Search

Abstract 1870 Poster Board I-895 Background: Enzastaurin is an oral serine/threonine kinase inhibitor that targets the PKC and PI3K/AKT pathways. Enzastaurin has demonstrated activity in preclinical models of multiple myeloma (MM), and clinical studies suggest activity and a favorable safety profile in a variety of hematological cancers. Enzastaurin has also demonstrated in-vitro synergy with bortezomib. Objectives: This phase I, open-label, multicenter, dose-escalation study was initiated to identify the recommended doses of enzastaurin and bortezomib in combination for phase II studies in patients (pts) with previously treated MM. Secondary objectives included evaluations of safety and response. Patients and Methods: A conventional dose-escalation scheme was applied. In dose level 1, pts received enzastaurin as a loading dose of 500 mg (250 mg po BID) on day 1 followed by daily doses of 125 mg po BID plus bortezomib 1.0 mg/m2 IV on days 8, 11, 15, and 18 in cycle 1 and days 1, 4, 8, and 11 thereafter. In dose level 2, pts received the same enzastaurin dose but a higher bortezomib dose (1.3 mg/m2). In dose level 3, pts received enzastaurin as a loading dose of 1125 mg (375 mg po TID) on day 1 followed by daily doses of 250 mg po BID plus 1.3 mg/m2 bortezomib. All treated pts were evaluated for response using the International Uniform Response Criteria (IURC; Durie et al. 2006) and European Group for Blood and Bone Marrow Transplantation (EBMT) criteria (Blade et al. 1998). All adverse events (AEs) were graded according to Common Toxicity Criteria for Adverse Events (CTCAE) v3.0. Results: A total of 23 pts, 4 in dose level 1, 3 in dose level 2, and 16 in dose level 3, were enrolled in the study, which is now closed to enrollment. There were 8 women and 15 men, with a median age of 62 years (range, 37–78 years); 91% of the pts had an ECOG performance status of 1 or 0, and the median number of prior systemic therapies was 3 (range, 2–12), with 17 pts previously treated with bortezomib. The median number of cycles completed was 4 (range, 1–20). No dose-limiting toxicities (DLTs) were observed; thus, dose level 3 was the recommended phase II dose. The combination was well tolerated with few grade 3/4 AEs. CTCAE drug-related grade 3/4 laboratory toxicities included: thrombocytopenia in 5 (22%) pts, anemia in 2 (9%) pts, increased creatinine in 1 (4%) pt, and hyponatremia in 1 (4%) pt. Drug-related grade 3/4 non-laboratory toxicities included: sensory neuropathy, prolonged QTc interval, and renal/genitourinary in 1 (4%) pt each. Serious drug-related AEs were increased serum creatinine and renal tubular necrosis in 1 (4%) pt and thrombocytopenia in 1 (4%) pt. The thrombocytopenia was not considered a DLT as the baseline platelet count was low secondary to MM. Five (22%) pts were discontinued from the study due to drug-related toxicities: renal tubular necrosis (also a serious AE) in 1 (4%) pt, peripheral neuropathy in 2 (9%) pts, neuralgia in 1 (4%) pt, and pain in extremity in 1 (4%) pt. There were no deaths on therapy; 1 pt died within 30 days of treatment due to progressive disease. Of the 23 enrolled pts, objective responses based on IURC criteria included 1 (4%) pt with a very good partial response (dose level 1), 2 (9%) pts with a partial response (in dose levels 2 and 3), 9 (39%) pts with stable disease, and 3 (13%) pts with progressive disease; 2 pts had no post-baseline response assessment, and 6 pts had unconfirmed stable disease or progressive disease. Two (9%) pts had a minimal response based on EBMT criteria. Activity was seen in pts regardless of prior exposure to bortezomib. Conclusions: The recommended phase II dose in patients with MM is enzastaurin 250 mg po BID with a loading dose of 1125 mg (375 mg po TID) on day 1 plus 1.3 mg/m2 bortezomib on days 1, 4, 8, and 11 (days 8, 11, 15, and 18 in cycle 1 only). The combination was generally well tolerated, and responses were observed. Disclosures: Ghobrial: Millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Research Funding; Celgene: Honoraria, Speakers Bureau. Munshi:Millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Yuan:Eli Lilly and Company: Employment. Schlossman:Millenium: Speakers Bureau; Celgene: Speakers Bureau. Laubach:Novartis: Consultancy. Anderson:Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Millenium: Consultancy, Honoraria, Research Funding. Lin:Eli Lilly and Company: Employment. Wooldridge:Eli Lilly and Company: Employment. Richardson:Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Keryx Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Meyers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gentium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Abstract 3867 Poster Board III-803 Background Enzastaurin is an oral serine/threonine kinase inhibitor that targets the PKC and PI3K/AKT pathways. Enzastaurin has demonstrated activity in preclinical models of multiple myeloma (MM) and Waldenstrom's macroglobulinemia (WM), and clinical studies suggest encouraging activity and a well-tolerated safety profile in a variety of hematologic cancers. We are conducting a multicenter, two (parallel) cohort, two-stage, phase II trial to determine whether further study of single-agent enzastaurin is warranted in patients with previously treated WM or MM. The primary objective is to assess the response rate (RR); secondary objectives include assessment of time to progression (TTP), safety, biomarkers, and the impact of adding dexamethasone to enzastaurin in patients with progressive disease (PD). Preliminary results for the WM cohort are reported here. Methods Eligible patients with WM and 1-5 prior therapies were enrolled and treated with 250 mg oral enzastaurin twice daily (1125-mg loading dose on day 1) in 28-day cycles. Patients continued for 8 cycles or until PD or unacceptable toxicity occurred. At the investigator's discretion, dexamethasone (20-40 mg po QD, days 1-4, 9-12, and 17-20 for 4 cycles; days 1-4 of each cycle thereafter) was added to enzastaurin in patients with PD. According to the Simon two-stage design, if 2 of the first 10 patients (in stage 1) experienced a minor response (MR) or better, then the study would be expanded to 29 patients (stage 2). Best response was determined according to the response assessment recommendations of the Third International Workshop on WM (IWWM). Adverse events were graded according to CTCAE version 3.0. Results Twenty-nine patients (7 females, 22 males) with WM were enrolled. The median age was 65.6 years (range: 51.7-82.3 years) and 93% of patients had an Eastern Cooperative Oncology Group performance status of 0. Patients had a median of 2 prior systemic therapies and 26 patients (89.7%) had prior rituximab. Patients completed a median of 4 cycles. Six patients received ≥6 cycles of enzastaurin treatment. Twenty patients remain on study. There were no drug-related discontinuations. None of the patients had a complete response (CR). One patient had a partial response (PR) and 7 patients had a minor response (MR), for a RR (CR+PR+MR) of 27.6%. Immunoglobulin M decreased by ≥25% in 11 patients. Three (10.3%) patients had a PD. One patient had a drug-related grade 3 wound complication; there were no other drug-related grade ≥3 toxicities. One patient died on study due to infection unrelated to enzastaurin. Conclusions Although the results are preliminary, enzastaurin appears to have activity and is well tolerated in patients with previously treated WM. The WM cohort was expanded to allow up to 50 patients to be treated on study. Disclosures: Ghobrial: Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Honoraria, Research Funding, Speakers Bureau. Lin:Eli Lilly and Company: Employment. Yuan:Eli Lilly and Company: Employment. Benhadji:Eli Lilly and Company: Employment. Wooldridge:Eli Lilly and Company: Employment. Leblond:Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria.

Syphilis has a number of stages, including a latent one, and may be overlooked or misdiagnosed if the possibility is not kept in mind. Adequate treatment during the primary stage results in a very high cure rate. The latent stage may last for years, during which time a woman may still give birth to an infected child. Symptomatic neurosyphilis occurs more often in men than women. Penicillin G is preferred to treat all stages of the disease; other antibiotics can be used for patients sensitive to penicillin.

Background: Single-agent rituximab therapy in patients with follicular lymphoma (FL) who have a low-affinity FcγRIIIa (158-FF or VF; F-carriers) is associated with a lower response rate (RR) and time to progression compared to patients with the high affinity genotype (158-VV). Through protein engineering, the humanized monoclonal antibody (mAb) AME-133v was optimized to achieve a 13-20-fold greater affinity for CD20, ~ 6-fold greater potency at mediating ADCC, and ~ 50% lower complement dependent cytotoxicity compared to rituximab in vitro. Methods: An open-label, multicenter, Phase 1/2 dose-escalation (3+3) study of AME-133v was initiated in patients with relapsed/refractory FL who were confirmed to be FcγRIIIa 158-F-carriers. Eligible patients were treated with four weekly infusions of AME-133v. The objectives of the study are to determine the safety and tolerability, PK profile, objective response rate, and duration of response. The Phase 1 portion is complete and is the subject of this report. Results: Twenty-three patients were enrolled and 22 (12M/10F; median age 61.5) received AME-133v IV once weekly for 4 doses at 2 (n = 3), 7.5 (n = 3), 30 (n = 4), 100 (n = 6) or 375 mg/m2 (n = 6). All treated patients were confirmed to be FcγRIIIa F-carriers (158-VF =12 and 158-FF =10). Patients treated on the trial received a median of 1 prior treatment regimen (range 0-4); 20/21 patients received prior treatment with rituximab and 18/21 patients had prior chemotherapy. Available safety data (n=20) revealed that 18/20 (90%) patients experienced transient adverse events (AEs) on the day of first infusion that were predominantly CTCAE Grades 1 (17/20, 85%) or 2 (6/20, 30%). One patient had transient Grade 3 bronchospasm responsive to standard care. AEs were reported on the day of subsequent infusions in 6 (30%), 2 (10%), and 4 patients (20%) for the 2nd, 3rd, and 4th infusions, respectively, and all were ≤ Grade 2. Neutropenia (n=1) at the 100 mg/m2 dose level was the only SAE reported by an investigator as related to AME-133v, and this event was the only DLT reported. Thus, the MTD was not established during dose escalation. Lymphocyte subset analysis showed that CD19+ B-cells were selectively decreased during and after treatment with AME-133v. The pharmacokinetic (PK) assessment of AME-133v is ongoing. Response data is available for 16 patients at dose levels 2-100 mg/m2. Investigator-assessed CR or PR (Cheson criteria) at 9 weeks was reported in 4/16 patients (25%) in the 2 (1/3), 30 (1/3), and 100 (2/6) mg/m2 cohorts. Conclusions: AME-133v is well tolerated at the doses tested, and the MTD was not established. B-cell depletion and clinical responses were observed in the phase 1 study portion. Accrual continues in Phase 2. Further safety, pharmacodynamic, and response data will become available and will be updated in the final abstract.

Dermatitis herpetiformis, pemphigus vulgaris, and bullous pemphigoid are uncommon, but not rare, blistering diseases. Accurate diagnosis is essential so that prognosis can be estimated and proper treatment begun. The systemic drugs used in treatment can cause major complications, and careful monitoring is vital. Management is best achieved with a team approach consisting of a primary care physician and a dermatologist.

An understanding of the causes and course of acute allergic contact dermatitis aids in recognition of this common problem. The most frequent cause is the Rhus group (poison ivy, oak, and sumac), and a large percentage of the US population is sensitized to this group of allergens. With severe cases, prompt administration of systemic corticosteroids alleviates discomfort and shortens the course of disease. Local treatment may give added relief. However, no treatment is as satisfactory as avoidance of contact.

The International Prognostic Factor Index (IPI) predicts survival in DLBCL in patients treated with chemotherapy. The Revised IPI (R-IPI) has been reported to be a simpler and more accurate predictor of outcome in patients treated with immunochemotherapy (rituximab and anthracycline-based chemotherapy). We evaluated the predictive value of the IPI and the R-IPI in an observational cohort of unselected patients treated with R-CHOP. Consecutive, newly diagnosed patients age 18 years and older with DLBCL were prospectively offered enrollment into our Lymphoma SPORE Registry. Pathology was centrally reviewed, and composite lymphomas and history of concurrent or prior cancers were excluded. All patients were actively followed for progression free progression (PFS) and overall survival (OS). Here we report on patients enrolled from 9/2002 – 6/2006. 229 patients with a median age of 62 years (range 20–93) were evaluated. 56% were >60 years of age, 16% had a performance score ≥2, 54% had an elevated LDH, 19% had >1 extranodal site, and 51% were stage III/IV. During follow-up, there were 63 progressions (28%) and 45 deaths (20%), and the median follow-up time for living patients was 34 months (range 6–61 months). As shown in the table and figure, the IPI and R-IPI were predictive for both PFS and OS (all p1 extranodal sites (HR=1.0; p = 0.96) were no longer significant; similar results were obtained for PFS. The IPI remains a strong predictor of PFS and OS in the immunochemotherapy era. Figure Figure Group % Pats 3 Y PFS HR 95% CI 3 Y OS HR 95% CI Standard IPI Low (0,1) 41% 87% 1.0 ref 93% 1.0 ref Low-Int (2) 22% 62% 3.1 (1.4, 6.8) 74% 4.2 (1.6, 11.1) High-Int (3) 21% 60% 3.1 (1.4, 6.8) 77% 3.4 (1.2, 9.7) High (4,5) 15% 39% 7.2 (3.4, 15.2) 47% 10.2 (4.0, 26.5) R-IPI Very good (0) 11% 96% 1.0 ref 100% 1.0 ref Good (1,2) 53% 74% 6.2 (0.8, 46.0) 84% - - Poor (3–5) 36% 52% 13.5 (1.8, 98.9) 65% -

Background: The fully human monoclonal IgG1 antibody HuMax-CD20 targets a novel epitope of the CD20 molecule on B-cells. HuMax-CD20 stops growth of engrafted B-cell tumors in SCID mice more efficiently than Rituximab and i.v. infusion of HuMax-CD20 in cynomolgus monkeys leads to profound, long lasting, dose-dependent B-cell depletion. Aim: The objective of the present trial was to establish the safety, efficacy and the pharmacokinetics of HuMax-CD20 in patients with chronic lymphocytic leukemia. Methods: Data are presented from an open label, dose-escalation, multicenter phase I/II clinical trial. 3 cohorts of 3 (A), 3 (B) and an extended cohort of 27 (C) patients with relapsed or refractory chronic lymphocytic leukemia (B-CLL) received 4 weekly i.v. infusions of HuMax-CD20 and were followed for 12 months. The first infusion was 100 mg, 300 mg and 500 mg in cohort A, B and C and the following 3 infusions were of 500, 1000 and 2000 mg, respectively. The endpoints were B-cell depletion, adverse events, objective response according to the NCI working group guidelines for CLL, time to progression, duration of response, time to next anti-CLL treatment, and pharmacokinetics. Data are presented from group C. Results: Median age was 63 years (range, 27–82); median time since diagnosis was 6.1 years (range, 1–14). Maximum tolerated dose was not reached and none of the patients developed human anti human antibodies. 13 of 27 patients (48%) reported infections and infestations most frequently CTC grade 1 or 2 events of nasopharyngitis, gastroenteritis, sinusitis and upper respiratory tract infection without causal relation to ofatumumab. All patients had pronounced reduction of the leukemic CD19+CD5+ cell counts. Objective response rate was 46% (12 of 26 evaluable patients) with 1 nPR and 11 PR. Median time to progression (TTP) was 133 days (95 % CI 105–158) in the full analysis population and 161 days (95 % CI 140–220) in the subgroup of responders. The duration of response was 112 days (95 %CI 100–133). Time to next anti-CLL therapy was 366 days (95 % CI 258-N.A.). AUC (median 344697 μg/mL*h; range 62709–1362933) correlated significantly to both TTP and time to next anti-CLL therapy to which parameters the clearance (Cl) of ofatumumab (median 10 mL/h; range 3–42) correlated inversely. | | Time to progression | Time to next anti-CLL therapy | |:-------------------------------------------------------------- | ------------------- | ----------------------------- | -- | | | ρ | p-value | n | ρ | p-value | n | | ρ: Spearman correlation coefficient, n: number of observations | | AUC,μg/mL*h | 0.55 | 0.005 | 24 | 0.62 | 0.001 | 24 | | Cl, mL/h | −0.59 | 0.003 | 23 | −0.58 | 0.003 | 23 | Correlation between survival endpoints and PK Conclusion: This analysis of data from the first study of ofatumumab in CLL patients provides an indication of clinical benefit associated with high exposure and low clearance.

We previously reported the TLR9 ligand CpG ODN can induce apoptosis of CLL cells. Interleukin 21 (IL-21), a recently discovered cytokine with structural homology to IL-2, IL-4 and IL-15, has pleiotropic effects on lymphocyte populations including NK, T and B cells. IL-21 is known to co-stimulate normal human B cell proliferation induced by CD40 ligation, and to inhibit B cell proliferation induced by anti-IgM antibodies and IL-4. We explored the impact of these two agents on CLL because of the overlapping nature of their signaling pathways. Gene chip array studies demonstrated CLL cells express the receptor for IL-21, and expression of this receptor is upregulated by CpG ODN. IL-21 as a single agent induced apoptosis of CLL cells in most samples studied. The combination of IL-21 and CpG ODN induced a greater degree of apoptosis than either agent alone. Figure Figure Dosing studies demonstrated synergy between these two agents in their ability to induce apoptosis of CLL cells. Figure Figure The effect of IL-21 and CpG ODN was also evaluated in peripheral blood from normal donors, and in umbilical cord blood. In both types of samples, therapy preferentially eliminated CD5(+) B-cells. Monoclonal antibody against CD5, but not control antibody, was able to inhibit the pro-apoptotic effect of IL-21. Our results suggest treatment with IL-21 and CpG ODN preferentially eliminates CD5(+) B cells in both malignant and benign samples, and may be a useful combination for the treatment of CLL or autoimmune disorders dependent elevated B1 cell levels. Ongoing studies are exploring the underlying signaling pathways which might be responsible for these effects.

Growing evidence indicates the affinity of mAb for CD16 (FcgRIII) plays a central role in the ability of the mAb to mediate anti-tumor activity. Both polymorphisms in CD16 and structure of mAb Fc can impact on the affinity between CD16 and mAb. Little is known about how affinity between mAb and CD16 impacts on the ability of mAb to activate NK cells. We evaluated how CD16 polymorphisms, and mAb with modified affinity for CD16, impact on NK cell phenotype and cytokine production. MAb consisted of R, anti-CD20 with enhanced affinity for CD20 (AME-133), and AME-133 with Fc engineered to have enhanced affinity for both CD20 and CD16 (Fc-eng-133). Peripheral blood mononuclear cells were obtained from normal subjects that were homozygous for high affinity CD16 (VV at position 158), homozygous low affinity (FF at 158), and heterozygotes and were mixed with mAb and Raji lymphoma cells at an effector:target ratio of 1:1. Higher concentrations of mAb were needed to induce CD16 modulation, CD54 upregulation, and IFNg production on NK cells from subjects with the lower affinity CD16 polymorphism. The dose of mAb needed to induce NK activation was lower with Fc-eng-133 irrespective of CD16 polymorphism. Measure of activation - % of NK cells CD54 bright: EC50 ng/ml (mean moAb concentration +/− SEM): N=4 per polymorphism R AME-133 Fc-eng-133 p At saturating mAb concentrations, peak NK activation was greater for Fc engineered AME-133 when compared to R mAb for all samples studied Ratio of Fc-eng-133 to R % NK cells CD54 bright 1.35 +/− 0.07 IFNg production 2.64 +/− 0.43 These data indicate tumor cells coated with mAb with enhanced affinity for CD16 are more effective at activating NK cells at both low and saturating mAb concentrations irrespective of CD16 polymorphism, and provide further evidence for the clinical development of such mAb with the goal of improving clinical response to mAb.

The fully human monoclonal IgG1 antibody HuMax-CD20 targets a novel epitope of the CD20 molecule on B-cells. HuMax-CD20 stops growth of engrafted B-cell tumors in SCID mice more efficiently than Rituximab and i.v. infusion of HuMax-CD20 in cynomolgus monkeys leads to profound, long lasting, dose-dependent B-cell depletion. Data are presented from an open label, dose-escalation, multicenter phase I/II clinical trial. 3 cohorts of 3 (A), 3 (B) and an extended cohort of 27 (C) patients with relapsed or refractory chronic lymphocytic leukemia (B-CLL) received 4 weekly i.v. infusions of HuMax-CD20 and will be followed for 12 months. The first infusion administered was 100 mg, 300 mg and 500 mg in cohort A, B and C. The following 3 infusions were of 500, 1000 and 2000 mg, respectively. Patients were premedicated with oral acetaminophen and i.v antihistamine and received i.v. glucocorticoids before first and second infusions. The endpoints are B-cell depletion, adverse events, objective response according to the NCI working group guidelines for CLL, time to progression, duration of response, time to next anti-CLL treatment, and pharmacokinetics. Biopsies and CT images are evaluated centrally. Median age was 61 years; median time since diagnosis was 6.3 years. Maximum tolerated dose was not reached. Adverse events were predominantly observed on days of infusion and as expected most frequently symptoms of cytokine release e.g. rash, increased sweating, fatigue, rigors, pyrexia, and headache. 5 serious adverse events assessed as related to HuMax-CD20 treatment have been reported: hepatic cytolysis, herpes zoster, neutropenia (2 patients) and one death from pneumonia at week 4. In cohorts A and B, markedly reduced CD19+CD5+ cell counts were observed in 3 of 6 patients one week after final treatment and the depletion was sustained in one of these patients. In cohort C a pronounced CD19+CD5+ reduction was demonstrated by all patients; in fact the lymphocyte counts were ≤4.0 x 109/L in 21 patients. At week 11, ≥50% reduction in the product of diameters of lymph nodes was observed in 12 of 20 evaluable patients with enlarged lymph nodes. A response rate of 52% (11 of 21 evaluable patients in cohort C) was observed at week 11: 4 clinical CR (bone marrow and CT pending), 7 PR, 3 SD and 7 PD. In conclusion, this preliminary analysis of data from the first 33 CLL patients treated with HuMax-CD20 demonstrated significant depletion of CD19+CD5+ cells, a favorable safety profile and an indication of clinical efficacy. An updated report for all patients at week 19 will be presented.

There is indirect but intriguing evidence that complement plays a role in the clinical response to rituximab and other mAb-based therapies of cancer. We identified a non-coding polymorphism in the C1qA component of complement that appears to result in a post-translational splice variant of the C1qA protein. We examined this polymorphism in 90 patients with follicular lymphoma who were treated with single agent rituximab to assess whether a correlation exists with clinical efficacy. The presence of an A versus a G allele at the C1qA[276] locus was determined using restriction fragment length polymorphism analysis by investigators blinded to the clinical outcome of the patients. The molecular and clinical data was then analyzed according to C1qA polymorphism, including measurement of radiographic response and duration of response, using methods similar to those used to evaluate the correlation between polymorphisms in CD16/CD32 genes and clinical outcome. No statistically significant difference in response rate was found based on C1qA polymorphism. However, prolonged remission was noted among those subjects that achieved remission (either PR or CR) for individuals who were carriers of the A allele at the C1qA[276] locus (AA or AG) compared to homozygous GG subjects. The strongest correlation was found among those subjects that achieved a complete remission to single agent rituximab. In this group, GG subjects had a time to progression of 250 days, while AA /AG subjects had time to progression of 830 days (HR=4.1, 95% CI=2.1–96.9). Multivariate Cox regression analysis of the joint effects of the C1qA, CD32 and CD16 polymorphisms showed that C1q[276] A allele was an independent factor for good prognosis, while FcgRIIIa 158 phenylalanine carrier and FcgRIIa 131 arginine carrier indicated poor survival. Thus, the relative risk was 0.2 for C1qA[276] AA/AG versus GG after controlling for CD32 and CD16 polymorphisms. The relative risks were 4.8 for CD32 HR versus HH and 6.16 for CD32 RR versus HH after controlling for complement and CD16 polymorphisms. The relative risks were 4.57 for CD16 VF against VV and 3.69 for CD16 FF versus VV after controlling for complement and CD32 polymorphisms. These data suggest polymorphisms in C1qA may impact on duration of response to rituximab therapy of follicular lymphoma. Ongoing studies are expanding this cohort, assessing whether this polymorphism correlates clinically with outcome in other malignancies or with other therapeutic approaches in lymphoma patients, and exploring the functional significance of this C1qA polymorphism. If further studies confirm that C1qA genetic polymorphisms correlate with duration of response to rituximab, it will have major implications on our understanding of the role of complement in the immune response to lymphoma, and on development of the next generation of mAb-based cancer treatments. | | Total | AA+AG | GG | p (log-rank test) | |:------------------------------------- | ----- | ----- | --- | ----------------- | | TTP=Median time to progression (days) | | All Subjects | 90 | 70 | 20 | | | Responders | 59 | 46 | 13 | | | CR | 27 | 22 | 5 | | | TTP Overall | 177 | 173 | 191 | 0.64 | | TTP Responders | 352 | 456 | 334 | 0.12 | | TTP CR | 798 | 830 | 250 | 0.007 | ![Figure][1] Complement C1qA polymorphism associates with freedom from progression in follicular lymphoma patients who achieve a CR after anti-CD20 therapy. Progression-free survival logrank curves were plotted by C1qA[276] AA and AG vs GG genotype. Cheson criteria were used to estimate complete clinical remission after one round of anti-CD20 therapy. [1]: pending:yes

6642 Background: Radiotherapy is frequently advocated as a standard therapy for patients with limited stage follicular small cleaved lymphoma (FSC) and follicular mixed small and large cell lymphoma (FM). Long-term analysis of institutional series have demonstrated one-third to one-half of patients have prolonged relapse free survival. Methods: This retrospective review of the SEER-9 database was conducted to determine the frequency and outcome of radiotherapy administration as part of the first course of treatment among a population-based cohort. ICD-O-2 diagnostic morphology codes were used to identify a cohort of patients with limited stage FSC and FM, diagnosed between 1983 and 2001. Results: A cohort of 3,165 patients was identified from nine SEER registries. The cohort was comprised of 1,687 (53.3%) females, 1,822 (57.9%) FSC, and 1,326 (42.1%) FM. The most frequent anatomic sites of presentation included head and cervical lymph nodes (37.2%), inguinal lymph nodes (22.0%), axillary lymph nodes (9.8%...

Background: CT imaging has routinely been used for assessing therapy response in most malignancies including Non-Hodgkins Lymphoma (NHL). The presence of residual tumor is generally categorized using the International Workshop Criteria from CT imaging and bone marrow biopsies for assessing response after treatment. CT imaging has limitations in assessment of response to therapy in NHL with false positive results due to residual masses having viable tumor cells in less than 20% and the remainder being fibrosis or necrosis. In addition false negative CT results are seen due to viable tumor cells in nodes measuring less than 1.5 cm in size. F-18 FDG PET scans provide metabolic imaging of viable tumor cells due to uptake and retention of F-18 fluorodeoxyglucose preferentially in malignant cells. Method: Forty-eight patients with aggressive NHL having completed anthracycline-based chemotherapy had the post therapy FDG PET scans and CT scans reviewed by experienced readers blinded from the comparison scan and from the clinical history. PET scans were read as positive or negative for abnormal FDG consistent with residual viable tumor and the CT was read as positive or negative for nodes greater than 1.5 cm in diameter. Records were reviewed for tumor histology and evidence of tumor relapse with a median follow-up of 35 months. Results: The FDG PET and CT imaging prediction of PFS at 2 years had positive predictive values of 67% and 38%, negative predictive values of 88% and 78%, and accuracy of 81% and 50% respectively. The sensitivity and specificity of the FDG PET scan was 71% and 82% for predicting disease progression within 2 years from beginning treatment. Conclusion: FDG PET imaging was compared with CT imaging done after completing initial chemotherapy for aggressive NHL and demonstrated superior prediction of tumor response status at 2 years. These results indicate that FDG PET imaging should be combined with bone marrow biopsy for restaging aggressive NHL after completion of chemotherapy. The use of FDG PET is more accurate and should replace response assessment by CT imaging in most pateints with aggressive NHL following treatment.

Immunostimulatory CpG-containing oligodeoxynucleotides (CpG ODN) are TLR9 agonists that mediate a number of immunologic effects in normal and malignant B cells including upregulation of immunogenic molecules. They are therefore felt to be attractive as potential components of immunotherapy for B cell chronic lymphocytic leukemia (B-CLL). The cytogenetic status of B-CLL is predictive of clinical prognosis, but little is known about how CpG ODN-mediated effects on B-CLL cells correlate with cytogenetic status. The present study was designed to explore the impact cytogenetic status has on in vitro B-CLL cell survival and immunogenicity. Since most in vitro studies to date have been performed under serum-low conditions, we also evaluated how the presence of autologous serum or plasma impacts on CpG ODN-mediated effects on B-CLL cells. B-CLL cytogenetic status by interphase FISH, as well as immunophenotype and cell survival in the absence or presence of CpG ODN was determined in 23 samples. CpG ODN decreased in vitro survival of B-CLL cells with good prognosis cytogenetics, but had little effect on cells with poor prognosis cytogenetics. In contrast, CpG ODN upregulated costimulatory and antigen-presenting molecules and enhanced allogeneic T cell response in samples with good and poor prognosis cytogenetics. The optimal concentration for CpG ODN-mediated effects in the presence of 100% autologous serum or plasma was higher (10–20 micrograms/ml ODN) than for serum-low conditions (2.5–5 micrograms/ml ODN). The observed inhibition of CpG ODN-mediated effects by serum directly correlated with a lower uptake of ODN into B-CLL cells in the presence of serum. In conclusion, CpG ODN induced changes in B-CLL consistent with enhanced immunogenicity in all samples studied, but induced apoptosis most effectively in the subset of B-CLL cells with good prognosis cytogenetics. Approximately 4-fold more CpG ODN was needed to induce these changes when serum was present as compared to low serum conditions due to decreased ODN uptake by the cells in the presence of serum. These studies suggest CpG ODN may be useful as immunotherapeutic agents for B-CLL irrespective of cytogenetic status because of their potential effects on immunogenicity. Higher systemic doses of CpG ODN than previously thought might be necessary to induce these changes because of the effect of serum proteins on ODN uptake.

BACKGROUND: When neutropenia without infection is encountered while treating Hodgkin’s Lymphoma (HL) with ABVD chemotherapy clinicians may choose to delay or reduce the chemotherapy dose or maintain the dose intensity and schedule with or without neutrophil growth factor support out of concern for neutropenic complications. We sought to determine the frequency of neutropenia and febrile neutropenia (FN) during ABVD chemotherapy. METHODS: We examined the medical records of all patients seen at Univ. of Iowa diagnosed with HL between 1/1/1990 and 12/31/2002 treated with ABVD chemotherapy. We reviewed the charts with complete chemotherapy dosing records to determine the incidence of neutropenia, dose reduction, dose delay and chart record of febrile neutropenia (FN). RESULTS: 218 patients were seen at UIHC with the diagnosis of HL. 104 patients were treated with ABVD chemotherapy. Adequate dosing data was available for 82 of these patients (894 treatments). On scheduled day of treatment (Day 1 and 15 of each cycle) at least Grade III neutropenia (ANC 4 days and/or dose reduction to < 80% of original doxorubicin dose following neutropenia occurred at only 10 of 165 treatments. No episodes of FN developed in this cohort. 155 treatments at the time of neutropenia were administered without dose reduction or dose delay. Growth factor support was co-administered in 55 (36.77%) of these treatments and the remaining treatments at the time of neutropenia (73.23%, n=100) were administered without growth factor support. One episode of FN developed in each of these subsets. No FN was observed following the 56 treatments administered with an ANC < 500, including 54 managed without DM (32 with GCSF support and 22 without). 672 treatments were administered with ANC ≥ 1000 resulting in 6 episodes of FN. DM was observed in 78 of these 672 treatments with 3 subsequent episodes of FN. 57 treatments (4 with DM, 23 with GCSF, 20 without GCSF, 14 unknown GCSF) had no available ANC data and were associated with one episode of FN. FN developed a total of 9 times in 8 of 82 patients over 894 treatments. CONCLUSION: Among HL patients treated with ABVD chemotherapy we found a high frequency of neutropenia - most commonly following treatment 1. We found a very low incidence of FN that was independent of neutropenia at the time of chemotherapy administration. Dose modification for neutropenia without infection at the time of ABVD administration is not required to reduce risk of FN, and should be avoided in settings where maintaining dose intensity is considered valuable.

6578 Background: Follicular lymphomas (FL) comprise 17% of non-Hodgkin lymphoma cases in the United States. Several single- and multi-institution groups have published analyses of long-term follow-up of FL patients, yet it remains unclear whether survival patterns in FL have changed over the past twenty years. Methods: Using data provided in the National Cancer Institute's SEER program, 12,088 patients with FL were identified by ICD-O-2 diagnostic codes: grade I (9693–9696), grade II (9691–9692), grade III (9697–9698), grade NOS (9690). Observed median survival curves and proportional death hazard ratios were calculated from Cox regression analysis using SAS version 8.2. SEER*Stat 5.0 was used to calculate relative survival rates where expected survival rates were based on mortality rates for the entire U.S. population. Survival probabilities were calculated accounting for diagnosis era (1983–89, 1990–99), age at diagnosis, gender, race, and tumor grade at diagnosis. Results: Compared with FL patients dia...

6533 Background: FDG-PET is increasingly being utilized for response assessment of NHL. The purpose of this study was to determine whether FDG-PET+CT result in a more accurate response classificati...

PreviewAmong the fibrosing diseases is a group of four related disorders that affect the hands, fingers, soles, and penis. Because these disorders may occur together, as well as singly, knowledge of their relationship is important to the treating physician. In this brief review, Dr Wooldridge stresses the common clinical features shared by these diseases.

A simple configuration is first proposed for the pores used by sodium and potassium ions in moving through the neural membrane. The voltage dependence of the ion current through a system of such pores is then derived from diffusion theory and shown not to agree well with experimental observation. Good agreement is obtained, however, when the end segments of the pores are modified to include constrictions and ion-specific trapping centers.

This paper examines the synaptic microchemistry required if a memory neuron is to have the operating characteristics previously attributed to it [Wooldridge, D.E. (1980) Proc. Natl. Acad. Sci. USA, 77,2305-2308]. It is concluded that the requirements can be met by a combination of membrane mechanisms not very different from those that are commonly postulated to explain the properties of known types of neurons.

With a source containing carbon enriched about ten times in ${\mathrm{C}}^{13}$, the violet CN bands have been photographed with a dispersion of 0.63A/mm. Measurements are given of the lines of low rotational quantum number in the 0,0, 0,1 and 0,2 bands of ${\mathrm{C}}^{13}$${\mathrm{N}}^{14}$, as well as of ${\mathrm{C}}^{12}$${\mathrm{N}}^{14}$. The vibrational constants of the normal states of both molecules are accurately determined, and give a value of the isotope mass coefficient $\ensuremath{\rho}=\frac{{{\ensuremath{\omega}}_{e}}^{i}}{{\ensuremath{\omega}}_{e}}$ of 0.97898\ifmmode\pm\else\textpm\fi{}0.00002, corresponding to a mass for ${\mathrm{C}}^{13}$ of 13.0088. This is in essential agreement with the mass-spectrograph value, and it is shown that the finer corrections to the isotope effect are negligible in this case.

1.1. Two new cases of Meigs' syndrome are presented and theories as to the pathogenesis of the syndrome are discussed. 2.2. In one of the cases it is of particular interest that the patient had been operated upon four years previously at which time the left ovary was found to be normal. During the intervening four years the ovary grew to the size of a small grapefruit and was shown at operation to be replaced by a typical fibroma. 3.3. During the preoperative course of the first patient a right pleural effusion, noted on admission, changed character from that of a simple transudate to a serosanguineous effusion with 65 per cent eosinophiles. No explanation is offered for the change in the nature of the effusion. 4.4. The second patient had a pseudomucinous cystadenoma of the right ovary with massive ascites and right pleural effusion.

Measurements have been made on the effects of temperature changes on the emission of secondary electrons from iron, nickel, cobalt, and molybdenum. Abrupt changes of one or two percent were observed to accompany the $\ensuremath{\alpha}\ensuremath{-}\ensuremath{\gamma}$ transition of iron, while the hexagonal to face-centered cubic transformation of cobalt was accompanied by a change in secondary emission of only about 0.4 percent. The magnetic transformation was found to alter the secondary emission coefficient of nickel by less than 0.3 percent. The temperature coefficient of secondary emission, in the case of nickel, cobalt, and molybdenum was found to be much less than the volume coefficient of expansion of the metal. The smallness of the temperature coefficient and the effect of the magnetic transformation are shown to lend support to the view that the secondary electrons are scattered or "absorbed" by an excitation process similar to that whereby they are originally produced.

Surface coupled heat release effect on oscillatory amplitude of pressure coupled response in solid propellant

Military research and development possesses features of interest to physicists other than the employment opportunities provided by projects in this field. Military systems development work, in particular, affords technical problems of unusual variety, the solution of which frequently involves a degree of scientific teamwork not commonly encountered in other forms of industrial research and development.

Results are presented of an experimental study consisting of two parts: 1) an investigation of the turbulent velocity fluctuation field in an isothermal boundary layer with homogeneous injection, and 2) a preliminary investigation of the turbulent velocity and temperature fluctuation fields in a boundary layer with both mass addition and combustion. The isothermal data indicate that the mean velocity profile with mass injection is well described by danger's universal velocity distribution when a pseudofriction velocity is defined using the maximum shear stress in the boundary layer. The turbulent intensities are increased significantly, and spectral measurements indicate that the additional energy is introduced at low wave numbers. As the mass addition rate increases, a progressively larger portion of the boundary layer tends to become isotropic in character, as though the interaction between the mean flow and the turbulence near the wall is damped by the blowing. Combustion measurements indicate that the turbulent intensity of the velocity fluctuation normal to the wall is approximately doubled near the wall, reflecting energy transfer from the combustion region to the turbulence. The spectral shapes obtained between the flame zone and the wall show distortion caused by combustion, as predicted by Eschenroeder.

The primary object of the work described here was to determine what properties of the tape and associated magnetic elements are responsible for the noise and signal output levels of magnetic recordings and, if possible, to display in specific equations the pertinent relation-ships connecting noise and signal levels with the physical properties of the tape and polepieces. In the course of the study, methods appeared for decreasing the noise and increasing the useful signal reproduced from magnetic tape. These methods and some of the use that Bell Telephone Laboratories and Western Electric have made of them are mentioned in the discussion. While some of the work described in this paper has implications for more than one type of magnetic recording process, perpendicular recording on tape1 is the actual subject matter dealt with. In every case discussed, the record medium was 0.050 inch wide and 0.0022 inch thick. Except where otherwise noted, a chrome-steel tape was used at a speed of 16 inches per second.

This paper outlines methods for calculating the ballistic behavior of hybrid propellant combinations. The effects of scaling, pressure level, and internal geometric configuration are examined, utilizing a machine analysis that is based upon heat-transfer-limited theory. It is shown that the crucial aspect of efficient hybrid grain design is the proper matching of the surface area progressivity to the regression rate-mass flux dependence. Consideration is given to the interaction between the convective and radiative modes of heat transfer and to general aspects of throttling. Regimes of operation where the heat-transfer-limited theory begins to break down are delineated.

The production of secondary emission by the interaction of bombarding electrons with the valence electrons of a metal target is quantum-mechanically treated. When the results are modified by considerations having to do with the relative rates of absorption of the primary and secondary particles, yield-vs.-bombarding energy curves are obtained which approximate the results of experiment. The primary voltage required for maximum yield, the effect of work function on the emission, and the energy range of the secondary particles are semi-quantitatively derived in terms of the properties of the target material.

The driving mechanism of high-amplitude axial-mode solid-rocket combustion instability, that appears as an oscillating shock wave in the combustion chamber, is considered. The pressure pulse associated with the traveling shock wave induces a burning rate-perturbation as the wave passes over the propellant surface. Of primary interest, in this paper is the interaction mechanism through which this burning-rate response supports the shock wave, causing combustion instability. A simplified analysis of this complex interaction provides a first-order estimate of the minimum combustion response that will drive the oscillating shock wave. Empolying a theoretical treatment of the propellant response, the, analysis predicts the limits of the stable operating regime on the basis of two criteria: (1) the traveling wave must oscillate at a frequency near the predicted resonant response frequency of the propellant and (2) the predicted response amplitude at the resonant frequency must exceed the theoretical minimum value required to drive the shock wave. The theoretical treatment is compared with data from motors 15 in., 23 in., 40 in., and 82 in. in length, using a range of propellants, and is shown to provide a consistent explanation of the experimental observations.

An apparatus has been constructed, similar to that of G. Hertz[3], making use of the difference in the thermal velocities of molecules of different weight to separate the isotopes of a gas. The problems of design and their solution are discussed in detail. Data are given to show the separation and equilibrium time of apparatus of several types, when used to separate mixtures of various initial concentrations of hydrogen and nitrogen, carbon dioxide and nitrogen, and carbon dioxide and argon. Mass spectrometer measurements on the end-products of a separation process performed on the neon isotopes, with an apparatus containing fourteen mercury diffusion pumps, show the separation to be the same as for mixtures of carbon dioxide and argon, for which the mass ratio, 44:40, is the same as the 22:20 ratio of the neon isotopes. Separation processes performed with an apparatus of twenty-four pumps on carbon dioxide-argon mixtures reveal that the separation factor--i. e., the ratio of the relative abundance of the heavy gas at one end of the system to its relative abundance at the other end, when equilibrium has been reached--and the equilibrium time are practically independent of the initial mixing ratio of the components. Hertz' approximate theory of the diffusion apparatus is extended to permit the calculation of the "enrichment factor"--i. e., the ratio of the relative abundance of the heavy gas at the "heavy" end of the system, after equilibrium is reached, to its relative abundance in the gas initially admitted to the system. The effects of impurities, viscosity, pressure gradients in the system, and insufficient pumping speed are discussed quantitatively. Work done on methane, to concentrate C13, and on nitrogen, to concentrate N15, is described. Photographs of the band spectra of C2, CN, and N2 are given which show isotope bends of sufficient intensity to make possible quantitative mass measurements on the rare isotopes C13 and N15. Methane has been produced containing 16% of C13, and nitrogen gas has been produced containing 3.3% of N15, instead of the 1% and 0.3% in the respective normal gases.

The relationship between open-field emotional reactivity and alcohol preference was investigated in crosses of the Maudsley and Roman rat lines. No significant differences were found in any of the behaviors between the respective reciprocal crosses. The scores on the two variables showed a positive correlation between open-field defecation (OFD) and alcohol preference. The findings confirmed a prediction for the relationship between OFD and alcohol preference in these genetic crosses. In light of the previous findings it would seem that OFD and alcohol preference are not directly related to each other, and emotional reactivity acts as a mediating process between the two behaviors. However, in these genetic crosses the observed relationship between OFD and alcohol preference can be explained by a possible genetic overlap between the mechanisms mediating these two behaviors.

The clinical evaluation of a fungicide is difficult. The tendency of fungous organisms to remain viable but go into resting states confuses the term “cure. With those problems in mind a project was designed to assay a new fungicide, 2-nitro-2-bromo-l-methoxy-l-phenylpropane. This compound shall henceforth be known by its commercial designation, P-594. f By the time that P-594 was brought to our attention the facts were already established that oral toxicity of this material was negligible and that therapeutic concentrations of the fungicide in a water soluble ointment base were not primary irritants for the skin of white rabbits (1). Moderate intraperitoneal toxicity for white mice was noted, the LDOO range being 195 ± 38 mg./kg. Also established were the facts that this material showed in vitro fungistasis for T. men-tagrophytes in a concentration of 1 mcg./ml. and for C. albicans in a concentration of 30 Mg./ml.