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PURPOSE Although the majority of patients with relapsed or refractory large B-cell lymphoma respond to axicabtagene ciloleucel (axi-cel), only a minority of patients have durable remissions. This prospective multicenter study explored the prognostic value of circulating tumor DNA (ctDNA) before and after standard-of-care axi-cel for predicting patient outcomes. METHODS Lymphoma-specific variable, diversity, and joining gene segments (VDJ) clonotype ctDNA sequences were frequently monitored via next-generation sequencing from the time of starting lymphodepleting chemotherapy until progression or 1 year after axi-cel infusion. We assessed the prognostic value of ctDNA to predict outcomes and axi-cel–related toxicity. RESULTS A tumor clonotype was successfully detected in 69 of 72 (96%) enrolled patients. Higher pretreatment ctDNA concentrations were associated with progression after axi-cel infusion and developing cytokine release syndrome and/or immune effector cell–associated neurotoxicity syndrome. Twenty-three of 33 (70%) durably responding patients versus 4 of 31 (13%) progressing patients demonstrated nondetectable ctDNA 1 week after axi-cel infusion ( P < .0001). At day 28, patients with detectable ctDNA compared with those with undetectable ctDNA had a median progression-free survival and OS of 3 months versus not reached ( P < .0001) and 19 months versus not reached ( P = .0080), respectively. In patients with a radiographic partial response or stable disease on day 28, 1 of 10 patients with concurrently undetectable ctDNA relapsed; by contrast, 15 of 17 patients with concurrently detectable ctDNA relapsed ( P = .0001). ctDNA was detected at or before radiographic relapse in 29 of 30 (94%) patients. All durably responding patients had undetectable ctDNA at or before 3 months after axi-cel infusion. CONCLUSION Noninvasive ctDNA assessments can risk stratify and predict outcomes of patients undergoing axi-cel for the treatment of large B-cell lymphoma. These results provide a rationale for designing ctDNA-based risk-adaptive chimeric antigen receptor T-cell clinical trials.

The prognosis of patients with large B-cell lymphoma (LBCL) that progresses after treatment with chimeric antigen receptor (CAR) T-cell therapy targeting CD19 (CAR19) is poor. We report on the first 3 consecutive patients with autologous CAR19-refractory LBCL who were treated with a single infusion of autologous 1 × 106 CAR+ T cells per kilogram targeting CD22 (CAR22) as part of a phase 1 dose-escalation study. CAR22 therapy was relatively well tolerated, without any observed nonhematologic adverse events higher than grade 2. After infusion, all 3 patients achieved complete remission, with all responses continuing at the time of last follow-up (mean, 7.8 months; range, 6-9.3). Circulating CAR22 cells demonstrated robust expansion (peak range, 85.4-350 cells per microliter), and persisted beyond 3 months in all patients with continued radiographic responses and corresponding decreases in circulating tumor DNA beyond 6 months after infusion. Further accrual at a higher dose level in this phase 1 dose-escalation study is ongoing and will explore the role of this therapy in patients in whom prior CAR T-cell therapies have failed. This trial is registered on clinicaltrials.gov as #NCT04088890.

Despite impressive progress, more than 50% of patients treated with CD19-targeting chimeric antigen receptor T cells (CAR19) experience progressive disease. Ten of 16 patients with large B cell lymphoma (LBCL) with progressive disease after CAR19 treatment had absent or low CD19. Lower surface CD19 density pretreatment was associated with progressive disease. To prevent relapse with CD19− or CD19lo disease, we tested a bispecific CAR targeting CD19 and/or CD22 (CD19-22.BB.z-CAR) in a phase I clinical trial (NCT03233854) of adults with relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL) and LBCL. The primary end points were manufacturing feasibility and safety with a secondary efficacy end point. Primary end points were met; 97% of products met protocol-specified dose and no dose-limiting toxicities occurred during dose escalation. In B-ALL (n = 17), 100% of patients responded with 88% minimal residual disease-negative complete remission (CR); in LBCL (n = 21), 62% of patients responded with 29% CR. Relapses were CD19−/lo in 50% (5 out of 10) of patients with B-ALL and 29% (4 out of 14) of patients with LBCL but were not associated with CD22−/lo disease. CD19/22-CAR products demonstrated reduced cytokine production when stimulated with CD22 versus CD19. Our results further implicate antigen loss as a major cause of CAR T cell resistance, highlight the challenge of engineering multi-specific CAR T cells with equivalent potency across targets and identify cytokine production as an important quality indicator for CAR T cell potency., Bispecific CAR T cells targeting CD19 and CD22 exhibit clinical activity and low toxicity in patients with large B cell lymphoma and B cell acute lymphoblastic leukemia, with relapses associated with loss of CD19 but not CD22.

Background: Fit patients (pts) with mantle cell lymphoma (MCL) are commonly treated with immunochemotherapy and consolidative high-dose therapy + stem cell rescue (cHDT/SCR), yet this approach has not demonstrated an overall survival (OS) benefit in a randomized trial. Outcomes for pts with high-risk MCL (TP53 aberrancy, high proliferation index, blastic histology) after cHDT/SCR are poor, and not all pts with MCL are eligible for this approach. Methods: We conducted a phase II study of sequential immunochemotherapy incorporating lenalidomide enriching for pts with high-risk disease features (defined as blastoid/pleomorphic histology and/or Ki67 >=30%). The three phases of tx were: 1) lenalidomide (15 mg daily, days 1-14) plus R-CHOP for four 21-day cycles; 2) R-HiDAC for 2 cycles (initially age-based cytarabine 1-3 g/m2; 3 g/m2 dose removed after 16 pts due to hematologic toxicity); and 3) rituximab monthly plus lenalidomide (15 mg daily) for 6 months (mos). Eligibility requirements were untreated stage II-IV MCL, KPS ≥70%, and adequate organ function; we sought ≥2/3 high-risk pts. We performed MRD testing on peripheral blood (cellular DNA) using the clonoSEQ Assay (Adaptive Biotechnologies). We obtained PET/CT and MRD testing after each phase of treatment and also MRD evaluation at 6 mos post-rituximab + lenalidomide maintenance. The primary endpoint was the rate of 3-yr progression-free survival (PFS), (acceptable PFS ≥75%, unacceptable ≤60%, based on desired proportion of high-risk pts). Results: Among 49 pts enrolled, 47 were evaluable for PFS (1 had progressive disease (PD) and 1 had toxicity during len-R-CHOP). Characteristics for 47 evaluable pts are shown in Table 1: 64% were high-risk and 18% had TP53 mutation. 45 completed maintenance (1 had PD during R-HiDAC and 1 withdrew to pursue cHDT/SCR) and 43 achieved complete response (CR), 1 stable disease, and 1 PD at end of treatment (EoT), yielding overall response rate of 91%, all CR (Figure 1). With a median follow-up of 2.8 yrs among survivors, the 3-yr PFS was 64% (95 CI 50, 82) and OS 85% (95 CI 74, 99). Three-yr PFS differed by TP53 status (14% mut vs. 85% wt, P < 0.0001, Table 2). Of 4 pts with PD, 3 had TP53 mutation and 1 had an unknown mutation status. Among TP53 wt pts, there was no significant difference in outcomes by risk (Table 2). MRD results were not obtained in 4 pts. Among 45 pts with MRD results, tumor clonal characterization for MRD evaluation was successful in 87% (39/45). MRD results are shown in Figure 2. Examining the initial phase of treatment (len-R-CHOP and R-HiDAC), among 37 pts with results at 1x10-5 sensitivity (1E5) following len-RCHOP, a substantial proportion (32%, 12/37 pts) remained MRD+ and 11 of 12 MRD+ pts post len-RCHOP converted to MRD- following R-HiDAC. At 1x10-6 sensitivity (1E6) following R-HiDAC, 5/20 pts were MRD+, and among responding pts, shorter median PFS was observed in MRD+ versus MRD- pts (23.1 mos vs. NR, P = 0.03). Examining the final phase of treatment (rituximab + lenalidomide maintenance) and observation period, among 37 pts with MRD results at 1E5 at EoT, 4 were MRD+, 2 of which were simultaneous (within 2 weeks of testing) with relapse; the remaining two MRD+ pts had median PFS 4.9 mos versus 37.4 mos for the 32 non-relapsed MRD- pts (P < 0.001). At 1E6, 6 pts who were MRD- at EoT converted to MRD+ after 6 mos of observation. MRD status at 1E6 at 6-mos post-EOT correlated with PFS: among 20 non-relapsed pts (6 MRD+, 14 MRD-), median PFS was 30.8 mos for MRD- versus 13.2 mos for MRD+ (P = 0.02). Conclusions: In a novel approach of sequential immunochemotherapy plus lenalidomide enrolling majority high-risk pts, outcomes for TP53-mutant pts were poor and we did not reach our primary endpoint of 3-yr PFS ≥75%. Among TP53-wt pts, this treatment program was highly effective even among pts with elevated Ki-67 (>=30%) and was associated with a high response rate, a 3-yr rate of PFS of 85%, and a high rate of MRD- at EoT. A substantial proportion of pts converted to MRD- after receipt of R-HiDAC, highlighting the efficacy of cytarabine in MCL. There was a high rate of MRD- after induction chemoimmunotherapy (Len-R-CHOP + R-HiDAC) at 1E5 (97%) and at 1E6 (80%), and the latter predicted remission duration. Several pts converted from MRD- to MRD+ at 6-mos post-EOT and eventually relapsed, suggesting that a more prolonged period of maintenance may be beneficial. Finally, MRD at 1E6 at 6 mos following EoT predicted response duration. Disclosures Batlevi: Life Sci, GLG, Juno/Celgene, Seattle Genetics, Kite: Consultancy; Janssen, Novartis, Epizyme, Xynomics, Bayer, Autolus, Roche/Genentech: Research Funding. Dogan:National Cancer Institute: Research Funding; EUSA Pharma: Consultancy; Takeda: Consultancy; Seattle Genetics: Consultancy; Corvus Pharmaceuticals: Consultancy; Physicians Education Resource: Consultancy; Roche: Consultancy, Research Funding; AbbVie: Consultancy. Drullinsky:Novartis: Research Funding; Roche: Research Funding. Gerecitano:Janssen: Current Employment. Hamlin:Portola Pharmaceutics: Consultancy; J&J Pharmaceuticals: Research Funding; Juno Therapeutics: Consultancy; Celgene: Consultancy; Incyte: Research Funding; Molecular Templates: Research Funding; Portola: Research Funding; Karyopharm: Consultancy. Ho:Invivoscribe, Inc.: Honoraria. Jacob:Adaptive Biotechnologies: Current Employment, Current equity holder in publicly-traded company. Matasar:Rocket Medical: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy; Takeda: Consultancy, Honoraria; GlaxoSmithKline: Honoraria, Research Funding; IGM Biosciences: Research Funding; Janssen: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Immunovaccine Technologies: Honoraria, Research Funding; Merck: Consultancy; Bayer: Consultancy, Honoraria, Research Funding; Juno Therapeutics: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Teva: Consultancy; Genentech, Inc.: Consultancy, Honoraria, Research Funding. Moskowitz:Incyte: Research Funding; Imbrium Therapeutics, L.P.: Consultancy; Seattle Genetics: Consultancy; Miragen Therapeutics: Consultancy; Merck: Consultancy; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Merck: Research Funding. Mullins:Adaptive Biotechnologies: Current Employment, Other: shareholder. Straus:Elsevier: Membership on an entity's Board of Directors or advisory committees, Other: CME writer; NY Lymphoma Rounds: Consultancy; Imedex, Inc.: Speakers Bureau; Karyopharm Therapeutics: Membership on an entity's Board of Directors or advisory committees; Targeted Oncology: Consultancy, Speakers Bureau; ASH: Other: Conference in December 2019 on HL to other physicians during ASH; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees; OncLive: Speakers Bureau; Takeda Pharmaceuticals: Research Funding, Speakers Bureau. Younes:BioPath: Consultancy; Daiichi Sankyo: Consultancy; Takeda: Consultancy; Novartis: Consultancy; AstraZeneca: Current Employment; BMS: Consultancy; Curis: Consultancy; Epizyme: Consultancy; HCM: Consultancy; Janssen: Consultancy. Zelenetz:Amgen: Consultancy; Celgene: Research Funding; Genentech/Roche: Consultancy; Sandoz: Research Funding; Novartis: Consultancy; Janssen: Consultancy; Adaptive Biotechnology: Consultancy; Celgene: Consultancy; Gilead: Consultancy; BeiGene: Membership on an entity's Board of Directors or advisory committees; Gilead: Research Funding; MorphoSys: Research Funding; MEI Pharma: Research Funding; Roche: Research Funding. Kumar:Celgene: Honoraria, Other: Honoraria for Advisory Board; Astra Zeneca: Honoraria, Other: Honoraria for Advisory Board; Celgene: Research Funding; Pharmacyclics: Research Funding; Adaptive Biotechnologies,: Research Funding; AbbVie: Research Funding; Seattle Genetics: Research Funding; Kite Pharmaceuticals: Honoraria, Other: Honoraria for Advisory Board.

Background: CNS invasion in aggressive lymphoma (including diffuse large B-cell [DLBCL], double-hit [DHL], Burkitt [BL] and plasmablastic lymphoma [PBL]) remains a major diagnostic and therapeutic challenge. Parenchymal CNS invasion requires a brain biopsy to diagnose, and conventional CSF evaluations lack sensitivity. Furthermore, determining which patients (pts) without CNS disease at diagnosis might be at high risk of future CNS relapse, and thus would most benefit from aggressive CNS prophylaxis, is difficult. Predictors that use clinical variables (e.g. the CNS-IPI) can select a high-risk group with ~10% risk of CNS relapse, but ~50% of events occur in low/intermediate-risk groups. We evaluated a novel CSF assay that detects clonotype-specific cell-free DNA (cfDNA) by next-generation sequencing (NGS) combined with multiplex PCR (Chang T et al, BMC Cancer 2020). This assay can identify minimal residual disease (MRD) in the plasma of pts with DLCBL and can predict systemic relapse (Roschewski et al, Lancet Oncol 2015). Methods: To examine the diagnostic sensitivity of the NGS-MRD assay in the CSF, we prospectively collected CSF from 6 pts with lymphomas who had known parenchymal or leptomeningeal CNS invasion. We also tested stored DNA from historical CSF samples of 8 pts with CNS lymphoma who tested negative by conventional IGH-PCR. We then enrolled 19 pts with newly diagnosed high-risk lymphomas without CNS invasion to examine the prognostic value of the NGS-MRD assay in the CSF collected at diagnosis. In the two-step assay, tumor-specific clonotype sequences were first identified from genomic DNA in primary tumor specimens using NGS of rearranged IGK, IGH (VJ or DJ), and IGL loci. Tumor-specific clonotypes were then selected for tracking in the CSF (split into acellular CSF fluid and cell pellet) and in paired plasma samples. The assay quantitated copy numbers of each tracked sequence per mL of acellular CSF or per 106 cells in the pellet, as well as tumor clonotype frequency (%) per all B-cells. Results: The NGS-MRD detected tumor-specific clonotype in 100% of CSF samples from pts with known CNS lymphoma (n=6; Fig A), including pts with isolated parenchymal-only CNS disease that was not detected by CSF cytology, flow cytometry, or IGH-PCR. For pts with CNS parenchymal disease, median cfDNA copy count in the CSF fluid was 2 /mL (range, 0.4-929) and median clonotype frequency was 9.0% (range, 0.03-68.9%). For pts with leptomeningeal disease, these values were 2233 /mL (1.2-5620) and 37% (1.7-98.4%), respectively (Fig. B). Furthermore, the NGS-MRD assay detected tumor clonotypes in DNA isolates from 6 historical CSF samples (collected in 2014-2018) of pts with known CNS disease, in which lymphoma was not detectable by conventional IGH-PCR (2 additional historical samples failed DNA quality check). Among 19 newly diagnosed pts with no known CNS invasion (median age 57, 42% women, median LDH 352 IU/L), 12 (63%) had DLBCL with high risk of CNS relapse by virtue of high CNS-IPI or epidural tumor, and 7 had other high-risk histologies (2 DHL, 2 BL, HIV+ PBL, and 2 lymphoblastic leukemias). The CSF NGS-MRD assay was positive for tumor-specific clonotype in 8 pts (42%). Median cfDNA copy count in the CSF fluid was 3 /mL (range, 0.9-15.6) and median clonotype frequency was 18.6% (range, 1.4-28.5%). We observed no significant correlation between the amount of cfDNA and number of red cells /mL of CSF (a measure of potential CSF contamination by blood during collection procedure; Fig. C) or between the amount of cfDNA in plasma and in CSF (Fig. D). With median follow-up of 11 months, no pts with negative baseline NGS-MRD assay in CSF relapsed, whereas 2 of 10 with a positive assay had a CNS relapse (12-month incidence, 29%; Fig. E), despite both pts having negative CNS imaging, CSF cytology, flow cytometry, and IGH-PCR at diagnosis. Conclusions: In this proof-of-concept study, the NGS-MRD CSF assay showed 100% sensitivity for diagnosing intraparenchymal CNS invasion in aggressive lymphomas that were not detected in the CSF using conventional methods. In a prospective cohort of newly diagnosed pts without baseline CNS invasion but at high clinical risk for CNS relapse, the assay identified lymphoma-derived cfDNA in 42% of cases. The 100% sensitivity and 100% negative predictive value of the assay for subsequent CNS relapse warrants further prospective evaluation as a potential tool for personalizing CNS-directed prophylaxis. Disclosures Olszewski: Spectrum Pharmaceuticals: Research Funding; TG Therapeutics: Research Funding; Adaptive Biotechnologies: Research Funding; Genentech, Inc.: Research Funding. Mullins:Adaptive Biotechnologies: Current Employment, Other: shareholder.

Purpose Cold static storage (CSS) is the standard method for heart preservation during transplantation (HTx). However, CSS beyond 4 hours increases the risk of primary graft dysfunction (PGD). Hypothermic ex vivo perfusion (HEVP) of donor hearts allows oxygen delivery during preservation, and may facilitate extended donor preservation without increasing PGD risk. We compared post-HTx survival, systemic inflammation and cardiac function following donor heart preservation by CSS (2 hrs) versus HEVP (2 and 8 hrs). Methods Brain death was induced in donor sheep for 24 hrs. Donor hearts were preserved by a) CSS for 2 hrs (n=7), b) HEVP for 2 hrs (n=4), or c) HEVP for 8 hrs (n=4). Orthotopic HTx was performed in matched recipients. Recipients were weaned from cardiopulmonary bypass and monitored for 6 hrs. Recipient blood was collected and assayed for inflammatory cytokines and cardiac markers. Cardiac function was assessed by echocardiography. Results Six-hour survival was 71% following CSS, and 100% following 2 and 8 hrs HEVP, respectively. Recipients systemic interleukin-6 and 8 levels were reduced using HEVP vs CSS. Post-HTx haemodynamic function was no different between groups, but HEVP reduced the requirement for vasoactive support compared to CSS (2 hrs CSS: 1.57±0.7; 2 hrs HEVP: 0.35±0.09; 8 hrs HEVP: 0.35±0.05 mmHg−1). HEVP was associated with reduced post-HTx lactate (2 hrs CSS: 11.4±1.8; 2 hrs HEVP: 5.2±0.7; 8 hrs HEVP: 6.7±1.3 mmol/L), more stable base excess and physiological pH in blood. Post-HTx cardiac function was no different between groups. Cardiac troponin I levels were comparable between CSS vs. 8 hrs HEVP, but reduced with 2 hrs HEVP. Conclusion Preliminary data on donor heart preservation by HEVP shows promising outcomes in comparison to CSS. Heart preservation by HEVP can be extended up to 8 hours, without compromising post-HTx recipient survival. HEVP may assist in overcoming limitations in preservation time associated with HTx, without increasing PGD risk.

Purpose Brain death (BD) causes metabolic and energetic imbalances leading to cardiac dysfunction, and predisposes the donor heart to further injury following heart transplantation (HTx). The metabolic mechanisms required for myocardial energy production during BD and subsequent HTx are poorly understood. Our aim was to determine the myocardial metabolic profile and mitochondrial function following donor BD and HTx. Methods Donor BD in sheep was induced by inflation of a catheter placed through the skull (catheter placement, but no inflation for SHAM), followed by 24 hrs monitoring, and heart procurement (n=6/group, BD vs. SHAM). Additional donor hearts exposed to BD/SHAM were flushed with cold St Thomas cardioplegia, and stored via cold static storage (CSS) for ∼2 hrs. Following standard orthotopic HTx, recipients were weaned off bypass and monitored for ≤6 hrs prior to heart procurement (n=4/group, BD-Tx vs. Sh-Tx). Cardiac mitochondrial function was assessed using high resolution respirometry. Metabolic profiles were determined in hearts using metabolomics. Cardiac mitochondrial function was also determined in two sheep that underwent HTx following BD and 8 hr hypothermic ex vivo perfusion (HEVP) preservation. Results BD caused significant right ventricular (RV) mitochondrial uncoupling (vs. SHAM). HTx following CSS also impaired RV mitochondrial function, with these effects more pronounced in hearts exposed to both donor BD and HTx. Early findings show that HEVP improved cardiac mitochondrial function post-HTx (vs. CSS). Metabolically, BD increased myocardial amino-acid utilisation and accumulation of glucose metabolites. Post-HTx, particularly in those exposed to donor BD, there was a significant decrease in metabolites involved in mitochondrial respiration (eg. NAD, Acetyl-CoA) and accumulation of fatty acids and xanthine (purine breakdown). Conclusion BD appears to trigger cardiac mitochondrial uncoupling. This may be a protective mechanism against higher amino-acid utilisation and glucose accumulation, in order to maintain adequate mitochondrial function for cell survival. HTx following CSS, particularly from BD donors, induces significant mitochondrial dysfunction, which occurs in response to upstream metabolic impairments. Strategies that improve cardiac mitochondrial function or metabolism (eg. HEVP) may assist to improve HTx outcomes.

7552 Background: Axicabtagene Ciloleucel (Axi-cel) is an autologous anti-CD19 CAR T-cell therapy approved for the treatment of relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL). Long‐term analysis of the Zuma‐1 clinical trial showed ~40% of patients remained progression-free at 2 years (Locke, Lancet Oncology 2018). Early identification of patients who will later progress after CAR T cell therapy may improve clinical care and patient outcomes. Methods: As of 2/1/2019, we enrolled 50 patients on a multi-institutional, prospective study measuring circulating tumor DNA(ctDNA) minimal residual disease (MRD) in r/r DLBCL patients undergoing treatment with Axi-cel. Using an next generation sequencing-MRD assay (Adaptive Biotechnologies; Seattle WA), ctDNA levels were measured pre, 0, 7, 14, 21, 28, 56, 90, 180, 270, and 365 days following Axi-cel infusion. A pre-planned comparison between EDTA, Streck, and CFD tubes for the initial 10 enrolled patients determined the CFD tube provided optimal analyte stability over 144 hours following sample collection. CFD tubes are being used to collect all study samples. Results: 24 subjects have 3 or more months clinical follow up and their treatment ctDNA MRD significantly associated with clinical outcomes. A day 28 landmark analysis shows 12 patients were MRD negative and 12 patients were MRD positive as defined by detection of none or any tumor-associated ctDNA, respectively. 10 of 12 MRD+ patients subsequently developed progressive disease. In contrast, only 2 MRD- patients subsequently progressed and the 10 other patients remain in a CR. (p = 0.0033, Fisher's exact test). With a median follow up of 237 days, median PFS after Axi-cel infusion for day 28 MRD+ vs. MRD- patients is 93 days vs. not reach, p = 0.0010 by Log-rank test. Median OS for day 28 MRD+ vs. MRD- patients is 281 days after Axi-cel infusion vs. not reach, p = 0.0399 by Log-rank test. Conclusions: After Axi-cel infusion, day 28 ctDNA-based MRD significantly associates with PFS and OS and identified early at-risk patients prior to progression. These results provide a rationale for designing MRD-based risk-adaptive CAR T-cell clinical trials.

Background: Down’s syndrome (DS) is the most common genetic cause of intellectual disability. People with DS are at an increased risk of Alzheimer’s disease (AD) compared to the general population. Neuroimaging studies of AD have focused on medial temporal structures; however, to our knowledge, no in vivo case–control study exists comparing the anatomy of dementia in DS to people with AD in the general population. We therefore compared the in vivo brain anatomy of people with DS and dementia (DS+) to those with AD in the general population. Method: Using MRI in 192 adults, we compared the volume of whole brain matter, lateral ventricles, temporal lobes and hippocampus in DS subjects with and without dementia (DS+, DS-), to each other and to three non-DS groups. These included one group of individuals with AD and two groups of controls (each age-matched for their respective DS and general population AD cohorts). Results: AD and DS+ subjects showed significant reductions in the volume of the whole brain, hippocampus and temporal lobes and a significant elevation in the volume of the lateral ventricle, compared to their non-demented counterparts. People with DS+ had a smaller reduction in temporal lobe volume compared to individuals with AD. Conclusions: DS+ and AD subjects have a significant reduction in volume of the same brain regions. We found preliminary evidence that DS individuals may be more sensitive to tissue loss than others and have less ‘cognitive reserve’.

Mathematical models of cardiac function at the cellular level include three major components, such as electrical activity, Ca(2+) dynamics, and cellular shortening. We developed a model for mouse ventricular myocyte contraction which is based on our previously published comprehensive models of action potential and Ca(2+) handling mechanisms. The model was verified with extensive experimental data on mouse myocyte contraction at room temperature. In the model, we implemented variable sarcomere length and indirect modulation of the tropomyosin transition rates by Ca(2+) and troponin. The resulting model described well steady-state force-calcium relationships, dependence of the contraction force on the sarcomere length, time course of the contraction force and myocyte shortening, frequency dependence of the contraction force and cellular contraction, and experimentally measured derivatives of the myocyte length variation. We emphasized the importance of the inclusion of variable sarcomere length into a model for ventricular myocyte contraction. Differences in contraction force and cell shortening for epicardial and endocardial ventricular myocytes were investigated. Model applicability for the experimental studies and model limitations were discussed.

Brain and whole body localization and distribution of 125I-leptin was determined after intraperitoneal administration to ob/ob and db/db mice, and was compared to inhibition of food intake. Food intake was not significantly inhibited at3 hours post-injection, but was decreased significantly at 6 h (p0.0007) and 24 h (p0.02) in ob/ob mice, times at which97 % of the radioactive dose was found in the urine. The highest concentrations of 125I-leptin at all time-points were found in the serum, liver and kidneys. These findings were verified by whole body autoradiography. Virtually no 125I-leptin was found in the CNS at later timepoints in either ob/ob or db/db mice. Coronal sectioning of entire brains from ob/ob and db/db mice revealed 125I radioactivity localized to the choroid plexus and in the ventricular space, but not in other CNS regions. No differences in localization, accumulation, or clearance of 125I-leptin in ob/ob vs. db/db mice were found in any of the tissues studied. The present studies demonstrate that the inhibitory effect of leptin on food intake in the ob/ob mouse persists for up to 24 hours after a single dose, despite the complete degradation and elimination of the labeled leptin during the first several hours after injection.

The structural abnormalities and functional characteristics of dysfunctional prothrombin variants in two new kindreds have been determined. Prothrombin Corpus Christi (family 1) was purified and found to have markedly reduced fibrinogen clotting activity, yet normal amidolytic and near-normal platelet aggregating activity. A transition (C to T) at nucleotide position 8885, present in the heterozygous form in affected family members, resulted in the substitution of Cys for Arg 382. This substitution results in the loss of a positive charge within the fibrinogen-binding exosite of thrombin, thus accounting for the observed functional defect. A heterozygous C to T transition was also present at position 19994 in other family members with a hypoprothrombinemic phenotype. This mutation results in the replacement of Gln 541 (CAA) by a premature stop codon (TAA). Prothrombin Dhahran (family 2) was found to have markedly reduced fibrinogen clotting activity, but normal amidolytic activity. Affected family members were found to have a G to A transition at nucleotide position 7312 resulting in the substitution of His for Arg 271. This substitution results in the abolition of a factor Xa cleavage site, yielding meizothrombin rather than thrombin, on activation of prothrombin Dhahran by factor Xa. All but one of the above mutations occur at CpG dinucleotides, thus further supporting the observation of a high incidence of CpG transitions in hereditary dysprothrombinemia. The significant bleeding tendencies of individuals homozygous for prothrombin Dhahran (prothrombin clotting activity 5% to 7%) contrast sharply with the absence of significant chronic bleeding in the proband expressing prothrombin Corpus Christi (prothrombin clotting activity 2%). Our findings underscore the capacity of thrombin to contribute to clinical hemostasis by mechanisms other than its fibrinogen clotting activity.

Evidence from the USA has emerged that thiazolidinediones may have a negative effect on the skeleton and increase the risk of fracture, but the association between thiazolidinediones use and fractures has not been evaluated in an Asian population. Using the 2000-2005 Taiwan National Health Insurance claims database, this Taiwanese population-based nested case-control study explored the association between thiazolidinediones use and hospitalisation for bone fracture in type 2 diabetic patients.In the study cohort of type 2 diabetic patients, we identified 18,003 patients with fracture and 90,015 matched controls. Multivariable conditional logistic regressions were used to estimate the association between exposure to thiazolidinediones and fractures. Duration of thiazolidinediones use was defined on the basis of cumulative days of exposure to thiazolidinediones during the year prior to the index date, i.e.30 days, 30 to 180 days and180 days.More type 2 diabetic patients with fractures than controls used thiazolidinediones (fractures 5.99% vs control 4.06%). Thiazolidinediones use was associated with hospitalisation for fracture and the association was stronger with longer term exposure to thiazolidinediones (30 days OR 1.32 [95% CI 1.09-1.54], p = 0.005; 30-180 days 1.42 [1.24-1.62], p0.0001; and180 days 1.54 [1.37-1.74], p0.0001). This dose-response relationship was significantly evident in women (30 days, 1.20 [0.93-1.55], p = 0.17; 30-180 days, 1.57 [1.32-1.86], p0.0001; and180 days, 1.76 [1.52-2.04], p0.0001), but not in men.Long-term exposure of type 2 diabetic patients to thiazolidinediones was associated with higher odds of fractures among women without a significant increase in odds of fractures among men.

The differentiation effects of sodium butyrate were examined in a series of human pancreatic adenocarcinoma cell lines: Panc-1, a poorly differentiated cell line; HPAF, a pleomorphic cell line isolated in this laboratory; and two clones of the parental HPAF cell line, well-differentiated CD11 and less-differentiated CD18. Incubation with 2 mM sodium butyrate induced a dramatic decrease in cell proliferation and saturation densities in culture and an increase in alkaline phosphatase activity. Of particular interest, incubation with sodium butyrate also caused a number of morphologic alterations in these cells, attributed to an induction of secretory differentiation. Following sodium butyrate treatment, CD18 cells were virtually indistinguishable from the more highly differentiated CD11 cells as evidenced by an increase in the number of profiles of rough endoplasmic reticulum and of Golgi. Intercellular and intracytoplasmic lumens, whose appearance is quite common in CD11 cells but nonexistent in untreated CD18 cells, appeared in these cells following only 5 days of sodium butyrate treatment. An increase in the cytoplasmic secretory elements was also observed in sodium butyrate-treated Panc-1 cells; however, lumen formation never occurred in these cells.

In recent years, intimal injuries to the aorta (minimal aortic injuries) have been diagnosed more frequently. We report the first case of pulmonary artery intimal injury in the setting of blunt trauma. We propose a number of theories regarding the pathogenesis, outcome, and treatment of pulmonary artery intimal injuries, drawing inferences from aortic intimal injuries. We conclude with a discussion on differentiating pulmonary artery intimal injury from the more common (but still rare) pulmonary artery dissection, using our case as an example.

A 52-year-old man presented with malaise and abnormal liver function tests: alanine aminotransferase 71 IU/ml (0–50), γ-glutamyltransferase 465 IU/ml (0–60), alkaline phosphatase 167 IU/ml (30–140), bilirubin 19 μmol (3–28). He had never …

The pattern of intragastric Helicobacter pylori colonization and its density may be determined by parietal cell function. H. pylori bacterial products can inhibit gastric acid secretion from the parietal cell. The aim of this investigation was to study the relationship between acid output and intragastric H. pylori distribution and colonization density in duodenal ulcer (DU) and non-ulcer subjects. The study included 14 patients with active DU, 10 with inactive DU and 10 non-ulcer dyspeptics.Acid output studies in response to fasting and maximal pentagastrin stimulation, basal (BAO) and peak (PAO) acid outputs were calculated. A quantitative assessment of H. pylori colonization density in biopsies from five sites of the gastroduodenum in the active ulcer group, and from the antrum in inactive duodenal ulcer and non-ulcer groups.There were negative correlations between total gastroduodenal bacterial colonization density and, PAO (r - 0.87, p = 0.0025) and BAO (r - 0.635, p0.02) in the active ulcer group. There were negative correlations between antral H. pylori colonization density and PAO in the active duodenal ulcer (r - 0.7449, p0.01) and non-ulcer (r - 0.5837, p0.1) groups but not in the inactive duodenal ulcer group (r - 0.1869, p0.2).An equilibrium is reached between gastroduodenal H. pylori colonization density and gastric acid secretory capacity in active duodenal ulcer disease. It is hypothesized that thresholds of bacterial load and acid secretory capacity, in combination, are required for active ulceration in DU disease.

e15117 Background: Management of advanced-stage PCa frequently requires multimodal therapy and there is a hypothesized benefit of consulting with multiple specialists prior to commencing active tre...

3620 Background: Management of stage III colon cancer (SIIICC) frequently focuses on cancer-specific survival, yet overall survival and adverse events also impact the net clinical benefit of cancer...

Heterogeneity of treatment effects and expenditures impacts the cost-effectiveness of health interventions. This study investigates the variation in costs, effects, and incremental cost-effectiveness ratios (ICERs) associated with chemotherapy in elderly patients with metastatic (M1) prostate cancer (PC) across race/ethnicity subgroups (non-Hispanic whites, non-Hispanic blacks, and others).Retrospective observational analysis.We examined patients age 66 years or older, identified by using the linked Surveillance, Epidemiology, and End Results-Medicare data set, who were diagnosed with M1 PC between 2000 and 2005. Cost data on the basis of Medicare reimbursements were available for 36 months after diagnosis. Mean costs and effects (life-years gained [LYG]) were adjusted for censoring. The baseline scenario examined PC-specific medical costs at 24 months and required survival of at least three months. Sensitivity analysis considered sampling uncertainty, selection into treatment, and adjustments to initial model assumptions.We identified 3,888 patients with M1 PC, of whom 24% (n = 930) received chemotherapy (primarily docetaxel and mitoxantrone). Twenty percent of observations were censored. The full sample ICER was $99,146 per LYG (95% CI, $75,042 to $130,195). Estimates for whites (ICER, $107,095; 95% CI, $78,391 to $148,272), blacks (ICER, $59,887; 95% CI, $22,860 to $121,509), and others (ICER, $123,909; 95% CI, $37,782 to $366,376) suggest considerable variation in the likelihood of chemotherapy being cost-effective. Results were similar in sensitivity analysis.Chemotherapy use in elderly patients with M1 PC is associated with an ICER of $99,146 per LYG. Subgroup analysis revealed heterogeneity in point estimates and considerable statistical uncertainty. To generate a reliable evidence base, efforts to increase the representation of minorities in health care data sets need to continue.

4655 Background: Disparities in access to health care across demographic groups have been widely documented for primary therapies of PCa and among patients (pts) with early-stage PCa. Less is known...

3613 Background: Clinical trials have demonstrated a survival benefit of oxaliplatin (OX)- or irinotecan (IRI)-based combination chemotherapy regimens for treatment of stage IV colon cancer patient...

e14069 Background: Randomized controlled trials and real world comparative effectiveness studies have suggested survival benefits with adjuvant oxaliplatin (OX)-based regimen in stage III colon can...

1104 Background: The NCCN GLs are the standard of care for the treatment of women with metastatic breast cancer (mBC). The primary aim of the current project is to assess concordance between the NC...

1092 Background: The prognosis for women with metastatic breast cancer (MBC) is worse for those who have triple negative MBC (TNMBC). Few reports have examined TNMBC in an elderly population. The US National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) database provides information on estrogen receptor (ER) status and progesterone receptor (PR) status but does not record human epidermal growth factor receptor 2 (HER2) status, making identification and analysis of TNMBC patients challenging. Methods: Females over the age of 65 with stage IV breast cancer were identified in the SEER-Medicare database. Patients with a prior history of breast cancer were excluded. Those who were (1) ER negative, (2) PR negative, (3) had an administrative claim for HER2 test, and (4) did not receive trastuzumab were classified as potential TNMBC (p-TNMBC). Results: Of 1,755 MBC patients who met the inclusion/exclusion criteria, 313 (17.8%) were p-TNMBC. p-TNMBC were younger than other MBC (76.0 vs. 77.6 ...

1032 Background: The NCCN GLs provide the standard of care for the treatment of women with metastatic breast cancer (mBC). The primary aim of the current project is to assess concordance between the NCCN GL recommendation for drug therapy and care received using the PM database (DB). The PM is a patient (pt) care DB that incorporates medical and pharmaceutical claims data for younger managed-care patients. Methods: Claims for pts diagnosed with metastatic breast cancer from 2002 to 2008 were examined. Overall, 26,476 women with metastatic breast cancer were identified. Median age was 40 years. Results: 26,260 (99%) patients were identified as premenopausal with 7,005 (28%) receiving antiestrogen (AE) therapy. Until 2005, the NCCN GLs recommended luteinizing hormone-releasing hormone (LHRH) agonists as an optional compliment to AE therapy for mBC. Prior to 2005, 37 of 2,838 pts (1%) received LHRH agonists. After 2005, 3% received nonconcordant therapy with LHRH agonists. After 2005, the NCCN GLs recommend ...

3603 Background: Cancer patients are at increased risk of venous thromboembolism (VTE). VTE risk varies with cancer treatments and patient clinical and sociodemographic characteristics, including a...

4658 Background: To date, docetaxel (D) is the only chemotherapy agent that has provided a survival benefit to metastatic castration resistant PCa patients (pts). The objective of this study was to...

e16074 Background: The survival benefit of D in treatment of hormone refractory PC (HRPC) has been established in the TAX327 trial, but it is unclear how this benefit would translate in a heterogeneous population. This study sought to simulate the survival impact of D in a population of older pts with M1 PC on androgen deprivation therapy (ADT). Methods: A combination of TAX327 trial data and SEER-Medicare (SM) data were used. In pts age 69+ and randomized to D (every 3 weeks, D3P) or mitoxantrone (M), trial data showed a survival benefit for D. Accordingly, SM pts age 69+ diagnosed with M1 PC between 1994 and 2002 and receiving only ADT were selected. Graphical plots and statistical tests were used to find best-fitting parametric survival functions for D3P, M, and SM pts. The survival benefit for D was imposed on unadjusted and covariate-adjusted SM survival curves. The simulated benefit was assessed at 12 mos and 24 mos post-diagnosis of M1 PC in SM pts. Results: There were 326 TAX327 trial pts (D3P = 159, M = 167) used in the analysis. Median survival was 15.7 mos (12.6 - 19) in the M arm and 18.9 mos [17 - 21.8] in the D3P arm (p = 0.03). There were 3,515 SM pts, based on inclusion criteria. Median survival benefit of D was 3.2 mos based on Kaplan-Meier estimates and 2.4 mos using parametric curves in the TAX327 69+ group. Following covariate-adjustment in the SM sample, at 12 mos post-diagnosis, the median survival in mos was 61.7 (CI 36.3 - 87) in the ADT group and 62 (CI 37.6 - 87.1) in the simulated ADT+D group (i.e., 0.3 mos simulated benefit of D). A 0.8 mos simulated benefit was found if D was initiated 24 mos post diagnosis (in pts more likely to have HRPC). Conclusions: The survival benefit of docetaxel from the TAX327 trial is attenuated in a heterogeneous SEER-Medicare sample, and the simulated survival benefit is larger among patients who are more likely to have hormone refractory prostate cancer. [Table: see text]

e17509 Background: The association between physician referrals and treatment receipt has been established in other disease settings. The impact of time to a medical oncologist or hematologist/oncologist (MOH) visit on survival has not been examined in patients (pts) with advanced prostate cancer (A-PC). The objective of this study is to determine whether the time to a MOH visit is associated with survival. Methods: The SEER-Medicare database was used for the analysis. Pts aged >65 diagnosed with A-PC between 1994 and 2002 and who visited a urologist post-diagnosis were included. Pts who saw a MOH before the urologist visit were excluded. For pts who saw a MOH, time to a MOH visit was identified using the diagnosis date and the urologist visit as starting points. Survival models were used to examine the effect of the time (in months) to MOH visit on survival, controlling for demographic, clinical, continuity-of-care, and ecological measures. Results: There were 6,498 pts in the sample (mean age 76 years, 82% White race). PC-specific mortality was 38%. Two-thirds (67%) of patients did not visit a MOH after visiting a urologist. Among those with a visit to a MOH, an additional month from diagnosis till the MOH visit was positively associated with PC mortality (HR: 1.03; p < 0.001) - i.e. a shorter time to a MOH visit was associated with PC survival. Similar results were obtained using the month of the urologist visit as the starting point (HR: 1.02; p < 0.001). Conclusions: Among A-PC patients who are referred to an oncologist, each additional month between diagnosis/urologist visit and the oncologist visit is associated with an increased relative risk of mortality. [Table: see text]

1037 Background: Onset of anthracycline-induced cardiotoxicity is well documented. However, information regarding the time of onset varies depending on literature. The purpose of this study was to compare the risk of cardiotoxicity among three cohort groups: anthracycline-containing-chemotherapy (ACC), no-anthracycline-containing-chemotherapy (NACC), and no-chemotherapy (control) groups. Methods: A retrospective cohort study was designed using commercial managed care claims database. Adult subjects (≥18) diagnosed with breast cancer, between January 1, 2002 to December 31, 2005, (index-period) were followed for 24 months. Subjects with a previous cardiotoxic events (CE), breast cancer diagnosis, or anthracycline-use 12-months prior to index date were excluded. Index date was the first chemotherapy claim date for ACC and NACC and non-chemotherapy medication claim date for controls. Cohorts were matched by index date and year of birth. CE was defined based on ICD-9-CM and Healthcare Common Procedure Coding System codes. Risk of CE was evaluated using a logistic model with and without adjusting for confounders. Results: 21,106 subjects were classified as ACC (n = 3,428), NACC (n = 7,125), and controls (n = 10,553). NACC cohort was significantly (p < 0.01) older (mean age: 62 years ±12.5) compared to ACC (53±9.7) or control cohorts (59±12.5). ACC cohort had a higher (p < 0.01) average degree of comorbidity, (1.8±0.8) compared to NACC (1.6±0.9) or control (1.3±0.8) as measured by Charlson comorbidity-index. Higher rates of CE were found within the ACC group compared to NACC and controls as early as month 3 post index-date and remained consistent over 24 months. At month 12 post index-date, 14% (n = 485) of ACC and 5% (n = 381) of NACC had CE compared to 3% (n = 310) of controls. After adjusting for all baseline differences, the odds ratio of CE compared to controls was 3.98 (95% CI: 3.27–4.85), and 1.31 (95% CI: 1.11–1.54) for ACC and NACC cohorts, respectively. The total mean costs were $59,287, $20,528, and $11,600, among ACC, NACC, and control cohorts respectively. Conclusions: Compared to NACC and controls, ACC cohorts had significantly higher risk of cardiotoxic events and seen as early as month 3 post treatment initiation. [Table: see text]

e17513 Background: ADT remains standard treatment for pts with M1 PC, with radiation (RT) and chemotherapy (CT) providing additional palliation. This population-based analysis evaluated if long-term survivors (LT) receiving ADT possessed different characteristics relative to short-term survivors (ST). Methods: Pts age >/= 66y in SEER Medicare diagnosed with M1 PC between 1998 and 2002 and receiving ADT with or without subsequent CT were identified. Median overall survival (OS) for the sample was used as a cut-off to categorize ST and LT pts. Within these categories, demographic, and clinical characteristics were evaluated. Results: 2,665 ADT pts were first identified who had median OS of 26 months (95% CI 24.0 - 27.0). 1,349 pts died at [Table: see text]

e17548 Background: Docetaxel and paclitaxel are widely used in treating breast cancer (BC), and both have hematologic toxicity commonly managed by costly growth factors (GFs). However, the extent of GFs use in real-world clinical practice has not been well documented. Methods: The Georgia Oncology Specialist Database was used and contained chemotherapy, medical and pharmacy claims, and lab results for nearly 170,000 patients with various types of cancer (2003–2008). Patients with stage I-III BC receiving docetaxel- or paclitaxel-containing regimens as adjuvant therapy were followed from 1 week prior to docetaxel or paclitaxel (index drug) initiation to the earliest of death, loss to follow-up, switch in taxane, or end of 90-day period post last dose of index drug. Incidence of GFs use per person-year was compared using univariate negative binomial (NB) model, median time to first GFs use was compared using Wilcoxon test. Multivariate analyses were performed on number of utilizations and time to first utilization adjusting for potential confounders. Results: Compared with paclitaxel (n = 433), docetaxel cohort (n = 216) had lower incidence per person-year of erythroid stimulating agents (ESAs) use (8.01 vs. 11.72, p = 0.008), while similar incidence of myeloid growth factors (MGFs) use (8.51 vs. 5.07, p = 0.541). Lower MGFs utilization in docetaxel patients (ratio of number of utilization = 0.821, p = 0.033), and similar ESAs utilization (ratio of number of utilization = 0.920, p = 0.305) were found. While descriptive analysis showed paclitaxel patients received first ESAs sooner than docetaxel patients (median length: 23 vs. 7 days, p < 0.001), and no difference in time to first MGFs use (median 8 days for both); multivariate analyses found docetaxel patients received first MGFs sooner (ratio of days = 0.828, p = 0.039), and no difference in time to first ESAs use (ratio of days = 1.091, p = 0.419). Conclusions: This analysis suggests that docetaxel is associated with lower utilization of MGFs. Studies examining the economic impact of GFs use associated with taxanes will need to be conducted. A potential limitation of this study is that the potential selection bias may not be fully adjusted. [Table: see text]

Aim:To compare Magnetic Resonance Imaging (MRI) findings in Alzheimer's dementia (AD) in the general population with Down's syndrome dementia.Background review: AD is characterised by cognitive dysfunction interfering with activities of daily living. Mild cognitive impairment (MCI) is an intermediate state between normal aging and dementia. People with Down's syndrome have an increased risk of developing AD. AD pathology initially appears in the entorhinal cortex, followed by the hippocampus and later in the temporal lobes. These areas are critical for memory functioning.Method:Volumetric analysis was performed on MRI brain scans using Measure software. Manual tracing was undertaken for the hippocampus, temporal lobes and lateral ventricles as well as the total brain volume of the cerebral hemispheres and cerebellum. Brain volumes were normalised as a percentage of traced intracranial volumes. Freesurfer software was used to obtain entorhinal cortical thickness measures. Statistical analysis was undertaken using SPSS15.Results:Subjects with AD (n=46), MCI (n=28) and controls (n=39) were compared with Down's syndrome demented subjects (DS+, n=20), non-demented subjects with Down's syndrome (DS-, n=45) and age-matched controls (n=43). Hippocampi, entorhinal cortex and temporal lobes were significantly reduced in AD and DS+ compared to controls. Lateral ventricles were significantly increased in AD and DS+ compared to controls. MCI and DS- produced findings between those of dementia and controls.Conclusions:Critical memory regions atrophy in dementia corresponding to decreased cognitive functioning. DS+ morphology is comparable to AD in the general population but the atrophy is less pronounced.

5160 Background: Appropriate staging is critical for the successful management of prostate cancer patients. Differences in tumor extent and the likelihood of being appropriately staged exist across...

8090 Background: C improves quality of life and survival in adv (Stage 3B w/ effusion and stage 4) NSCLC in clinical trials. Little is known about actual patterns of C and survival effects among E....

6574 Background: Despite effectiveness of adj Ch for Stage 3 CC, prior research documented lower tx rates in E and African American (AA) pts. This population-based study identified sociodemographic...

7549 Background: Little is known about patterns of tx for elderly w/ LA NSCLC ( IIIa, IIIb w/o effusion). Combined modality tx (CMT) (chemotherapy, C and radiation, R) is indicated for “fit” patien...

4014 Background: Although sociodemographic disparities in colon cancer (CC) treatment (tx) have been documented, less attention has focused on age disparities. We estimated the modifying effect of ...

6607 Background: A randomized phase III trial of sunitinib vs. IFN-a as first-line therapy for patients with mRCC is ongoing. An interim analysis of this study demonstrated superiority for the primary endpoint, progression-free survival (PFS), in the sunitinib arm vs. the IFN-a arm (median PFS = 11 months [95% CI: 10–12] vs. 4 months [95% CI: 4–6]; P No significant financial relationships to disclose.

During a two year period, 65 patients with Stage II non-seminomatous testis cancer were randomized to receive adjuvant chemotherapy and radiation. Of the 52 evaluable patients, 23 received radiation followed by chemotherapy (sequential), and 29 received the same chemotherapy as initial treatment, but had drug treatment temporarily interrupted for radiation (sandwich). The combined treatment was well tolerated, but did not eliminate recurrence. With regard to duration of survival and disease-free survival, no statistically significant difference could be found between the sequential and sandwich approaches.

Summary With a limiting dilution technique, clones have been established from the human pancreatic adenocarcinoma cell line, HPAF. Phenotypic analysis by a panel of murine monoclonal antibodies demonstrated distinct profiles of antigenic expression between the clones. However, identical isozyme patterns of different clones indicated their common origin from the parental HPAF cells. Two clones, CD11 and CD18, appeared to be arrested at different stages of secretory epithelial cell differentiation. CD11 cells demonstrated many characteristics of a well-differentiated state, including the formation of ductal structures with polarized, long columnar-shaped cells, the presence of secretory granules in the cytoplasm, high DU-PAN-2 antigen expression in nude mouse xenografts, and a longer doubling time (42 h) in tissue culture. In contrast, CD18 cells exhibited characteristics of a poorly differentiated state, including solid nests of isoprismatic cells without luminal spaces and cellular polarization, absence of secretory granules and DU-PAN-2 antigen expression in xenografts, and a shorter doubling time (26 h) in tissue culture. Since no culture systems of normal pancreatic ductal cells are currently available, these two pancreatic adenocarcinoma clones may provide a unique system to study genes and antigens related to pancreatic ductal cell differentiation.

During a two year period, 65 patients with Stage II non-seminomatous testis cancer were randomized to receive adjuvant chemotherapy and radiation. Of the 52 evaluable patients, 23 received radiation followed by chemotherapy (sequential), and 29 received the same chemotherapy as initial treatment, but had drug treatment temporarily interrupted for radiation (sandwich). The combined treatment was well tolerated, but did not eliminate recurrence. With regard to duration of survival and disease-free survival, no statistically significant difference could be found between the sequential and sandwich approaches.

Eighty patients had idiopathic renal hematuria and normal renal function. Renal biopsy showed minimal changes or focal glomerulonephritis in two thirds of the patients. The remainder exhibited diffuse proliferative glomerulonephritis and included nine patients with segmental glomerular sclerosis. Electron microscopy disclosed alterations of the capillary loop in 23 biopsy specimens and electron-dense deposits in 11. Immunofluorescent microscopy identified glomerularbound immunoglobulins, C3, or fibrinogen in 58% in a generalized distribution. IgG was the immunoglobulin seen most commonly. IgA and IgM were present in 14 and 13 biopsy specimens, respectively. These findings suggest that idiopathic renal hematuria is a clinical syndrome rather than a single disease with varying underlying renal findings. Both immunologic and nonimmunologic mechanisms may be involved, and the prognosis is favorable even in patients followed up for 11 years.