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For patients who have chronic myeloid leukemia (CML), one of the primary treatment options is administration of nilotinib 300 mg twice daily (BID). In previous studies which compared outcomes associated with nilotinib or imatinib treatment, nilotinib achieved a higher rate of deep molecular response (MR). We conducted a phase II, open‐label, multicenter study to investigate an intrapatient nilotinib dose‐escalation strategy for patients with newly diagnosed chronic‐phase (CP) CML based on early MR4.5 achievement. The primary study endpoint was achievement of MR4.5 by 24 months following the initiation of nilotinib 300 mg BID. Fifty‐three patients were enrolled, 51 received nilotinib, and 37 completed the treatment. An increase in the nilotinib dose (to 400 mg BID) was allowed when patients satisfied our criteria for no optimal response at any time point. The median (range) dose intensity was 600 (207‐736) mg/day. Of 46 evaluable patients, 18 achieved an optimal response and 28 did not. Of the latter, nine patients underwent dose escalation to 400 mg BID, and none achieved MR4.5. The remaining 19 patients could not undergo dose escalation, 12 (63%) because of adverse events (AEs), and 7 (37%) for non‐AE related reasons. Four of these patients achieved MR4.5. The MR4.5 rate by 24 months was 45.7%. The progression‐free, overall and event‐free survival were each 97.6%. No new safety concerns were observed. Our findings support the use of continuous nilotinib at a dose of 300 mg BID for newly diagnosed patients with CML‐CP., The N‐Road study aimed to determine the optimal treatment strategy for nilotinib use in patients with newly diagnosed CML‐CP based on early achievement of deep molecular response. Most patients received nilotinib at a dose of 300 mg BID and were able to achieve an early deep molecular response. Together with the finding that none of the patients whose dose was escalated to 400 mg BID achieved MR4.5, we consider that continuous nilotinib at a dose of 300 mg BID may be the optimal treatment strategy for newly diagnosed patients with CML‐CP.

Chronic myeloid leukemia (CML) is a myeloproliferative disorder caused by the BCR-ABL1 tyrosine kinase1,2. ABL1-selective tyrosine kinase inhibitors (TKIs) including nilotinib have dramatically improved the prognosis of patients with CML3–7. The ultimate goal of CML treatment is likely to be TKI-free maintenance of deep molecular response (DMR), which is defined by quantitative measurement of BCR-ABL1 transcripts on the international scale (IS)8, and durable DMR is a prerequisite to reach this goal9. Thus, an algorithm to enable the early prediction of DMR achievement on TKI therapy is quite valuable. Here, we show that our mathematical framework based on a clinical trial dataset10 can accurately predict the response to frontline nilotinib. We found that our simple dynamical model can predict nilotinib response by using two common laboratory findings (observation values): IS11,12 and white blood cell (WBC) count. Furthermore, our proposed method identified patients who failed to achieve DMR with high fidelity according to the data collected only at three initial time points during nilotinib therapy. Since our model relies on the general properties of TKI response, our framework would be applicable to CML patients who receive frontline nilotinib or other TKIs in clinical practice.Significance StatementChronic myeloid leukemia (CML) is a myeloproliferative disorder caused by the BCR-ABL1 tyrosine kinase. The goal of this treatment is the sequential achievement of deep molecular response (DMR). Tyrosine kinase inhibitors (TKIs) are effective in the reduction because they inhibit CML cell proliferation. However, because of individual differences in the TKI efficacy, some patients are unable to achieve DMR, so that early prediction of DMR reachability is necessary for personalized medicine. By combining time series analysis and mathematical modeling, we developed a mathematical method that accurately predicts patients who do not achieve DMR in the early stages of TKI administration. Our prediction method gives a basis of effective personalized treatments for CML patients.

The purpose of this trial was to evaluate the efficacy of 2-year consolidation therapy with nilotinib, at a dose of 300 mg twice daily, for achieving treatment-free remission in chronic myeloid leukemia patients with a deep molecular response (BCR-ABL1IS ≤0.0032%). Successful treatment-free remission was defined as no confirmed loss of deep molecular response. We recruited 96 Japanese patients, of whom 78 sustained a deep molecular response during the consolidation phase and were therefore eligible to discontinue nilotinib in the treatment-free remission phase; of these, 53 patients (67.9%; 95% confidence interval: 56.4–78.1%) remained free from molecular recurrence in the first 12 months. The estimated 3-year treatment-free survival was 62.8%. Nilotinib was readministered to all patients (n=29) who experienced a molecular recurrence during the treatment-free remission phase. After restarting treatment, rapid deep molecular response returned in 25 patients (86.2%), with 50% of patients achieving a deep molecular response within 3.5 months. Tyrosine kinase inhibitor withdrawal syndrome was reported in 11/78 patients during the early treatment-free remission phase. The treatment-free survival curve was significantly better in patients with undetectable molecular residual disease than in patients without (3-year treatment-free survival, 75.6 versus 48.6%, respectively; P=0.0126 by the log-rank test). There were no significant differences in treatment-free survival between subgroups based on tyrosine kinase inhibitor treatment before the nilotinib consolidation phase, tyrosine kinase inhibitor-withdrawal syndrome, or absolute number of natural killer cells. The results of this study indicate that it is safe and feasible to stop tyrosine kinase inhibitor therapy in patients with chronic myeloid leukemia who have achieved a sustained deep molecular response with 2 years of treatment with nilotinib. This study was registered with UMIN-CTR (UMIN000005904).

Intravascular large B-cell lymphoma (IVLBCL) is a rare disease entity of malignant lymphoma, characterized by selective growth of lymphoma cells within the vessel lumina in various organs [1]. The ...

High-resolution Rutherford backscattering spectrometry (HR-RBS) and X-ray reflectivity (XRR) are both powerful tools that can be used to investigate thin film structures with the same depth resolution. HR-RBS can be used to analyze low-density contrast films since it reveals the chemical composition in films. The elemental information aids the XRR analysis of films containing localized hydrogen atoms and low-electron-density contrast layers.

Pradimicin BMY-28864 (Pm) is an antibiotic effective against yeasts and fungi, and is known to bind mannose in the presence of Ca2+. We examined spectroscopically the mode of interactions among Pm, Ca2+, and glycosides of mannose and mannose oligosaccharides (Manalpha1-OMe, Manalpha1-2Manalpha1-OMe, Manalpha1-3Manalpha1-OMe, Manalpha1-4Manalpha1-OMe, Manalpha1-6Manalpha1-OMe, Manalpha1-6(Manalpha1-3)Manalpha1-OMe, and Man9GlcNAc2-Asn, a high mannose type N-linked oligosaccharide). All the mannosides interacted with Pm in the presence of Ca2+ and caused absorbance changes. The absorbance changes occurred nonlinearly with respect to the carbohydrate concentration and do not follow a simple binding isotherm equation, suggesting a unique multistep interaction mode. The concentrations that induced half the maximum absorbance change were approximately 10 mM for the mono- and di-mannosides and around 1.5 mM for the trimannoside and Man9GlcNAc2-Asn. Methyl alpha-D-glucopyranoside, methyl alpha-D-galactopyranoside, lactose, and myo-inositol did not affect the absorbance of Pm up to 50 mM. Ca2+ alone also influenced the absorbance of Pm. The absorbance between 200 and 700 nm decreased hypochromically when Ca2+ was added. The concentration that gave half the maximum absorbance decrease caused by Ca2+was around 15 microM. Our results suggest that two Pm molecules bind one C a2+, and each Pm binds two mannosyl residues.

Thermal stress and displacement analysis as well as thermal stress intensity facters (TSIF) are given for the cases of an infinite plate (medium) having a free hole or a rigid inclusion of arbitrary shape under steady state heat flow from infinity. The hole whose surface is insulated or fixed at elevated temperature is also considered. Unified treatment of the analytical solutions for the above cases is obtained by use of the power series type of mapping function and complex variable method. Several numerical results are shown by graphical representation.

In this paper, the problem of an infinite plate containing a circular or elliptical hole under a steady-state point heat source is considered. The analysis is based on the complex variable method using a conformal mapping technique. Stress and displacement fields are obtained as a closed-form solution under the condition of a point heat source applied at an arbitrary point. Several numerical examples are shown in graphical representations.

Background : Nilotinib is a potent and selective inhibitor of BCR-ABL. In the Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients (ENESTnd) trial, frontline nilotinib therapy at 300 mg twice daily (BID) resulted in a higher rate of deep molecular response (DMR) compared to imatinib therapy in patients with chronic myelogenous leukemia in the chronic phase (CML-CP). Furthermore, in the ENESTxtend study, many patients with suboptimal response or treatment failure achieved a major molecular response (MMR) after the nilotinib dose was increased to 400 mg BID from 300 mg BID. The present study was aimed at investigating a strategy of intra-patient nilotinib dose escalation for patients with newly diagnosed CML-CP in order to achieve MR4.5early. Methods : N-Road is a multicenter phase II clinical study for patients with newly diagnosed CML-CP, in which nilotinib was administered at 300 mg BID for 24 months. In this study, increasing the nilotinib dose to 400 mg BID was allowed if patients satisfied the criteria for no optimal response at any time points. The criteria for no optimal response were defined as follows: BCR-ABL1 > 10% on the International Scale [IS] after 3 months, BCR-ABL1 > 1% on the IS after 6 months, BCR-ABL1 > 0.1% on the IS after 12 months, BCR-ABL1 > 0.0032% on the IS after 18 months, two consecutive losses of MMR, and two consecutive losses of MR4.5 (BCR-ABL1 ≤ 0.0032% on the IS). The primary endpoint was the cumulative MR4.5rate by 24 months after the initiation of nilotinib treatment. Results: Between August 2012 and July 2015, 53 Japanese patients were enrolled, of whom 51 were evaluated in the study. The median patient age was 50 years. The ratio of men to women was 33:18. The numbers of patients with low, intermediate, high Sokal risk scores was 21 (41.2%), 21 (41.2%), and 6 (11.8%), respectively, and 3 (5.9%) had an unknown risk. The median duration of nilotinib treatment was 23.8 months (range, 4.1-26.3 months). Of the patients, 33 (64.7%) completed 24 months of treatment, 7 (13.7%) had ongoing treatment, and 11 (21.6%) discontinued treatment because of adverse events (AEs; n=4), protocol deviation (n=1), loss to follow-up (n=3), death (n=1), insufficient effect (n=1), or consent withdrawal (n=1). The cumulative MR4.5 rate (95% confidence interval [CI]) in the 46 evaluable patients was 52.0% (36.9-69.0%) by 24 months (Figure). The cumulative MR4.0 and MMR rates were 60.9% (46.1-76.0%) and 83.5% (69.6-93.5%) by 24 months, respectively. Among the 46 evaluable patients, 26 satisfied the criteria for no optimal response. The dose was increased in 6 of the 26 patients but not in the remaining 20 patients for the following reasons,: hematological AEs (n=3), non-hematological AEs (n=9), achievement of MR4 at 18 months (n=2), patient refusal (n=4), and unknown (n=2). Although 4 patients with no optimal response achieved MR4.5, all of them did not receive an increased treatment dose. The actual mean dose intensities in the patients with or without optimal response were 570 and 560 mg/day, respectively. None of the patients had disease progression, and 1 patient died of an unknown cause during the study. The estimated rates (95% CI) of progression free survival and overall survival at 24 months were 98% (84-100%) and 98% (84-100%), respectively. The most common (≥20%) non-hematological AEs of any grade were rashes (47%), headache (34.2%), fatigue (21.6%) and nausea (23.5%). The most common (≥5%) grade 3/4 laboratory abnormalities were increased lipase (10.6%), decreased phosphate (12.2%) and increased alanine aminotransferase (7.8%). Cardiovascular events were observed to be ischemic heart disease in 2 patients (3.9%). Conclusion: In this study, it was difficult to evaluate the efficacy of nilotinib dose escalation to achieve MR4.5 early because the dose could not be increased to 400 mg BID in many patients who did not show optimal response. However, as we were unable to increase the dose to 400 mg BID in many patients because of AEs and as nilotinib therapy demonstrated superior MR4.5, these results might support continuous nilotinib therapy using a dosage of at least 300 mg BID for newly diagnosed CML. Disclosures Nishiwaki: Novartis PHARMA: Research Funding.

Human blood coagulation factor X has two N-linked oligosaccharides at Asn39 and Asn49 residues and two O-linked oligosaccharides at Thr17 and Thr29 residues in the region of the factor X activation peptide (XAP) which is cleaved off during its activation by factor IXa. We determined the structure of oligosaccharides in the XAP region of human factor X. Four glycopeptides each containing a glycosylation site were isolated by digestion of XAP with endoproteinase Asp-N followed by reversed-phase HPLC. N-linked oligosaccharides released from the glycopeptides by glycoamidase A digestion were derivatized with 2-aminopyridine. Pyridylamino(PA)-oligosaccharides were separated by HPLC into neutral and sialyl oligosaccharides using an anion-exchange column. Structures of oligosaccharides and their contents at each glycosylation site were determined by a two-dimensional sugar mapping method. The contents of the neutral oligosaccharides at Asn39 and Asn49 residues were 32.5% and 30.0%, respectively. Six neutral and twelve monosialyl oligosaccharides isolated from both N-linked glycosylation sites showed similar elution profiles composed of bi-, tri- and tetra-antennary complex type oligosaccharides. The predominant component in neutral oligosaccharides was biantennary without a fucose residue. Two major monosialyl oligosaccharides were also biantennary without fucose and with a Neu5Ac alpha 2-->6 residue. In addition, the structures of O-linked oligosaccharides at Thr17 and Thr29 residues were suggested to be disialylated Gal beta 3GalNAc sequences by their component analyses.

We propose a three-dimensional (3-D) sugar-mapping technique for pyridylaminated (PA) neutral and sialyl oligosaccharides as a powerful structural characterization of N-linked oligosaccharides using only picomoles of samples. The new map consists of the elution data from 42 different sialyl oligosaccharides, 26 of which are mono-, 7 of which are di-, 7 of which are tri-, and 2 of which are tetra-sialylated oligosaccharides. The 20 standard sialyl oligosaccharides were released from human serum and calf fetuin by digestion with glycoamidase A. The other 22 standard sialyl oligosaccharides were obtained by subsequent digestion of the above 20 sialyl oligosaccharides with beta-galactosidase, beta-N-acetylhexosaminidase, alpha-fucosidase, and alpha 2-->3 specific sialidase. The present 3-D mapping method involves the following four steps: First, a neutral and sialyl PA-oligosaccharide mixture is separated by HPLC on the diethylaminoethyl (DEAE) column according to the sialic acid content, and the elution data are considered as one of the three dimensions (Z-axis). Then, neutral, mono-, di-, tri-, and tetra-sialyl oligosaccharides are individually separated on the octadecylsilyl (ODS)-silica (X-axis) and amide-silica (Y-axis) columns. The fourth step is to plot the coordinates on a two-dimensional (2-D) map. Thus, for each of the groups separated on the DEAE column, a 2-D map can be achieved. By repeating the whole process for each group of different sialylation, the layers of the 2-D map lined up on the Z-axis form a 3-D map.(ABSTRACT TRUNCATED AT 250 WORDS)

Spindle-shaped diffuse large B-cell lymphoma (Sp-DLBCL) has been recognized as a rare morphologic variant of DLBCL. However, the biological processes that contribute to the specific features of Sp-DLBCL remain poorly understood. In this study, a combined immunophenotypic and genetic analysis was performed in 10 Sp-DLBCL. First, we investigated several unique markers for anaplasia (CD30, ALK, CD68, and EBER-ISH), mesenchyma (SMA, desmin, and vimentin), and B-cell differentiation (CD10, BCL6, and MUM1). We also performed conventional cytogenetic and fluorescence in situ hybridization studies to look for common chromosomal break points (BCL2, BCL6, and MYC). We found that most Sp-DLBCLs were germinal center B cell-like and that none had any other specific phenotypes or any karyotypic abnormalities. Instead, T cells, CD68-positive macrophages and SMA-positive myofibroblasts were significantly increased in Sp-DLBCL when compared with conventional GCB origin DLBCL cases (n = 10) (P = 0.012, P < 0.001, and P < 0.0001, respectively). To further characterize Sp-DLBCL, we next compared the expression of fibroblast growth factor 2 (FGF2) and transforming growth factor-β1 (TGFβ1) between the two types of DLBCL. Finally, we confirmed that the number of FGF2- and TGFβ1-positive stromal cells was markedly increased in Sp-DLBCL and that the difference between these and conventional GCB origin DLBCLs was significant (P < 0.0001 and P = 0.0017, respectively). Thus, T-cell/myofibrohistio-rich stromal alterations in Sp-DLBCL, especially those mediated by TGFβ1 and FGF2, may play a role in the transition of lymphoma cells into those with spindle-shaped features.

The response criteria proposed by European Leukemia Net are useful to predict the prognosis of de novo chronic myeloid leukemia (CML) patients in the chronic phase (CP) treated with imatinib. However, the clinical significance of late suboptimal response, which is defined as the achievement of CCgR without MMR after 18 months, is controversial. In this study, we retrospectively analyzed the clinical courses of 16 CML-CP patients, who satisfied the criteria for late suboptimal response. The median duration of imatinib treatment was 62 (25∼87) months. The median starting dose of imatinib was 400 mg/day. Imatinib dose was escalated to 600∼800 mg/day in 10 patients for various reasons. Among 4 patients who continued high-dose imatinib for late suboptimal response, 2 patients subsequently achieved MMR, and BCR-ABL mRNA transcript levels were decreasing in 2 patients. However, imatinib was kept at 300 or 400 mg/day in 6 patients. Among these six patients, 4 patients achieved MMR, while 2 failed to achieve MMR. None of 16 patients progressed to the acute phase or blast phase. Imatinib dose escalation was effective for late suboptimal response. Furthermore, a second tyrosine kinase inhibitor such as nilotinib may be more potent to reduce the risk of disease progression by achieving earlier MMR.

High-resolution Rutherford backscattering spectrometry (HRBS) in combination with grazing angle argon sputtering was carried out to characterize the interface of aluminum-nickel (Al-Ni) alloy and amorphous-silicon films in a thin film transistor (TFT) for liquid crystal display (LCD). After thinning the top Al-Ni layer by a 1-keV Ar sputtering, the sensitivity of the interface oxygen was improved to be twice higher than that before sputtering. The results revealed that the oxygen at the interface relates to the contact characteristics.

Abstract 5104 Introduction: Intravascular large B-cell lymphoma (IVLBCL) is a rare disease entity of malignant lymphoma, characterized by the selective growth of lymphoma cells within the lumina of vessels in various organs. Although recent reports showed that prompt and accurate diagnosis lead to better outcomes, absence of typical clinical manifestations and its aggressive behavior frequently makes it difficult. LR11 (also called SorLA or SORL1) is a type I membrane protein, from which a soluble form (sLR11) is released by proteolytic shedding. sLR11 is originally known to be a biomarker of carotid intima-media thickness. We have recently found that LR11 is expressed on human leukemia cell lines, and sLR11 is released in its culture medium. Serum sLR11 levels are significantly elevated in patient serum samples with acute leukemia and B cell lymphomas, and are associated with tumor burden and bone marrow invasion. Based on these findings, we hypothesized that LR11 may be also expressed and released from IVLBCL cells; therefore we evaluated its clinical importance in IVLBCL. Materials and methods: Serum samples and paraffin embedded tumor specimens were obtained from 6 patients who were histologically diagnosed as IVLBCL from 2009 to 2012. Specimens were subjected to immunostaining using anti-LR11 antibody, and serum sLR11 levels were measured by ELISA method. Patient laboratory and clinical data were collected retrospectively. Also, serum samples from 75 healthy volunteers, and 10 patients with collagen diseases presenting similar clinical manifestations as IVLBCL were analyzed. Results: Tissue samples of IVLBCL were obtained by bone marrow biopsy (N=2), transbronchial lung biopsy (N=2), and random skin biopsy (N=2). Biopsy specimens showed that cytoplasm of IVLBCL cells were specifically immunoreacted against the anti-LR11 antibody (Figure 1). Median serum sLR11 level of IVLBCL patients was 86. 0 ng/ml (mean ± SD: 201. 8 ± 260. 0 ng/ml), which was significantly elevated than those of healthy volunteers (median: 8. 4 ng/ml, mean±SD: 8. 8 ± 1. 8 ng/ml, p Conclusions: We have identified LR11 as a novel molecule which was proven to be expressed in IVLBCL cells and circulated in patients' serum. LR11 immunostaining clearly highlights the tumor cells and sLR11 enables to distinguish IVLBCL from other differential diagnosis by serum evaluation. These findings suggest that LR11 is a useful diagnostic tool for IVLBCL, and serum sLR11 is a sensitive biomarker for diagnosis and disease monitoring of this challenging disease. Disclosures: No relevant conflicts of interest to declare.

The photochemical and subsequent thermal reactions of phoborhodopsin (pR490), which mediates the negative phototaxis (phobic reaction) of Halobacterium halobium, were investigated by low-temperature spectrophotometry. At room temperature, the absorption spectrum of pR490 displayed vibrational structure with a maximum at 490 nm and a shoulder at 460 nm, which were remarkably sharpened by cooling, resulting in the appearance of two well-separated peaks. On irradiation of pR490 at -170 degrees C, a photo-steady-state mixture composed of pR490 and two photoproducts, P520 and P480, was formed. P480 had an absorption maximum at 480 nm and thermally converted to pR490 above -160 degrees C, while P520 had an absorption maximum at 515 nm and thermally converted to P350, the next intermediate, above -60 degrees C. Above -30 degrees C, P350 was converted to P530, and then reverted to pR490. P520, P350, and P530 may correspond to K, M, and O intermediates of bacteriorhodopsin, respectively, on the basis of their absorption spectra, but the intermediates corresponding to L and N intermediates were not observed. On the basis of these results, a new scheme of the photoreaction cycle of pR490 was presented.