Background:Treatment of relapsed refractory multiple myeloma (RRMM) is complex and requires evaluation of disease and patient factors to maximize efficacy and minimize toxicity. As survival has improved with therapeutic advances, maintaining quality of life has become an important aspect of multiple myeloma treatment. Results from cohort B of the ongoing phase 2 MM‐014 trial (NCT01946477) have demonstrated that pomalidomide (POM) + low‐dose dexamethasone (LoDEX) + daratumumab (DARA) is safe and effective in patients with RRMM after first‐ or second‐line lenalidomide (LEN)‐based treatment.Aims:To evaluate the impact of POM+ LoDEX + DARA on health‐related quality of life (HRQoL) in patients with RRMM who received this regimen after first‐ or second‐line LEN.Methods:Patients with RRMM and 1 to 2 prior lines of treatment, LEN‐based treatment as their most recent regimen, and progressive disease during or after their last treatment line were eligible for inclusion in cohort B. In 28‐day cycles, patients received POM 4 mg/day on days 1–21 + LoDEX 40 mg/day (20 mg/day if aged > 75 years) on days 1, 8, 15, and 22, and DARA 16 mg/kg IV on DEX dosing days of cycles 1 and 2, then on days 1 and 15 of cycles 3–6, and then on day 1 of cycle 7 and beyond. Thromboprophylaxis was mandatory. The primary endpoint was overall response rate. HRQoL, an exploratory endpoint for cohort B, was assessed via EQ‐5D.Results:As of 15 October 2018, 108 patients were evaluable for HRQoL. Baseline characteristics were similar to those of the ITT population (N = 112). EQ‐5D completion rates for each cycle (1–6) were ≥ 88%. Through 6 treatment cycles, mean change from baseline in the EQ‐5D index and VAS health score was stable. At cycle 6, minimum clinically important improvement in the EQ‐5D index (≥ 0.1) and VAS health score (≥ 6) was achieved by 28.8% and 39.0% of patients, respectively. EQ‐5D index values were stable; however, a trend toward improvement was observed in usual activities, pain/discomfort, and anxiety/depression (Figure).Summary/Conclusion:In patients with RRMM who received POM + LoDEX + DARA after first‐ or ‐second‐line LEN based treatment, HRQoL was maintained or trended toward improvement, despite the combination of 3 drugs with distinct toxicity profiles. In context with the previously reported safety and efficacy data from cohort B of MM‐014, the results of this HRQoL analysis further support the earlier use of POM‐based treatment in RRMM immediately following treatment with LEN.image

BACKGROUND:The Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) are associated with increases in janus kinase 2 (JAK2) signaling, often resulting from the JAK2 V617F mutation. LY2784544 (gandotinib) is a potent, selective, small-molecule inhibitor of JAK2 that has potential dose-dependent selectivity for the JAK2 V617F mutation and may inhibit additional JAK2 mutant isoforms in nonclinical testing.METHODS:A multicenter, single-arm, outpatient phase 2 study evaluated the efficacy, safety, and pharmacokinetics (PK) of gandotinib administered to patients (120 mg once daily) with MPNs, including polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF). Between May 2012 and March 2015, 138 patients received at least one dose of study drug.FINDINGS:Most frequent Grade 3 or 4 treatment-emergent adverse events that were considered study-drug related were anemia (11.6%), hyperuricemia (3.2%), fatigue (2.9%), diarrhea (2.2%), and thrombocytopenia (2.2%). Overall response rates (ORRs) in patients with JAK2 V617F-mutated PV, ET, and MF were 95%, 90.5%, and 9.1%, respectively, while patients with ET and MF without the JAK2 V617F mutations had ORRs of 43.7% and 0%, respectively.INTERPRETATIONS:LY2784544 demonstrated efficacy in JAK2 V617F-mutated MPNs, including in patients previously on ruxolitinib therapy, who had an ORR of 3.3%. At the 1-year visit, 44% of patients experienced a ≥50% improvement in the MPN-Symptom Assessment Form Total Symptom Score, and 26% of patients had a 50% reduction in Brief Fatigue Inventory score.

Purpose/Objective(s)Non-Hodgkin's Lymphoma (NHL) B-Cell subtype is generally very sensitive to Chemotherapy and Rituxan. In patients who have developed refractory disease, the course of disease is usually rapidly fatal. Many NHL B-Cells express CD-20 Antigen. Such patients may be candidates for Radioimmunotherapy (RIT) with tositumomab murine monoclonal antibody conjugated with I-131, which can bind to CD-20 expressing cells with potentially lethal effects. We present results in 65 patients treated according to the Bexxar CP98-020 Protocol.Materials/MethodsInitially, candidates for Bexxar CP98-020 Protocol were patients with NHL expressing CD-20 which had become refractory to Chemotherapy and Rituxan. Since 2006, seven patients have received primary treatment for NHL with RIT. Eligibility criteria included Platelet count > 100,000, less than 25% involved bone marrow, and no kidney dysfunction. In addition, the patients could not be pregnant or breast feeding. Between 2001 and 2010, 65 patients received I-131 labeled Antibody. The total body dose was 75 cGy for platelet counts > 150,000 and 65 cGy for platelet 100-150,000. Activity ranged from 60 mCi to 120 mCi.ResultsMedian follow-up was 58 months (range, 6-112 months). The response rate was 73.8% (48/65), with complete response achieved in 26.2% (16/65) of the patients. Median progression free survival was 16 months. All seven patients treated with primary RIT remain free of recurrence, with follow-up periods ranging from 24-60 months. Toxicity was moderate, with 7.7% (5/65) of patients experiencing profound (Platelets < 10,000) thrombocytopenia, which was prolonged, lasting more than 20 weeks. There were no bleeding complications, and no patient required a transfusion. For the remaining 60 patients, platelet counts decreased mildly for 4-6 weeks following RIT, and then returned to normal values by 10-20 weeks.ConclusionsRIT has yielded promising 5 year results in NHL patients' refractory to Chemotherapy and Rituxan. Toxicity has been acceptable. RIT may be considered for first line treatment in some cases of NHL. Purpose/Objective(s)Non-Hodgkin's Lymphoma (NHL) B-Cell subtype is generally very sensitive to Chemotherapy and Rituxan. In patients who have developed refractory disease, the course of disease is usually rapidly fatal. Many NHL B-Cells express CD-20 Antigen. Such patients may be candidates for Radioimmunotherapy (RIT) with tositumomab murine monoclonal antibody conjugated with I-131, which can bind to CD-20 expressing cells with potentially lethal effects. We present results in 65 patients treated according to the Bexxar CP98-020 Protocol. Non-Hodgkin's Lymphoma (NHL) B-Cell subtype is generally very sensitive to Chemotherapy and Rituxan. In patients who have developed refractory disease, the course of disease is usually rapidly fatal. Many NHL B-Cells express CD-20 Antigen. Such patients may be candidates for Radioimmunotherapy (RIT) with tositumomab murine monoclonal antibody conjugated with I-131, which can bind to CD-20 expressing cells with potentially lethal effects. We present results in 65 patients treated according to the Bexxar CP98-020 Protocol. Materials/MethodsInitially, candidates for Bexxar CP98-020 Protocol were patients with NHL expressing CD-20 which had become refractory to Chemotherapy and Rituxan. Since 2006, seven patients have received primary treatment for NHL with RIT. Eligibility criteria included Platelet count > 100,000, less than 25% involved bone marrow, and no kidney dysfunction. In addition, the patients could not be pregnant or breast feeding. Between 2001 and 2010, 65 patients received I-131 labeled Antibody. The total body dose was 75 cGy for platelet counts > 150,000 and 65 cGy for platelet 100-150,000. Activity ranged from 60 mCi to 120 mCi. Initially, candidates for Bexxar CP98-020 Protocol were patients with NHL expressing CD-20 which had become refractory to Chemotherapy and Rituxan. Since 2006, seven patients have received primary treatment for NHL with RIT. Eligibility criteria included Platelet count > 100,000, less than 25% involved bone marrow, and no kidney dysfunction. In addition, the patients could not be pregnant or breast feeding. Between 2001 and 2010, 65 patients received I-131 labeled Antibody. The total body dose was 75 cGy for platelet counts > 150,000 and 65 cGy for platelet 100-150,000. Activity ranged from 60 mCi to 120 mCi. ResultsMedian follow-up was 58 months (range, 6-112 months). The response rate was 73.8% (48/65), with complete response achieved in 26.2% (16/65) of the patients. Median progression free survival was 16 months. All seven patients treated with primary RIT remain free of recurrence, with follow-up periods ranging from 24-60 months. Toxicity was moderate, with 7.7% (5/65) of patients experiencing profound (Platelets < 10,000) thrombocytopenia, which was prolonged, lasting more than 20 weeks. There were no bleeding complications, and no patient required a transfusion. For the remaining 60 patients, platelet counts decreased mildly for 4-6 weeks following RIT, and then returned to normal values by 10-20 weeks. Median follow-up was 58 months (range, 6-112 months). The response rate was 73.8% (48/65), with complete response achieved in 26.2% (16/65) of the patients. Median progression free survival was 16 months. All seven patients treated with primary RIT remain free of recurrence, with follow-up periods ranging from 24-60 months. Toxicity was moderate, with 7.7% (5/65) of patients experiencing profound (Platelets < 10,000) thrombocytopenia, which was prolonged, lasting more than 20 weeks. There were no bleeding complications, and no patient required a transfusion. For the remaining 60 patients, platelet counts decreased mildly for 4-6 weeks following RIT, and then returned to normal values by 10-20 weeks. ConclusionsRIT has yielded promising 5 year results in NHL patients' refractory to Chemotherapy and Rituxan. Toxicity has been acceptable. RIT may be considered for first line treatment in some cases of NHL. RIT has yielded promising 5 year results in NHL patients' refractory to Chemotherapy and Rituxan. Toxicity has been acceptable. RIT may be considered for first line treatment in some cases of NHL.

Non-Hodgkin's Lymphoma (NHL) B-Cell subtype is generally very sensitive to Chemotherapy and Rituxan. In patients who have developed refractory disease, the course of disease is usually rapidly fatal. Many NHL B-Cells express CD-20 Antigen. Such patients may be candidates for Radioimmunotherapy (RIT) with tositumomab murine monoclonal antibody conjugated with I-131, which can bind to CD-20 expressing cells with potentially lethal effects. We present results in 60 patients treated according to the Bexxar CP98-020 Protocol. Initially, candidates for Bexxar CP98-020 Protocol, were patients with NHL expressing CD-20 which had become refractory to Chemotherapy and Rituxan. Since 2006, six patients have received primary treatment for NHL with RIT. Eligibility criteria included Platelet count > 100,000, less than 25% involved bone marrow, and no kidney dysfunction. In addition, the patients could not be pregnant or breast feeding. Between 2001 and 2009, 60 patients received I-131 labeled Antibody. The total body dose was 75 cGy for Platelet counts > 150,000 and 65 cGy for Platelet counts of 100,000–150,000. Activity ranged from 60 mCi to 120 mCi. Median follow-up was 60 months (range, 6–94 months). The response rate was 73.3% (44/60), with complete response achieved in 28.3% (17/60) of the patients. Median progression free survival was 14 months. All six patients treated with primary RIT remain free of recurrence, with follow-up periods ranging from 12–56 months. Toxicity was moderate, with 8.3% (5/60) of patients experiencing profound (Platelets < 10,000) thrombocytopenia, which was prolonged, lasting more than 20 weeks. There were no bleeding complications, and no patient required a transfusion. For the remaining 55 patients, Platelet counts decreased mildly for 4–6 weeks following RIT, and then returned to normal values by 10–20 weeks. RIT has yielded promising results in NHL patients refractory to Chemotherapy and Rituxan. Toxicity has been acceptable. While follow-up is short, RIT may be considered for first line treatment in some cases of NHL.

Non-Hodgkin's Lymphoma (NHL) B-Cell subtype, is generally very sensitive to Chemotherapy and Rituxan. In patients who have developed refractory disease, the course of disease is usually rapidly fatal. Many NHL B-Cells express CD-20 Antigen. Such patients may be candidates for Radioimmunotherapy (RIT) with tositumomab murine monoclonal antibody conjugated with I-131, which can bind to CD-20 expressing cells with potentially lethal effects. We present results in 52 patients treated according to the Bexxar CP98-020 Protocol. Initially, candidates for Bexxar CP98-020 Protocol, were patients with NHL expressing CD-20 which had become refractory to Chemotherapy and Rituxan. Since 2006, four patients have received primary treatment for NHL with RIT. Eligibility criteria included Platelet count >100,000, less than 25% involved bone marrow, and no kidney dysfunction. In addition, the patients could not be pregnant or breast feeding. Between 2001 and 2008, 52 patients received I-131 labeled Antibody. The total body dose was 75 cGy for Platelet counts >150,000 and 65 cGy for Platelet 100-150,000. Activity ranged from 60 mCi to 120 mCi. Median follow-up was 54 months (range, 6-84 months). The response rate was 73.0% (38/52), with complete response achieved in 26.9% (14/52) of the patients. Median progression free survival was 14 months. All four patients treated with primary RIT remain free of recurrence, with follow-up periods ranging from 12-38 months. Toxicity was moderate, with 9.6% (5/52) of patients experiencing profound (Platelets < 10,000) thrombocytopenia, which was prolonged, lasting more than 20 weeks. There were no bleeding complications, and no patient required a transfusion. For the remaining 47 patients, Platelet counts decreased mildly for 4-6 weeks following RIT, and then returned to normal values by 10-20 weeks. RIT has yielded promising results in NHL patients' refractory to Chemotherapy and Rituxan. Toxicity has been acceptable. RIT may be considered for first line treatment in some cases of NHL.

Purpose/Objective(s)Non-Hodgkin's Lymphoma (NHL) B-Cell subtype, is generally very sensitive to Chemotherapy and Rituxan. In patients who have developed refractory disease, the course of disease is usually rapidly fatal. Many NHL B-Cells express CD-20 Antigen. Such patients may be candidates for Radioimmunotherapy (RIT) with tositumomab murine monoclonal antibody conjugated with I-131, which can bind to CD-20 expressing cells with potentially lethal effects. We present results in 38 patients treated according to the Bexxar CP98-020 Protocol.Materials/MethodsInitially, candidates for Bexxar CP98-020 Protocol, were patients with NHL expressing CD-20 which had become refractory to Chemotherapy and Rituxan. Since 2006, three patients have received primary treatment for NHL with RIT. Eligibility criteria included Platelet count >100,000, less than 25% involved bone marrow, and no kidney dysfunction. In addition, the patients could not be pregnant or breast feeding. Between 2001 and 2007, 38 patients received I-131 labeled Antibody. The total body dose was 75 cGy for Platelet counts >150,000 and 65 cGy for Plt 100–150,000. Activity ranged from 60 mCi to 120 mCi.ResultsMedian follow-up was 42 months (range 6–72 months). The response rate was 73.7% (28/38), with complete response achieved in 26.3% (10/38) of the patients. Median progression free survival was 14 months. All three patients treated with primary RIT remain free of recurrence, with follow-up periods ranging from 8–26 months. Toxicity was moderate, with 10.5% (4/38) of patients experiencing profound (Platelets <10,000) thrombocytopenia, which was prolonged, lasting more than 20 weeks. There were no bleeding complications, and no patient required a transfusion. For the remaining 34 patients, Plt counts decreased mildly for 4–6 weeks following RIT, and then returned to normal values by 10–20 weeks.ConclusionsRIT has yielded promising results in NHL patients refractory to Chemotherapy and Rituxan. Toxicity has been acceptable. While follow-up is short, RIT may be considered for first line treatment in some cases of NHL. Purpose/Objective(s)Non-Hodgkin's Lymphoma (NHL) B-Cell subtype, is generally very sensitive to Chemotherapy and Rituxan. In patients who have developed refractory disease, the course of disease is usually rapidly fatal. Many NHL B-Cells express CD-20 Antigen. Such patients may be candidates for Radioimmunotherapy (RIT) with tositumomab murine monoclonal antibody conjugated with I-131, which can bind to CD-20 expressing cells with potentially lethal effects. We present results in 38 patients treated according to the Bexxar CP98-020 Protocol. Non-Hodgkin's Lymphoma (NHL) B-Cell subtype, is generally very sensitive to Chemotherapy and Rituxan. In patients who have developed refractory disease, the course of disease is usually rapidly fatal. Many NHL B-Cells express CD-20 Antigen. Such patients may be candidates for Radioimmunotherapy (RIT) with tositumomab murine monoclonal antibody conjugated with I-131, which can bind to CD-20 expressing cells with potentially lethal effects. We present results in 38 patients treated according to the Bexxar CP98-020 Protocol. Materials/MethodsInitially, candidates for Bexxar CP98-020 Protocol, were patients with NHL expressing CD-20 which had become refractory to Chemotherapy and Rituxan. Since 2006, three patients have received primary treatment for NHL with RIT. Eligibility criteria included Platelet count >100,000, less than 25% involved bone marrow, and no kidney dysfunction. In addition, the patients could not be pregnant or breast feeding. Between 2001 and 2007, 38 patients received I-131 labeled Antibody. The total body dose was 75 cGy for Platelet counts >150,000 and 65 cGy for Plt 100–150,000. Activity ranged from 60 mCi to 120 mCi. Initially, candidates for Bexxar CP98-020 Protocol, were patients with NHL expressing CD-20 which had become refractory to Chemotherapy and Rituxan. Since 2006, three patients have received primary treatment for NHL with RIT. Eligibility criteria included Platelet count >100,000, less than 25% involved bone marrow, and no kidney dysfunction. In addition, the patients could not be pregnant or breast feeding. Between 2001 and 2007, 38 patients received I-131 labeled Antibody. The total body dose was 75 cGy for Platelet counts >150,000 and 65 cGy for Plt 100–150,000. Activity ranged from 60 mCi to 120 mCi. ResultsMedian follow-up was 42 months (range 6–72 months). The response rate was 73.7% (28/38), with complete response achieved in 26.3% (10/38) of the patients. Median progression free survival was 14 months. All three patients treated with primary RIT remain free of recurrence, with follow-up periods ranging from 8–26 months. Toxicity was moderate, with 10.5% (4/38) of patients experiencing profound (Platelets <10,000) thrombocytopenia, which was prolonged, lasting more than 20 weeks. There were no bleeding complications, and no patient required a transfusion. For the remaining 34 patients, Plt counts decreased mildly for 4–6 weeks following RIT, and then returned to normal values by 10–20 weeks. Median follow-up was 42 months (range 6–72 months). The response rate was 73.7% (28/38), with complete response achieved in 26.3% (10/38) of the patients. Median progression free survival was 14 months. All three patients treated with primary RIT remain free of recurrence, with follow-up periods ranging from 8–26 months. Toxicity was moderate, with 10.5% (4/38) of patients experiencing profound (Platelets <10,000) thrombocytopenia, which was prolonged, lasting more than 20 weeks. There were no bleeding complications, and no patient required a transfusion. For the remaining 34 patients, Plt counts decreased mildly for 4–6 weeks following RIT, and then returned to normal values by 10–20 weeks. ConclusionsRIT has yielded promising results in NHL patients refractory to Chemotherapy and Rituxan. Toxicity has been acceptable. While follow-up is short, RIT may be considered for first line treatment in some cases of NHL. RIT has yielded promising results in NHL patients refractory to Chemotherapy and Rituxan. Toxicity has been acceptable. While follow-up is short, RIT may be considered for first line treatment in some cases of NHL.

12020 Background: TMZ is an alkylating agent with activity in a variety of neoplasms. The optimal schedule of administration for TMZ has not been established and only a few studies have studied it in combination with other agents. Repair of TMZ-induced DNA damage is associated with the activity of O-6 alkylguanine-DNA-alkyl transferase (AGT). Preclinical and clinical data indicate that prolonged exposure to TMZ results, not only in enhanced DNA alkylation, but also in depletion of AGT. This serves as the rationale to study TMZ using protracted schedules. Methods: The aim of this study was to determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of oral TMZ given daily for 14 days with weekly paclitaxel in pts with advanced cancers. Forty-five pts received 136 cycles of TMZ at escalating doses (50, 75, 100, 125 and 150 mg/m2/day × 14 days) plus paclitaxel at 80 mg/m2 on days 1, 8, and 15. Pts were stratified as lightly (LP) or heavily (HP) pretreated and MTD defined as the dose level (DL) at which 1/6 patients developed DLT. Results: Twenty-four LP patients were treated at 5 DLs with all but one evaluable for toxicity. Febrile neutropenia and grade 3 thrombocytopenia were the DLTs. MTD in this group was the 125 mg/m2/day level. Twenty-six HP were treated at 5 DLs and 21 were evaluable for toxicity. Febrile neutropenia and grade 3 thrombocytopenia were the DLTs. MTD for this group was also 125 mg/m2/day. Thirty-eight (84%) pts were evaluable for response after 2 cycles of therapy. Three (8%) pts had a partial response (lung, lymphoma, ependymoma), 20 (53%) remained stable and 15 (39%) developed disease progression. Six (16%) pts remained stable for 6 cycles or more (2 sarcomas, 2 lung, 1 pancreas, 1 glioblastoma). Conclusions: We concluded that combining oral TMZ at a dose of 125 mg/m2/day for 14 days with standard-dose weekly paclitaxel is safe in both HP and LP pts. [Table: see text]

4635 Background: Prospective randomized multi-center studies have demonstrated safety/efficacy of single 1.0 mCi/kg doses of 153Sm-EDTMP in relieving pain/reducing opioid use in patients (pts) with symptomatic bone metastases. Toxicity was restricted to reversible sdecreases in white blood cells (WBCs) and platelets (PLTs). Less data exist on safety profiles of repeated dose radiopharmaceuticals. Methods: We prospectively investigated safety of multiple dose 153Sm-EDTMP in two separate clinical setting of pts with bone metastases: a) symptomatic patients (primarily hormone-refractory prostate cancer) received multiple doses of 1.0 mCi/kg based on symptom recurrence and normalized WBC and PLT counts, and b) hormone-sensitive stage chemotherapy naive D2 prostate cancer patients received multiple higher doses at fixed intervals in combination with hormone therapy. Results: Repeat doses (range 2–11 doses/patient) at 1 mCi/kg were given to 54 pts. The mean WBC nadir (% baseline) was 3.6±1.1 (49%), 3.6±1.1 (54%), and 3.5±0.9 (57%) for pts administered 1, 2, or ≥3 doses (respectively). Mean PLT nadir (and % baseline) was 129±37 (50%), 105±49 (48%), and 93±38 (50%). No grade 4 PLT or grade 4 WBC toxicities were noted. At the higher fixed interval dose of 2.0 mCi/kg/dose q 12 weeks (four planned cycles), 2/6 hormone sensitive D2 pts were unable to receive fourth cycles due to persistently low PLTs. An additional group (6 pts) with D2 prostate cancer planned to receive 3 doses at 2.0 mCi/kg/dose q 16 weeks. The three planned doses were completed in 5/6 pts. At this dose/schedule, the mean WBC nadir (and % baseline) was 2.5±0.5 (46%), 2.4±0.5 (52%), and 2.5±0.7 (57%) for pts administered 1, 2, or 3 doses. The mean PLT nadir (and % baseline) was 113±69 (47%), 110±45 (60%), and 102±21 (52%). Time to nadir was 5–6 weeks for both WBC and PLTs. No grade 3–4 PLT toxicities were observed but 5/6 pts had grade 3 WBC decreases. No grade 4 WBC decreases were noted. Conclusions: These data indicate that multiple doses of 1 mCi/kg of Samarium-153-lexidronam can be safely administered to pts provided normal WBCs and PLTs are present at dosing. For fixed interval dosing, we conclude that 2.0 mCi/Kg/dose q 16 weeks X 3 is safe in chemotherapy-naïve D2 prostate cancer pts. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Cytogen Cytogen

Purpose/Objective: Our experience of performing radioimmunotherapy dosimetry, radiation safety and clinical results using the Bexxar sponsored Iodine-131 labeled tositumomab are presented. A mathematical model developed for dosimetry for I-131 labeled radioimmunoconjugate (RIC) is presented. The dependence of mCi/Kgm of prescribed dose with residence time is analyzed. The distribution of residence time, total effective dose equivalent (TEDE) for the public and the exposure rate measured from the patient immediately following dose administration is presented for all the patients. The variation of platelet counts following therapy on all the patients treated with I-131 labeled RIC is analyzed. Materials/Methods: We have been using the Bexxar sponsored I-131 labeled RIC called Tositumomab for treatment of non-Hodgkin′s lymphoma since 2001, we have treated 11 patients since then. Patient specific dosimetry was performed on all patients using 5 mCi dosimetric dose and whole body counts performed at 0, 48 and 168 hours following dose administration. The total body residence time (TBRT), for 37% of activity to remain in the patient was determined using the 3 whole body counts. A spread sheet program was used for calculating the net count rates and the data was fitted to a mathematical model, which was used for calculating the TBRT. Based on the study, a relationship between TBRT and the calculated therapeutic activity expressed as mCi/kgm body mass was established. All patients treated were discharged on the same day, after therapeutic dose was administered, with radiation safety precautions called "safe release". The variation of TEDE was studied as a function of TBRT and exposure rate measured at 1 meter prior to discharge. The platelet counts taken before and after treatment at weekly and monthly intervals were used for estimating the recovery period following therapy. The clinical results of the patients treated at our center will be discussed. Results: A mathematical model was established for calculation of TBRT based on the total body counts. The calculated mCi/Kgm decreased with TBRT for both group of patients treated with total body dose of 65 cGy and 75 cGy. The mCi/Kgm was the same for 65cGy and 75 cGy for TBRT greater than 100 hours. From the results of 11 patients, the TEDE to public ranged from 175 to 325 cGy, while the exposure rate measured on the patient at 1 meter was less than the permissible value reported in the literature for safe release. The platelet counts decreased to a minimum after 2 weeks following therapy and then reached normal after 6 to 9 weeks in all 9 patients and for the remaining 2 patients, the recovery period was unusually longer due to prior chemotherapy regimen. The whole body scans taken on selected patients, during dosimetry will be presented for demonstrating the bio-distribution of the tracer. Conclusions: We have implemented the radioimmunotherapy technique for non-Hodgkin′s lymphoma as an out patient therapy procedure. All patients tolerated the treatment very well and there were no anaphylactic reaction observed during treatment and no elevation of TSH or HAMA after the treatment as evidenced from the follow up. One patient had up normal uptake in thyroid during dosimetry study and therefore, the patient was treated with Y-90 ibritumomab (Zevalin). The clinical response; partial and complete response for 11 patients was in line with the published data.

Physical vapour deposition (PVD) titanium aluminium nitride coated cutting tools are used extensively in global manufacturing for reducing production costs and improving productivity in a number of aggressive metal-cutting operations, namely, dry and high-speed machining. In this investigation, the performance of Ti1−xAlxN and Ti1−x−yAlxCryN coatings was assessed on Co-HSS twist drills used to machine grey cast iron. The failure criterion for drills was defined as a critical sized flank wear land at the outer corners of the drills. Using this criterion, the average tool life of uncoated twist drills was increased by factors of 2.5, 3.0 and 3.0 by Ti0.59Al0.41N, Ti0.27Al0.19Cr0.54N and Ti0.21Al0.14Cr0.65N coatings, respectively. Notwithstanding the similar increase in average tool life, the Ti1−x−yAlxCryN coatings produced more consistent results than the Ti1−xAlxN coated drills with standard deviations of 67, 3 and 19 holes, respectively. This result has significant practical implications in manufacturing, since drills are not replaced on an individual basis, but rather on a preset tool change frequency. The present paper discusses the performance of Ti1−xAlxN and Ti1−x−yAlxCryN coated drills in terms of average and practical drill life and concludes with remarks on the characterisation of PVD coatings and their significance on the performance of Co-HSS twist drills when dry machining grey cast iron.

Recent advances in cutting tool materials and PVD surface coatings are making high-speed dry machining an increasingly viable machining operation in commercial manufacturing sectors. High oxidation resistant coatings, such as TiAlN, are used extensively in global manufacturing for reducing production costs and improving productivity in such aggressive metal-cutting operations. In this investigation, the performance of TiN, Ti1−xAlxN and Ti1−x−yAlxCryN coatings was assessed on Co-HSS twist drills used to machine an automotive grade grey cast iron. As part of the study, two experimental methods were used to characterise the performance of the twist drills, namely, by an audible ‘screech’ and measurement of the progression of outer corner flank wear lands. Both techniques showed that a single layer TiN coating failed to outperform even uncoated twist drills when dry machining grey cast iron under aggressive machining conditions. However, using the measurement of outer corner flank wear technique, the average tool life of uncoated twist drills was increased by factors of 4.5, 6.5 and 6.9 by Ti0.59Al0.41N, Ti0.27Al0.19Cr0.54N and Ti0.21Al0.14Cr0.65N coatings, respectively. In the case of ‘screech’ failure, the average tool life of uncoated twist drills was increased by factors of 3.9, 7.3 and 10.8 by Ti0.59Al0.41N, Ti0.27Al0.19Cr0.54N and Ti0.21Al0.14Cr0.65N coatings, respectively. The performance of twist drills was also assessed using a number of quantitative techniques, namely, measurement of thrust and torque, hole diameter and drill wear. The latter was also observed using scanning electron microscopy (SEM) which showed an early onset of workpiece material transfer at the margins of the uncoated drills. In the case of the PVD coated drills, an improvement in the tribological interaction between the coatings and the grey cast iron workpiece resulted in a significant reduction in material transfer at the drill margins. The above results are discussed in terms of their affect on hole diameter and cutting forces.

Victoria Hospital, London, Ontario, Canada; Mount Vernon Hospital, UCH London and Westin Park Hospital, UK; Scott and White Clinic, TX, USA

The overall goal of this project is the development of a new methodology for translating advances in molecular level understanding of toxicological responses into a predictive tool for dose response in whole animals and humans exposed to single compounds or mixtures of compounds. The methodology incorporates a mechanistic cellular level model into a PBPK (physiologically based pharmacokinetic) model which simultaneously guides the development of an in vitro cell culture analog (CCA) to the PBPK. Where the PBPK specifies an organ, (e.g., liver) the in vitro or CCA system contains a compartment with the appropriate cell or cell population (e.g., hepatocytes for the liver). The CCA has significant advantages over other in vitro systems and PBPK systems used independently for evaluating metabolic responses to drugs or potentially toxic chemicals where the exchange of metabolites between organs is likely to be important. The CCA system is superior to a PBPK because an a priori description of complete metabolism is not required and secondary, unexpected interactions can be detected. The CCA system, unlike other in vitro systems, gives a dynamic response that realistically simulates in vivo interactions between organs. Furthermore, the CCA allows dosing on the same basis as animal tests (e.g., milligrams per kilogram of body mass equivalent). Because the construction of a CCA is guided by a PBPK, this approach allows extrapolation to low doses and across species, including extrapolation to humans. We have constructed a prototype system and have conducted proof-of-concept experiments using naphthalene as a test chemical. These experiments clearly demonstrate the ability to generate a reactive metabolite in one compartment and detect its effects (on LDH release and glutathione depletion) in a second compartment. However, this prototype device would be expensive to replicate and requires nearly constant supervision from a trained investigator. For this concept to replace animals an inexpensive, self-regulating device is needed. An initial design to accomplish this goal is described as well as the corresponding model using naphthalene as a test compound. (c) 1996 John Wiley & Sons, Inc.