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By taking a small-scale perspective, Bedouin pastoral space in the Israeli Negev in the modern period has been misinterpreted as chaotic by various Israeli institutions. In critiquing this ontology we suggest that a knowledge gap with regard to an appropriate scale of understanding Bedouin settlement patterns and mechanisms of sedentarisation is at its root, and that a larger-scale analysis indicates that their space is in fact highly ordered. Field surveys and interviews with the local Bedouin showed that household cultivation plots in the Negev Highland during the period of the British Mandate were organised at a large scale through natural and man-made landscape features reflecting their structure, development and deployment in a highly ordered space. This analysis carries significant implications for understanding pastoral spaces at the local scale, particularly offering better comprehension of various sedentary forms and suggesting new approaches to sustainable planning and development for the Bedouin.

Technological analyses of material recovered from the excavations at Tel Yarmuth offer new insights into the nature of Canaanean blade technology, the structure of manufacture, and the place of this sophisticated production system in Early Bronze Age society. Detailed study of the entire range of Canaanean production waste, debitage, and tools shows clearly the use of the lever pressure technique for blade removals. The presence of evidence for all stages of reduction on the site, including collection and reduction of nodules, production of blades, and conversion of blades into tools, indicates on-site production. Nevertheless, the absence of any evidence for a proper workshop suggests that blades were both brought in as trade items from off-site workshops, most likely by the knappers themselves, and manufactured specially on demand, by those same knappers. Reconstructing the specialized production and exchange system, considering the skills required for the manufacture of these blades, the number of blades that can be produced by a specialist, and the general distribution of waste both at Tel Yarmuth and in general, it is likely that only a relatively few specialists were actually required for the Canaanean production system any time., L’analyse technologique du matériel de Tel Yarmouth offre de nouvelles perspectives sur la nature du débitage cananéen et sur la structure de cette production très élaborée en la replaçant dans la société de l’âge du Bronze ancien. L’étude détaillée de tous les éléments de la production, débris, produits bruts et outils, montre clairement l’utilisation de la technique de la pression au levier. La présence dans le site de toutes les phases de la chaîne opératoire, y compris la collecte et la réduction de nodules, le débitage des lames et la transformation des lames en outils, indique que la production avait lieu sur place. L’absence de preuves d’un atelier proprement dit suggère que les lames étaient importées comme biens d’échange depuis des ateliers hors site, probablement par les tailleurs, et produites sur demande par ces mêmes tailleurs. En considérant le savoir-faire et les connaissances impliqués, le nombre de lames que chaque spécialiste pouvait produire et la répartition des débris, aussi bien à Tel Yarmouth que dans d’autres sites, la reconstruction de cette production spécialisée et de son système d’échange suggère que seul un nombre limité de tailleurs était engagé dans la production des lames cananéennes., Manclossi Francesca, Rosen Steve A., De Miroschedji Pierre. The Canaanean Blades from Tel Yarmuth, Israel: A technological analysis. In: Paléorient, 2016, vol. 42, n°1. pp. 49-74.

Summary There is a lack of published data examining non-cytotoxic options for the frontline treatment of patients with high-tumour burden (HTB) indolent non-Hodgkin lymphoma (iNHL). We completed a multicentre phase II study for patients with untreated HTB iNHL (NCT00369707) consisting of three induction cycles of weekly bortezomib and rituximab followed by an abbreviated consolidation. Forty-two patients were treated and all were evaluable; the most common histology was follicular lymphoma (FL) (n = 33, 79%). Patient characteristics included median age 62 years (40–86); 38% bulky disease; 19% malignant effusions; 91% advanced-stage disease; and median FL International Prognostic Index (FLIPI) score was 3. Therapy was well tolerated with few grade 3/4 toxicities including minimal neurotoxicity. On intent-to-treat, the overall response rate (ORR) at end of therapy was 70% with a complete remission (CR) rate of 40% (FL: ORR 76%, CR 44%). With 50-month median follow-up, 4-year progression-free survival (PFS) was 44% with 4-year overall survival (OS) of 87% (FL: 44% and 97%, respectively). Four-year PFS for FLIPI 0–2 vs. 3–5 was 60% vs. 26% respectively (P = 0·02), with corresponding OS rates of 92% and 81% respectively (P = 0·16). Collectively, bortezomib/rituximab is a non-cytotoxic therapeutic regimen that was well tolerated and resulted in long-term survival rates approximating prior rituximab/cytotoxic chemotherapy series for untreated HTB FL.

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.

Purpose: To determine whether acute kidney injury (AKI) is identified within the US Food and Drug Administration’s Adverse Events and Reporting System (FDA AERS) as an adverse event resulting from bisphosphonate (BP) use in cancer therapy. Methods: A search of the FDA AERS records from January 1998 through June 2009 was performed; search terms were “renal problems” and all drug names for BPs. The search resulted in 2,091 reports. We analyzed for signals of disproportional association by calculating the proportional reporting ratio for zoledronic acid (ZOL) and pamidronate. Literature review of BP-associated renal injury within the cancer setting was conducted. Results: Four hundred eighty cases of BP-associated acute kidney injury (AKI) were identified in patients with cancer. Two hundred ninety-eight patients (56%) were female; mean age was 66 10 years. Multiple myeloma (n 220, 46%), breast cancer (n 98, 20%), and prostate cancer (n 24, 5%) were identified. Agents included ZOL (n 411, 87.5%), pamidronate (n 8, 17%), and alendronate (n 36, 2%). Outcomes included hospitalization (n 304, 63.3%) and death (n 68, 14%). The proportional reporting ratio for ZOL was 1.22 (95% CI, 1.13 to 1.32) and for pamidronate was 1.55 (95% CI, 1.25 to 1.65), reflecting a nonsignificant safety signal for both drugs. Conclusion: AKI was identified in BP cancer clinical trials, although a safety signal for BPs and AKI within the FDA AERS was not detected. Our findings may be attributed, in part, to clinicians who believe that AKI occurs infrequently; ascribe the AKI to underlying premorbid disease, therapy, or cancer progression; or consider that AKI is a known adverse drug reaction of BPs and thus under-report AKI to the AERS.

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.

This study evaluates the incidence of bone fractures in women with BC.We found that women with invasive breast cancer are at an increased risk for bone fractures, with fractures most commonly occurring at lower extremity and vertebral sites. The risk is further increased in women undergoing cancer therapy.Bone loss and fractures in breast cancer have generally been attributed to aromatase inhibitor use. This study assessed the incidence of fractures after invasive breast cancer diagnosis and evaluated bone density and FRAX risk calculation at time of fracture occurrence.Retrospective cohort study of women with invasive breast cancer [June 2003-December 2011] who participated in an academic hospital based genetic biobank. Demographic and clinical characteristics were abstracted from the electronic medical record (EMR).A total of 422 women with invasive breast cancer were assessed; 79 (28 %) sustained fractures during the observation period; fractures occurred at multiple skeletal sites in 27 cases (116 fractures). The incidence of fractures was 40 per 1000 person-years. Women who sustained fractures were mostly white and had a family history of osteoporosis (36.9 %, p = 0.03) or history of a prior fracture (6/79, p = 0.004). Fractures occurred 4.0 years (range 0-12 years) after cancer diagnosis. Fracture cases had femoral neck bone mineral density (BMD) of 0.72 + 0.12 g/cm(2), T-score of -1.2, that is, within the low bone mass range. Fractures most commonly occurred in lower extremities, vertebral, and wrist sites. Hip fractures accounted for 11 % of fractures, occurring at a median age of 61 years.Fractures occur shortly after commencing cancer therapy. Rapid bone loss associated with cancer therapy may precipitate fractures. Fractures occur at relatively higher BMD in BC. Occurrence of fractures in invasive breast cancer raises the possibility of cancer-induced impairment in bone quality.

Optimal frontline therapy for peripheral T-cell lymphoma (PTCL) in the modern era remains unclear.We examined patient characteristics, treatment, and outcomes among 341 newly diagnosed PTCL patients from 2000 to 2011. Outcome was compared with a matched cohort of diffuse large B-cell lymphoma (DLBCL) patients, and prognostic factors were assessed using univariate and multivariate analyses.PTCL subtypes included PTCL, not otherwise specified (PTCL-NOS) (31%), anaplastic large T-cell lymphoma (ALCL) (26%), angioimmunoblastic T-cell lymphoma (23%), NK/T-cell lymphoma (7%), acute T-cell leukemia/lymphoma (6%), and other (7%). Median age was 62 years (range 18-95 years), and 74% had stage III-IV disease. Twenty-three (7%) patients received only palliative care whereas 318 received chemotherapy: CHOP-like regimens (70%), hyperCVAD/MA (6%), or other (18%). Thirty-three patients (10%) underwent stem-cell transplantation (SCT) in first remission. The overall response rate was 73% (61% complete); 24% had primary refractory disease. With 39-month median follow-up, 3-year progression-free survival (PFS) and overall survival (OS) were 32% and 52%. PFS and OS for PTCL patients were significantly inferior to matched patients with DLBCL. On multivariate analysis, stage I-II disease was the only significant pretreatment prognostic factor [PFS: hazard ratio (HR) 0.54, 95% confidence interval (CI) 0.34-0.85, P = 0.007; OS: HR 0.42, 95% CI 0.22-0.78, P = 0.006]. ALK positivity in ALCL was prognostic on univariate analysis, but lost significance on multivariate analysis. The most dominant prognostic factor was response to initial therapy (complete response versus other), including adjustment for stage and SCT [PFS: HR 0.19, 95% CI 0.14-0.28, P0.0001; OS: HR 0.26, 95% CI 0.17-0.40, P0.0001]. No overall survival difference was observed based on choice of upfront regimen or SCT in first remission.This analysis identifies early-stage disease and initial treatment response as dominant prognostic factors in PTCL. No clear benefit was observed for patients undergoing consolidative SCT. Novel therapeutic approaches for PTCL are critically needed.

Objective To investigate the safety and efficacy of immune ablation with subsequent autologous hematopoietic stem cell transplantation (HSCT) in severe rheumatoid arthritis (RA). Methods Four patients with refractory RA and poor prognostic indicators were treated. Stem cells were collected and lymphocytes were depleted by 2.3–4.0 logs. The conditioning regimen included cyclophosphamide (200 mg/kg), antithymocyte globulin (90 mg/kg), and, for 1 patient, total body irradiation (TBI) with 400 cGy. Improvement was evaluated according to the American College of Rheumatology (ACR) preliminary definition of improvement in RA (ACR 20), and also according to the ACR 50 and ACR 70 criteria. Results HSCT was well tolerated. Three patients fulfilled the ACR 70 criteria at 1 month and 3 months post-HSCT. One patient did not fulfill the ACR 20 criteria because of persistent joint tenderness, despite improvement of the joint swelling. At 6 months post-HSCT, 1 patient fulfilled the ACR 70 criteria and 1 fulfilled the ACR 50 criteria, and these 2 patients fulfilled the ACR 70 criteria at 9 months post-HSCT. The other 2 patients (including the patient who received TBI) did not meet the ACR 20 criteria at 6 months and 9 months post-HSCT. The only patient with followup of >9 months fulfilled the ACR 70 criteria at 20 months post-HSCT. Conclusion In this series, autologous HSCT was safe and effective in inducing major clinical response and maintained significant benefit for 2 patients at 9 months and 20 months posttreatment, respectively. Sustained response did not occur for 2 of 4 patients. A regimen dose-response effect may exist, but the addition of TBI did not prevent disease relapse for 1 of the patients. More aggressive T cell depletion of the autograft, use of a myeloablative regimen, or use of an allograft may be necessary to decrease relapse rates.

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.

Multiple sclerosis, systemic lupus erythematosus, and rheumatoid arthritis are immune-mediated diseases that are responsive to suppression or modulation of the immune system. For patients with severe disease, immunosuppression may be intensified to the point of myelosuppression or hematopoietic ablation. Hematopoiesis and immunity may then be rapidly reconstituted by reinfusion of CD34+progenitor cells. In 10 patients with these autoimmune diseases, autologous hematopoietic stem cells were collected from bone marrow or mobilized from peripheral blood with either granulocyte colony-stimulating factor (G-CSF) or cyclophosphamide and G-CSF. Stem cells were enriched ex vivo using CD34+ selection and reinfused after either myelosuppressive conditioning with cyclophosphamide (200 mg/kg), methylprednisolone (4 g) and antithymocyte globulin (ATG; 90 mg/kg) or myeloablative conditioning with total body irradiation (1,200 cGy), methylprednisolone (4 g), and cyclophosphamide (120 mg/kg). Six patients with multiple sclerosis, 2 with systemic lupus erythematosus, and 2 with rheumatoid arthritis have undergone hematopoietic stem cell transplantation. Mean time to engraftment of an absolute neutrophil count greater than 500/μL (0.5 × 109/L) and a nontransfused platelet count greater than 20,000/μL (20 × 109/L) occurred on day 10 and 14, respectively. Regimen-related nonhematopoietic toxicity was minimal. All patients improved and/or had stabilization of disease with a follow-up of 5 to 17 months (median, 11 months). We conclude that intense immunosuppressive conditioning and autologous T-cell–depleted hematopoietic transplantation was safely used to treat these 10 patients with severe autoimmune disease. Although durability of response is as yet unknown, all patients have demonstrated stabilization or improvement.

Multiple sclerosis (MS) is a disease of the central nervous system characterized by immune-mediated destruction of myelin. In patients with progressive deterioration, we have intensified immunosuppression to the point of myeloablation. Subsequently, a new hematopoietic and immune system is generated by infusion of CD34-positive hematopoietic stem cells (HSC). Three patients with clinical MS and a decline of their Kurtzke extended disability status scale (EDSS) by 1.5 points over the 12 months preceding enrollment and a Kurtzke EDSS of 8.0 at the time of enrollment were treated with hematopoietic stem cell (HSC) transplantation using a myeloablative conditioning regimen of cyclophosphamide (120 mg/kg), methylprednisolone (4 g) and total body irradiation (1200 cGy). Reconstitution of hematopoiesis was achieved with CD34-enriched stem cells. The average time of follow-up is 8 months (range 6-10 months). Despite withdrawal of all immunosuppressive medications, functional improvements have occurred in all three patients. We conclude that T cell-depleted hematopoietic stem cell transplantation can be performed safely in patients with severe and debilitating multiple sclerosis. Stem cell transplantation has resulted in modest neurologic improvements for the first time since onset of progressive disease although no significant changes in EDSS or NRS scales are evident at this time.

Patient navigation has emerged as a promising strategy for addressing racial-ethnic and socioeconomic disparities in cancer-related care. However, little is known about the impact of patients’ perception of the quality of navigation on patient outcomes. We examined the impact of better-rated navigators on patients’ satisfaction with cancer-related care. The sample included 1,593 adults (85.8 % with abnormal cancer screening and 14.2 % with confirmed cancer diagnosis) who received patient navigation. We defined better-rated navigators as those scoring above the first quartile of mean scores on the Patient Satisfaction with Interpersonal Relationship with Navigator scale. We defined patient satisfaction based on scores above or below the median of the Patient Satisfaction with Cancer-Related Care (PSCC) scale. We controlled for patient and site characteristics using backward selection logistic regression analyses. Among patients with abnormal screening, having a better-rated navigator was associated with higher score on the PSCC (p

Objectives: Intrathecal infusion pumps are increasingly used to deliver analgesics for chronic intractable pain. This trial evaluated the accuracy and efficacy of the new Prometra® Programmable Pump System for intrathecal administration of morphine sulfate to treat chronic intractable pain. Methods: One hundred and ten patients were given continuous intrathecal morphine sulfate and assessed monthly for up to six months. Accuracy was determined as the ratio of delivered to programmed drug volume (DP ratio). Efficacy was assessed using the visual analog and numeric rating scales and the Oswestry Disability Index. Results: The mean accuracy of the Prometra pump was 97.1%, with a 90% confidence interval of 96.2–98.0%. Decreases in pain and disability were reported at 68.4% of patient visits. No unanticipated adverse events or device complications were reported. Conclusions: The Prometra pump provides an accurate, effective, and safe system for intrathecal administration of morphine sulfate for treatment of chronic intractable pain.

Background Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the western population. Although genetic factors are considered to contribute to CLL etiology, at present genomic aberrations identified in CLL are limited compared with those identified in other types of leukemia, which raises the question of the degree of genetic influence on CLL. We performed a high-resolution genome scanning study to address this issue. Findings Using the restriction paired-end-based Ditag Genome Scanning technique, we analyzed three primary CLL samples at a kilobase resolution, and further validated the results in eight primary CLL samples including the two used for ditag collection. From 51,632 paired-end tags commonly detected in the three CLL samples representing 5% of the HindIII restriction fragments in the genomes, we identified 230 paired-end tags that were present in all three CLL genomes but not in multiple normal human genome reference sequences. Mapping the full-length sequences of the fragments detected by these unmapped tags in seven additional CLL samples confirmed that these are the genomic aberrations caused by small insertions and deletions, and base changes spreading across coding and non-coding regions. Conclusions Our study identified hundreds of loci with insertion, deletion, base change, and restriction site polymorphism present in both coding and non-coding regions in CLL genomes, indicating the wide presence of small genomic aberrations in chronic lymphocytic leukemia. Our study supports the use of a whole genome sequencing approach for comprehensively decoding the CLL genome for better understanding of the genetic defects in CLL.

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.

Objectives To study the clinical features, therapeutic responses, and outcomes in patients with folliculotropic mycosis fungoides (FMF) and to compare our single-center experience of 43 patients with the findings from the Dutch Cutaneous Lymphoma Group. Setting A single-center experience from the Northwestern University Multidisciplinary Cutaneous Lymphoma Group. Patients Forty-three patients with FMF were included in the study and compared with 43 age- and stage-matched patients with classic epidermotropic mycosis fungoides (MF) with similar follow-up time. Results Folliculotropic mycosis fungoides showed distinct clinical features, with 37 patients having facial involvement (86%) and only 6 having lesions limited to the torso (14%). The morphologic spectrum of lesions is broad and includes erythematous papules and plaques with follicular prominence with or without alopecia; comedonal, acneiform, and cystic lesions; alopecic patches with or without scarring; and nodular and prurigolike lesions. Sixty-five percent of patients had alopecia, which in 71% of cases involved the face. Severe pruritus was seen in 68% of patients. In general, patients responded poorly to skin-directed therapy and in almost all cases required systemic agents to induce even a partial remission, including patients with early-stage disease. Overall survival was poor. Patients with early-stage disease (≤IIA) had a 10-year survival of 82%, which took a steep drop off to 41% by 15 years. Patients with late-stage disease (≥IIB) had an outcome similar to those patients in the control group with conventional epidermotropic MF of a similar stage. Conclusions The morphologic spectrum of clinical presentation for FMF is broad and distinct from those in conventional MF. This is at least partially attributed to the ability of FMF to simulate a variety of inflammatory conditions afflicting the follicular unit. The disease course is aggressive, and many patients, including those with early disease, show a poor outcome particularly between 10 and 15 years after the initial onset of disease. Response to skin-directed therapy is poor even in early-stage disease, and our best results were seen with psoralen plus UV-A (PUVA) therapy with oral bexarotene or PUVA with interferon alfa. These findings corroborate those of the Dutch Cutaneous Lymphoma Group and further validate the classification of FMF as a distinct entity.

Background Primary cutaneous marginal zone lymphoma is recognized as a unique subset of low-grade cutaneous B-cell lymphoma with indolent course in the current World Health Organization-European Organization on Research and Treatment of Cancer classification system. However, few large series on this entity have been reported, including the new TNM ( t umor, (lymph) n ode, m etastasis) classification for non–mycosis fungoides cutaneous lymphomas. Objective We aimed to characterize the clinical features including new TNM classification for non–mycosis fungoides cutaneous lymphomas, as well as outcomes and responses to therapy in 30 patients with primary cutaneous marginal zone lymphoma. Results Primary cutaneous marginal zone lymphoma typically presents with deep-seated nodular or papular lesions on the upper extremities or trunk (25/30). Disease course is indolent and none of 30 patients died of disease. Sustainable complete remissions were obtained only in patients with T1a (n = 3) and T2a (n = 1) disease. Most patients have persistent stable disease independent of treatment. Two patients developed systemic disease and 5 developed large cell transformation. Limitations The average follow-up time was 63 months (range, 3-204 months). Longer follow-up time is needed to determine whether patients with untreated persistent stable disease are at greater risk relative to patients treated aggressively early in the disease course. Conclusions Primary cutaneous marginal zone lymphoma is a distinct subtype of marginal zone lymphoma with an indolent disease course. Patients with T1a or T2a disease (ie, single lesions or a localized cluster of lesions) may achieve sustained complete remission, whereas patients with multiple nonlocalized lesions are unlikely to maintain complete remission independent of treatment modality. Systemic involvement is typically preceded by large cell transformation and may be an indication for more systemic therapy. Death from disease is rare.

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.

Background Allogeneic hematopoietic stem cell transplantation has proved to be an effective therapeutic option in various hematologic neoplastic disorders. Because patients with advanced cutaneous T-cell lymphoma have a poor prognosis, with minimal possibilities of sustained remission, we studied the therapeutic potential of hematopoietic stem cell transplantation. Observations Three young patients with refractory tumor stage mycosis fungoides underwent allogeneic HLA-matched sibling transplantation with combined marrow and CD34-enriched peripheral blood stem cell transplantation after cytoreductive chemotherapy and total-body irradiation. Complete and sustained clinical and histologic remission was achieved in 2 patients, and both remain disease free 4½ years and 15 months later. One patient was in complete remission for 9 months, followed by limited cutaneous recurrence. Mild graft-vs-host disease and graft-vs-tumor effect have contained the recurring disease as a low-grade process. Conclusions Allogeneic hematopoietic stem cell transplantation has the potential for sustained remission and the possibility of cure for young patients with advanced and recalcitrant cutaneous T-cell lymphoma. Even in the absence of complete remission, an allogeneic graft-vs-tumor effect may provide an immune mechanism to control the malignant T-cell process and alter the natural history of disease.

Background: Aggressive non-Hodgkin's lymphomas are common among patients infected with HIV. Although such lymphomas are mostly of the B-cell type, various cases of cutaneous T-cell lymphoma (CTCL) have also been reported. Recent reports suggest that some HIV-related lymphoproliferative conditions may not be clonal processes, but polyclonal lymphoid proliferations. Objective: We reviewed our experience with HIV patients seen at the dermatology clinics for possible CTCL. Methods: A retrospective study was performed to evaluate clinical, laboratory, and histologic findings of HIV-infected patients with atypical T-cell cutaneous infiltrates. Results: We observed 9 patients with advanced HIV infection and a cutaneous eruption characterized by a dense infiltrate of lymphocytes resembling mycosis fungoides histopathologically, but composed of CD8 + cells. Although clonality was not identified in any of the 6 cases tested, 3 patients had similar CD8 + infiltrates involving lymph nodes or bone marrow. Of the 9 patients, 8 died of AIDS wasting syndrome or infections in less than 1 year. Conclusion: Cutaneous and systemic infiltrates with polyclonal CD8 T lymphocytes can be seen in patients with advanced HIV infection and profound CD4 lymphopenia. The clinical presentation may resemble CTCL and is associated with a poor outcome. (J Am Acad Dermatol 1999;41:722-7.)

Abstract 2028 Purpose: Current treatment of advanced stage cutaneous T cell lymphoma (CTCL) includes a number of chemotherapy agents which provide good response rates, but with often short duration. Hematopoietic cell transplantation (HSCT) has the potential to offer a durable remission due to graft-versus-lymphoma effect. We conducted a retrospective study to report the outcome of HSCT in patients with refractory CTCL. Methods: From Feburary 1997 through May 2012, twenty-one patients (22–65 yo) with advanced, refractory CTCL underwent HSCT from HLA-identical sibling (n=13), unrelated donor (n=5), umbilical cord (n=1), syngeneic (n=1) and autolougous (n=1) sources. There were 7 tumor stage MF, 6 Sézary syndrome, 2 erythrodermic MF, 1 folliculotropic MF, 1 aggressive CD8+ T cell lymphoma (Berti's type), 2 γ-δ TCL, 1 α-β TCL and 1 CD30-negative large cell peripheral TCL. The intensity of the conditioning regimen was conventional in 10 and reduced in 11. At the time of HSCT, the median disease duration was 5.4 years (1–17 y). Most patients were heavily pretreated, having failed a median number of four (1–9) lines of therapy. The stage of the disease at the time of HSCT was IIB (n=9), III (n=2), IVA (n=9), and IVB (n=1). Results: For the 21 patients evaluated there was a median follow-up of 62 months (3–186 mo). 11 patients had relapse post-transplant: 5 patients had an early relapse (100 days). Relapsed disease appeared to be of a lower grade clinically than at pre-transplantation and responded to therapies they had previously failed. 1 early relapse died of disease (SS, auto-SCT) and 1 late relapse died of disease (γ-δ TCL, RIC allo-SCT). Of the nine remaining relapsed patients, 1 has died of a cerebral hemorrhage. (CD30-neg large cell peripheral TCL, alloSCT) and 1 of GVHD (γ-δ TCL, RIC allo-SCT). Of the 7 remaining relapsed patients, 4 went into CR with reduction of immunosuppression. 14 patients developed acute GVHD (fatal in 3), and 10 developed chronic GVHD. Of the surviving patients (n=15) all are in CR. Overall survival was 71%, with a median OS of 27.1 months (range, 0.5–185.9). Progression free survival (PFS) was 43% with a median PFS of 4.1 months (range, 0.5–80). Conclusions: Our results suggest that HSCT can induce durable clinical remissions in patients with refractory CTCL through graft-versus-lymphoma effect. Disclosures: No relevant conflicts of interest to declare.

To extend artifact and/or draft functionality in E-L, you must first have a working knowledge of how E-L is used. E-L is extended from within, by using the system to develop new functionality and then to augment the plexes that describe the structure of the artifacts system. This guide assumes you are familiar with the E-L Users' Manual. To add a tool to the system, you will also need to know how to develop C or Common Lisp programs using E-L, so you should also have read either the C and Unix Artifacts Manual or the Common Lisp Artifacts Manual.

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]

Traditional therapy for patients with symptomatic and/or high-risk indolent NHL most commonly includes rituximab combined with multiagent cytotoxic chemotherapy. However some patients are not able to tolerate chemotherapy due to advanced age and/ or co-morbidities. Further, combination of novel, targeted agents (non-chemotherapeutic) have been infrequently tested in newly diagnosed indolent NHL patient populations. Overall response rate (ORR) with single-agent rituximab in prior data for untreated indolent NHL was 73% with a complete remission (CR) rate of 37% following maintenance therapy (JCO 2002; 20: 4261), although a good portion of patients in that series had low tumor burden at study entry. We hypothesized that frontline bortezomib and rituximab therapy would be effective and well tolerated for untreated “high tumor burden” indolent NHL. We have conducted a Simon 2-stage phase II trial for untreated indolent NHL. All patients were required to have “high tumor burden” as defined by Groupe D’Etude des Lymphomes Folliculaires (GELF) criteria. Induction therapy consisted of 3 cycles: bortezomib given at 1.6 mg/m2 days 1, 8, 15, and 22 q35 days for all 3 cycles and rituximab at 375 mg/m2 x 4 weekly doses for cycle 1, then day 1 only for cycles 2 and 3. Abbreviated consolidation therapy was subsequently given with 1 dose of each drug q2 months x 8 months. Responses were assessed by computerized tomography (CT) according to Cheson criteria (JCO 1999). We report here the results of the first stage of this 2-stage trial. Twenty-two patients have enrolled, of whom 17 were in the 1st stage. There were 9 women and 8 men; median age was 63 years (range 46–78 years). 14 patients had follicular lymphoma (FL), 2 marginal zone lymphoma, and 1 small lymphocytic lymphoma. 13 of 17 patients had stage IV disease and 4 had stage III. The median Follicular Lymphoma International Prognostic Index (FLIPI) was 3 (range 1–4) and the median follow-up was 13 months (range 1–24 months). Responses according to cycle number are shown in Table 1. After only 1 cycle, the ORR was 29% (all partial remissions (PRs)) with 71% stable disease (SD). Following cycle 3, ORR was 59% (24% CR). From cycle 1 to 3, 4/5 PRs converted to CR, 6 SDs converted to PR, while 1 PR and 4 SDs progressed or were removed from the study at physician discretion. 8 of 12 eligible patients have completed consolidation therapy. Following consolidation, 1 PR converted to CR and 2 SDs converted to PR for an ORR of 71%. According to histology, the ORR among FL patients after consolidation therapy was 86% (CR 36%, PR 50%). Therapy was very well tolerated. Grade 3 toxicities seen were lymphopenia, partial small bowel obstruction, and fatigue (all in 1 patient); no grade 4 toxicities occurred. Furthermore, no cytopenias or neurotoxicity was seen. Accrual to the 2nd stage is being completed. In summary, we found in the 1st stage of this phase II trial that bortezomib/rituximab combination therapy for untreated high tumor burden indolent NHL is well tolerated and active. Response rates improved throughout therapy (i.e., from cycle 1 through consolidation), although the CR rate achieved was low compared with chemotherapy-based regimens. Chemotherapy-based therapy should be considered standard therapy for frontline “high tumor burden” indolent NHL, although non-chemotherapy options may be considered for patients not anticipated to tolerate intensive therapy. Furthermore, responses seen here with bortezomib/rituximab, in a uniform high tumor burden patient population, were similar to rituximab alone in lower tumor burden populations. Analysis of clinical trials/reports in indolent NHL should include critical assessment of patient selection and future trials in high tumor burden should incorporate novel therapies into rituximab-chemotherapy based regimens. Table 1. Response according to cycle/treatment. | | After Cycle 1 | After Cycle 3* | Following consolidation therapy** | |:---------------------------------------------------------------------------------------------------:| ------------- | -------------- | --------------------------------- | | *Three patients had PD, while 2 patients were taken off study (without PD) at physician discretion. | | **Eight of 12 eligible patients have completed post-induction therapy. | | ORR | 29% (5/17) | 59% (10/17) | 71% (12/17) | | CR | 0% | 24% (4/17) | 30% (5/17) | | PR | 29% (5/17) | 35% (6/17) | 41% (7/17) | | SD | 71% (12/17) | 12% (2/17) | 0% | | PD/off trial | 0% | 29% (5/17) | 29% (5/17)

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...

Purine nucleoside combination therapy, with and without immunotherapy has become the standard treatment approach to CLL. Past approaches, other than stem cell transplantation, have not been successful in curing the disease. Inherent resistance of CLL precursors, impaired immune surveillance (T-cells, NK cells) and microenvironmental abnormalities may all play a role in the ability to effectively eradicate leukemia. PCR has been successfully employed for previously treated (Lamanna 2006) and previously untreated (Kay 2007) patients with CLL. In addition, CA has been added to FCR (Wierda 2006) to treat relapsed/refractory CLL disease. We designed a study to evaluate PCR followed by CA for relapsed/refractory CLL. This ECOG study includes, in addition to response criteria, molecular correlates (FISH anomalies and CpG karyotype), risk parameters analysis, including CD38, ZAP-70 and IgVH mutational status. We assessed the baseline and sequential changes in the angiogenic status of patients by measuring plasma VEGF, bFGF, thrombospondin and their immune status via T-cell repertoire. From September 2004 to September 2006, 32 patients with relapsed/refractory CLL were enrolled in the protocol. The protocol combined 2 regimens (PCR and CA). Step 1, PCR, was planned for 6 monthly cycles. Steps 2 and 3 consisted of short term CA (4 weeks) or standard CA (18 weeks) depending upon Step 1 response. There were 3 ineligible, 1 not evaluated, and 28 evaluable patients. FISH anomalies revealed that 8 patients had a homozygous or heterozygous 13q-defect, 9 had complex FISH defects (more than one FISH anomaly), 5 patients had FISH anomalies that included del(17p13.1), 4 patients had FISH anomalies that included 6q-and 3 had FISH anomalies that included 11q-. CD38 was positive in 10 patients, 11 were ZAP-70 positive and 12 of 19 patients tested had unmutated type clones. The planned 6 cycles of Step 1 (PCR) was administered to 14/32 patients (44%), the others receiving 0–5 cycles. All responses were considered partial responses (11/29; 37.9%), with 2 patients (6.9%) demonstrating progressive disease. However, patients receiving the planned 6 cycles of PCR, achieved a partial response of 71% (10/14) with 2 cases of tumor lysis syndrome. Toxicity (Step 1-PCR) was predominately myelosuppressive (Grade 1–4). A case of chronic idiopathic polyneuropathy and a case of “paraneoplastic pemphigus” were reported. There were 4 deaths. CMV reactivation was diagnosed in 2 patients, neither of which was fatal. During Step 2 (CA), short-term administration in one patient led to grade 3 skin toxicity, which limited administration. During long-term administration of CA (PR, PD, SD) (n=7), infectious complications occurred in 6 patients all of whom developed grade 4 lymphopenia. The median survival for the entire group was 15 months. In conclusion, a significant number of heavily pre-treated and poor prognosis patients with CLL will respond to PCR. Further analysis will determine whether a significant number of patients will achieve a higher level of response and longer survival after CA administration. Studies of association of outcome with the risk parameters are ongoing and will be presented with the clinical response data.

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]

Multiple Myeloma (MM) is a clonal B-cell malignancy characterized by the accumulation of terminally differentiated plasma cell in the bone morrow, which accounts for 10% of all hematological cancers. Despite major advance of last decade, MM remains an incurable disease in need of new therapeutic approaches. Leflunomide was originally developed as an immunosuppressive drug capable of alleviating the severity of autoimmune disease and preventing allograft and xenograft rejection and it has been FDA approved to use in the treatment of rheumatoid arthritis (RA) since 1998. It rapidly converted in gastrointestinal tract and plasma to open ring metabolite A771726. In current study, we examine the effects of A771726 to the growth of MM cell lines in vivo and show that A771726 inhibits the proliferation of four different well-characterized MM cell lines (MM.1, U266, RPMI8226 and MDR10V) in a dose- and time- dependent manner, regardless their sensitivity to the conventional chemotherapies. Cell cycle analyses further demonstrate that G1-S phase transition is blocked by A771726 in those cells. Moreover, we find that, at higher concentration, A771726 is able to induce apoptosis in at least two of the cell lines tested as measured by an increase of the cells with subG1 DNA content, an increasing in caspase activity and cleavage of caspase substrate. Previous studies suggested that A771726 exerts its anti-proliferate function mostly by inhibiting de novo pyrimidine synthesis in lymphocyte and supplementation of the cultures with exogenous uridine could prevent A771726-induced cell cycle block by restoring the intracellular UTP and CTP lever. However, we find that additions of exogenous uridine can prevent neither A771726-induced cell cycle block nor apoptosis in the MM cell lines tested, suggesting a novel mechanism. It shall be noted that pharmacologically, the highest concentration of A771726 (200uM) used in our study is readily achievable in the plasma through current drug regiment of Leflunomide in RA patients. Since its approval, Leflunomide has been proved to be an effective antirheumatic drug with mild side effects. Given the results from current study, we are tempting to suggest that Leflunomide might also provide a safe alternative in the treatment of MM. The vast knowledge gained from clinical use of Leflunomide in last six year will greatly help us greatly in testing this hypothesis in a clinical setting in a near future.

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.

We reviewed our multicenter experience with gamma-delta (γδ) T-cell lymphomas first presenting in the skin. Fifty-three subjects with a median age of 61 years (range, 25 to 91 y) were diagnosed with this disorder. The median duration of the skin lesions at presentation was 1.25 years (range, 1 mo to 20 y). The most common presentation was deep plaques (38 cases) often resembling a panniculitis, followed by patches resembling psoriasis or mycosis fungoides (10 cases). These lesions tended to ulcerate overtime (27 cases). Single lesions or localized areas of involvement resembling cellulitis or pyoderma were reported in 8 cases. The most common anatomic site of involvement was the legs (40 cases), followed by the torso (30 cases) and arms (28 cases). Constitutional symptoms were reported in 54% (25/46) of the patients, including some with limited skin involvement. Significant comorbidities included autoimmunity (12 cases), other lymphoproliferative disorders (5 cases), internal carcinomas (4 cases), and viral hepatitis (2 cases). Lymphadenopathy (3/42 cases) and bone marrow involvement (5/28 cases) were uncommon, but serum lactose dehydrogenase (LDH) was elevated in 55% (22/39) of the patients. Abnormal positron emission tomography and/or computed tomography scans in 20/37 subjects mostly highlighted soft tissue or lymph nodes. Disease progression was associated with extensive ulcerated lesions resulting in 27 deaths including complications of hemophagocytic syndrome (4) and cerebral nervous system involvement (3). Median survival time from diagnosis was 31 months. Skin biopsies varied from a pagetoid pattern to purely dermal or panniculitic infiltrates composed of intermediate-sized lymphocytes with tissue evidence of cytotoxicity. The most common immunophenotype was CD3+/CD4⁻/CD5⁻/CD8⁻/BF1⁻/γ-M1+/TIA-1+/granzyme-B+/CD45RA-/CD7-, and 4 cases were Epstein-Barr virus positive. This is the largest study to date of cutaneous γδ T-cell lymphomas and demonstrates a variety of clinical and pathologic presentations with a predictable poor outcome.

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.