell viability, namely the T-cell receptor (TCR) pathway and interferon response pathway. To elucidate candidate genes that may have therapeutic importance and to further explore the clinical relevance of our data set, in a pilot study, we interrogated the gene expression profile of a set of CTCL patients normalized to normal CD4+ T-cells. We then selected those genes whose expression is negatively correlated between CTCL patients and drug treated CTCL cell lines. From this pilot study, we have identified members of the TCR pathway that are over-expressed in CTCL patients and strikingly down-regulated by combined inhibition of PKC and GSK3. Taken together, these observations prompted us to further explore genes of the TCR signaling cascade as potential therapeutic targets. These data will provide the basis for downstream target identification for further drug development. Disclosures: No relevant conflicts of interest to declare.

e16576 Background: Bisphosphonates, in particular zoledronic acid (ZA), have been associated with renal toxicity manifested as deterioration in renal function and potential renal failure. Preclinic...

6090 Background: The timely identification of unknown toxicities of cancer drugs is an important, unsolved problem. Because of their cytotoxic effects, distinguishing cancer drug toxicity from dise...

Background: Lapatinib, a dual kinase inhibitor against EGFR and HER2, has activity in metastatic HER2+ breast cancer. Nab-paclitaxel has been found to be one of the most active agents in metastatic breast cancer. Its combination has not been studied in the neoadjuvant setting. We have conducted a pilot neoadjuvant trial in HER2+ patients (pts) combining lapatinib with nab-paclitaxel.Methods: Females with newly diagnosed breast cancer (stage I-III) received four cycles of lapatinib 1000 mg po/day and nab-paclitaxel 260mg /m2 IV every three weeks. Postoperative therapy was at the discretion of the investigator. The accrual goal of 30 pts has been met. The primary endpoint was clinical response rate (CRR) with secondary endpoints including pathologic complete response (pCR), toxicity, and proliferation, apoptosis and angiogenesis markers.Results: A total of 28 pts have completed all therapy to date. The most common toxicities were rash, neuropathy, fatigue and myalgias. Most toxicities were grade 1/2 although one pt developed grade 3 rash and five pts grade 3 diarrhea. Nab-paclitaxel was dose reduced in 8 and lapatinib in 10 of 104 cycles. No cardiac toxicity was observed. Response data is available on 25 pts. CRR was 88% with four complete clinical responses and 18 patients with partial clinical response. Three patients had stable disease. Four patients achieved pCR.Summary of efficacy and toxicityResponse Non-hematologic ToxicityGrade 1/2Grade 3/4Hematologic toxicity Overall response22 (88%)Nausea7 (25%)1 (3.6%)Anemia9 (32.1%)Complete response4 (16%)Rash19 (67.8%)1 (3.6%) Partial response18 (72%)Fatigue17 (60.7%)2 (7.2%) Stable disease3 (12%)Neuropathy14 (50%)0 pCR4 (19.0%)Arthralgias/17 (60.7%)1 (3.6%) Diarrhea15 (53.6%)5 (17.9%) Conclusions: The combination of lapatinib and nab-paclitaxel is very active as first-line treatment in HER2+ breast cancer. Toxicities, including rash and diarrhea were observed and medically managed. Patients did not receive prophylactic medications for rash or diarrhea Updated clinical data on all 30 patients as well as correlative markers will be presented. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1091.

Background: Liposomal formulations such as pegylated liposomal doxorubicin (PLD) were developed to improve the therapeutic index and overall benefit of the anthracyclines (A). Lapatinib (L) is a selective and highly competitive inhibitor of ErbB1 and ErbB2 tyrosine kinases. The combination of conventional doxorubicin and an ErbB2 targeting agent (trastuzumab) was effective but led to an unacceptable risk of cardiac toxicity. The combination of PLD and L however may be effective with less cardiac risk. Methods: This is an open-label, phase I, dose-escalation trial of PLD at 20, 30, 45 and 60 mg/m2 IV every 4 weeks (maximum of 8 doses) and L, 1500 mg po daily until progression in patients (pts) with metastatic breast cancer (MBC). EGFR and/or ErbB2 positivity was not required. Prior chemotherapy, endocrine therapy and trastuzumab were allowed however prior A use was limited to 240 mg/m2 of doxorubicin or 600 mg/m2 of epirubicin. Initially, prior EGFR targeting therapies were not allowed however the trial was subsequently amended to allow prior lapatinib. Concomitant CYP3A4 inducers/ inhibitors were not allowed. A left ventricular ejection fraction (LVEF) of ≥ 50% was required. The primary objective was to evaluate the safety, tolerability and feasibility of the combination of PLD and L, particularly with respect to cardiac safety. MUGAs were performed at entry and every 8 weeks thereafter. Results: 16 patients (PLD: 20 mg/m2 - 4 pts; 30 mg/m2 - 3 pts; 45 mg/m2 – 6 pts; 60 mg/m2- 3 pts) with a mean age of 53 yrs (range, 33-68) have been treated for a total of 30 treatment cycles. Dose-limiting toxicity (DLT) was not reached. One pt experienced an LVEF drop to < 50% after 4 cycles however this was accompanied by a pericardial effusion felt to be secondary to progressive disease. Adverse events observed include: grade IV- mucus plugging and knee pain in 1 pt each; grade III- fatigue and hand-foot-syndrome (HFS) in 2 pts each and edema, diarrhea, dizziness, headache, stomatitis and skin toxicity in 1 pt each; grade I/II in ≥2 pts- anemia, leucopenia, fatigue, shortness of breath, pain, nausea, stomatitis, anorexia, diarrhea, increased alkaline phosphatase or transaminases, hypoalbuminemia and hyperglycemia. Preliminary response data in 11 evaluable pts reveals 1 PR, 3 SD, and 8 PD. Event-free and overall survival curves are as shown.Conclusions: In the first 16 pts treated, the combination of PLD and L has been well tolerated without treatment-related cardiac toxicity. One pt experienced an LVEF drop to < 50%, however this was felt likely to be disease-related. DLT was not reached however grade 3 HFS occurred in 2 out of 3 pts in the 60 mg/m2 cohort. A pharmacokinetic interaction cohort at the 45 mg/m2 dose is planned. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3096.

e20617 Background: Epidermal growth factor receptor inhibition by monoclonal antibodies and tyrosine kinase inhibitors has demonstrated activity in solid tumors. However, blockade of EGFR in skin results in disabling skin toxicity that may lead to therapeutic dose modification or interruption. This study compares cutaneous histological alterations among four EGFR inhibitors (EGFRIs): cetuximab (C), erlotinib (E), lapatinib (L) and panitumumab (P). Methods: Punch skin biopsies from patients with papulopustular rash were collected from 8 patients per each EGFRI (n=32). Two dermatopathologists performed independent blinded assessment of epidermis, dermis, follicle and inflammatory infiltrates. Histologic features were rated as 0 (absent) or 1 (present), with the exception of dyskeratosis, rated from 0 (absent) to 2 (severe) and infiltrate, rated from 0 (absent) to 3 (most prominent). Where variation occurred, scores were reconciled and combined for analysis. Results: Epidermal atrophy was observed for C, E, L and P (range 0–1, median 1, 1, 0, 0.5, respectively) and neutrophilic follicular infiltrate was observed for C, E, L and P (range 0–3, median 0.5, 3, 0, 3, respectively). Neutrophilic dermal infiltrate (range 0–3) and follicular neutrophilic pustules (range 0–1) were most prevalent in P (median 0.5), whereas the median for C, E and L was 0. A mononuclear dermal infiltrate (range 0–3) was least prevalent with C (median 0) while E, L and P had a median of 0.5. Concretions (range 0–1) were most prevalent for E (median 1), whereas the median for C, L and P was 0. Conclusions: Lapatinib, a dual ErbB1/2 inhibitor, induced the least structural disarray and inflammation in the skin as measured by median scores for epidermal atrophy, neutrophilic dermal and follicular infiltrates, neutrophilic pustules and lack of bacterial concretions. These histological data confirm a more benign pattern of rash with lapatinib compared to single ErbB1 inhibitors. [Table: see text]

8531 Background: Progressive multifocal leukoencephalopathy (PML) is a demyelinating disorder of the brain caused by the reactivation of latent JC polyoma virus. PML is associated with profound imm...

1079 Background: Liposomal formulations such as pegylated liposomal doxorubicin (PLD) were developed to improve the therapeutic index and overall benefit of the anthracyclines (A). L is a selective and highly competitive inhibitor of ErbB1 and ErbB2 tyrosine kinases. The combination of conventional doxorubicin and an ErbB2 targeting agent (trastuzumab), while effective, led in a randomized phase III trial to an unacceptable risk of cardiac toxicity. The combination of PLD and L however may be effective with less cardiac risk Methods: This is an open-label, phase I, dose-escalation trial of PLD at 20, 30, 45 and 60 mg/m2 IV every 4 weeks (maximum of 8 doses) and L, 1,500 mg po daily until progression in patients (pts) with MBC. EGFR and/or ErbB2 positivity was not required. Prior chemotherapy, endocrine therapy and trastuzumab were allowed however prior A use was limited to 240 mg/m2 of doxorubicin or 600 mg/m2 of epirubicin and prior EGFR targeting therapies were not allowed. Concomitant CYP3A4 inducers/ inhibitors were not allowed. A left ventricular ejection fraction (LVEF) of ≥ 50% was required. The primary objective was to evaluate the safety, tolerability and feasibility of the combination of PLD and L, particularly with respect to cardiac safety. MUGAs were performed at entry and every 8 weeks thereafter. Results: 7 patients (PLD: 20 mg/m2 - 3 pts; 30 mg/m2 - 3 pts; and 45 mg/m2 - 1 pt) with a mean age of 43 yrs (range, 33–68) have been treated for a total of 14 treatment cycles. Dose-limiting toxicity (DLT) has not been reached. One pt experienced an LVEF drop to < 50% after 4 cycles however this was accompanied by a pericardial effusion felt to be secondary to progressive disease. Adverse events observed include: grade III/IV- none; grade I/II in ≥2 pts- rash, nausea, and anorexia; grade II leukopenia, fatigue, alopecia, diarrhea, headache were also seen in 1 pt each. Preliminary response data in 4 evaluable pts reveals 1 PR, 1 SD, and 2 PD. Conclusions: In the first 7 pts treated, the combination of PLD and L has been well tolerated. One pt experienced an LVEF drop to < 50%, however this was felt likely to be disease-related. DLT has not yet been reached and accrual is ongoing. No significant financial relationships to disclose.

8039 Background: MCL has been historically classified as CD23-, but CD23+ immunophenotype (IP) is identified in a significant minority of patients (pts). It is unclear whether clinicopathologic or survival differences exist between CD23- and CD23+ MCLs. Methods: MCL diagnosis was based on morphology, IP with associated cyclinD1-positivity and/or t(11;14). We identified MCL pts treated at our institution from 1997–2006. We investigated IP (CD23 by flow cytometric analysis), pt characteristics, prognostic factors, and survival. Results: We identified 54 pts (16F/38M), of whom 89% had stage IV disease, IPI = 3 in 57%, 38% elevated LDH, 26% high B2- microglobulin, 30% bulky disease (= 7cm), and 39% with peripheral blood involvement. Thirty-three pts (61%) had CD23- disease, 14 (26%) CD23+ MCL, and 7 (13%) had variable CD23 expression (CD23+/CD23- varied in tissue sites). The only clinicopathologic differences between CD23- and CD23+ pts were increased incidence of extranodal disease (besides marrow or gastrointestinal [GI]) in the former (58% vs. 21%, respectively; p=0.029; most commonly lung or CNS disease); while splenomegaly was more common in the latter (71% vs. 42%; p=0.11). Ki67 staining was not predictive of CD23 status or survival among either IP. Treatment was overall similar in both CD23 groups. Table 1 shows survival for all pts and CD23- pts compared to CD23+ MCL. Cox regression prognostic analysis among all pts (n=54) showed that IPI = 3, bulky disease, and high B2-microglobulin were associated with inferior event-free survival (EFS), while CD23+ MCL and stem cell transplant in first remission were associated with improved EFS (all No significant financial relationships to disclose. [Table: see text]

Estrogen receptor (ER) determinations were performed on cytosol preparations of Ficoll-Hypaque density separated mononuclear cells from 11 patients with chronic lymphocytic leukemia (CLL). The presence of ER was noted in 8 of 11 specimens (73%). ER ranged from 431 fmole/mg to 4.3 fmole/mg cytosol protein. Two types of receptor subunits were observed at the 8S and 4S region of the sucrose gradient. In addition, 1 of 3 Epstein-Barr virus (EBV) transformed B-lymphoblastoid cell lines from healthy donors had a measurable amount of ER. Patient R.L., who was refractory to standard chemotherapy and radiation and was ER positive, experienced a minor response to Tamoxifen therapy, with subsequent loss of ER. The demonstration of ER in CLL suggests that this malignancy may have a hormone-dependent subpopulation of cells.

In this study, 212 untreated primary pulmonary and pleural neoplasms were studied immunohistochemically with the monoclonal antibody HYB-612 which detects the multidrug resistance (MDR)-related P-glycoprotein (gp180). A tumor was considered positive for the expression of the MDR phenotype, even if a single rare positive cell was detected. Using this criterion, all of the various histologic subtypes were found to express MDR to varying degrees. The frequency of expression of this phenotype was found to be notably higher in non-small-cell carcinomas than in small-cell carcinomas. These findings are consistent with the known clinical responses of these neoplasms. The detection of gp180 in untreated lung neoplasms may be predictive of the responsiveness of neoplasms to chemotherapeutic agents. In addition, its presence or absence might be useful in determining the appropriate treatment protocol for given patients.

A radiolabeled murine monoclonal antibody (T101) was used for imaging and therapy of six patients with cutaneous T cell lymphoma (CTCL). Radioimmunodetection was performed with a 5.6 to 13.1 mCi 131I-T101 preparation (9.6 to 10.5 mg). A therapeutic dose of 100.5 to 150.1 mCi 131I on 9.9 to 16.9 mg of antibody was administered to five patients, with subsequent retreatment following plasmapheresis in three patients at the time of disease progression. All patients responded to their initial therapy and two patients responded to retreatment. Regression of skin lesions and peripheral adenopathy was witnessed. All patients reported resolution of their chronic pruritus. The duration of response ranged from 3 weeks to 3 months. Acute toxicity included fevers, pruritus, and mild dyspnea in two instances. Myelosuppression was seen in patients receiving the 144.7 mCi, 145.0 mCi, and 150.1 mCi 131I-T101 doses. Radioimmunodiagnostic and therapy studies included gamma scintigraphy, plasma, urinary, and wholebody antibody clearances, and biodistribution determined from skin, bone marrow, and liver biopsies. Immunologic studies included immunoperoxidase staining of target tissues, immunofluorescent flow cytometric analysis on peripheral blood and bone marrow, assays for serum blocking factors, determination of a human antimouse antibody (HAMA) response, and quantitation of circulating T101 levels. These preliminary data suggest that 131I-T101 has therapeutic potential in CTCL and that myelosuppression will be the limiting toxicity.