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1
Wang, Haiyan. "AN EXISTENCE THEOREM FOR QUASILINEAR SYSTEMS." Proceedings of the Edinburgh Mathematical Society 49, no. 2 (May 30, 2006): 505–11. http://dx.doi.org/10.1017/s0013091504001506.
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AbstractThis paper deals with the existence of positive radial solutions for the quasilinear system $\text{div}(|\nabla u_i|^{p-2}\nabla u_i)+\lambda f^i(u_1,\dots,u_n)=0$, $|x|\lt1$, $u_i(x)=0$, on $|x|=1$, $i=1,\dots,n$, $p\gt1$, $\lambda>0$, $x\in\mathbb{R}^N$. The $f^i$, $i=1,\dots,n$, are continuous and non-negative functions. Let $\bm{u}=(u_1,\dots,u_n)$, $\|\bm{u}\|=\sum_{i=1}^n|u_i|$,$$ f_0^i=\lim_{\|\bm{u}\|\to0}\frac{f^i(\bm{u})}{\|\bm{u}\|^{p-1}}, $$$i=1,\dots,n$, $\bm{f}=(f^1,\dots,f^n)$, $\bm{f}_0=\sum_{i=1}^nf_0^i$. We prove that the problem has a positive solution for sufficiently small $\lambda>0$ if $\bm{f}_0=\infty$. Our methods employ a fixed-point theorem in a cone.
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Yu, Xinting, Shi Song Rong, Xiujing Sun, Guofang Ding, Weilin Wan, Liying Zou, Shaowen Wu, Ming Li, and Danhua Wang. "Associations of breast milk adiponectin, leptin, insulin and ghrelin with maternal characteristics and early infant growth: a longitudinal study." British Journal of Nutrition 120, no. 12 (October 30, 2018): 1380–87. http://dx.doi.org/10.1017/s0007114518002933.
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AbstractBreast milk (BM) hormones have been hypothesised as a nutritional link between maternal and infant metabolic health. This study aimed to evaluate hormone concentrations in BM of women with and without gestational diabetes mellitus (GDM), and the relationship between maternal factors, BM hormones and infant growth. We studied ninety-six nulliparous women with (n 48) and without GDM and their exclusively breastfed term singletons. Women with GDM received dietary therapy or insulin injection for euglycaemia during pregnancy. Hormone concentrations in BM, maternal BMI and infant growth were longitudinally evaluated on postnatal days 3, 42 and 90. Mothers with GDM had decreased concentrations of adiponectin (Pcolostrum<0·001; Pmature-milk=0·009) and ghrelin (Pcolostrum=0·011; Pmature-milk<0·001) and increased concentration of insulin in BM (Pcolostrum=0·047; Pmature-milk=0·021). Maternal BMI was positively associated with adiponectin (β=0·06; 95 % CI 0·02, 0·1; P=0·001), leptin (β=0·16; 95 % CI 0·12, 0·2; P<0·001) and insulin concentrations (β=0·06; 95 % CI 0·02, 0·1; P<0·001), and inversely associated with ghrelin concentration in BM (β=–0·08; 95 % CI –0·1, –0·06; P<0·001). Among the four hormones, adiponectin was inversely associated with infant growth in both the GDM (βweight-for-height=–2·49; 95 % CI –3·83, –1·15; P<0·001; βhead-circumference=–0·39; 95 % CI –0·65, –0·13; P=0·003) and healthy groups (βweight-for-height=–1·42; 95 % CI –2·38, –0·46; P=0·003; βhead-circumference=–0·15; 95 % CI –0·27, –0·03; P=0·007). Maternal BMI and GDM are important determinants of BM hormone concentrations. Milk-borne adiponectin is determined by maternal metabolic status and plays an independent down-regulating role in early infant growth.
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Brynes, Russell K., Raymond S. M. Wong, Maung M. Thein, Kalpana K. Bakshi, Paul Burgess, Dickens Theodore, and Attilio Orazi. "A 2-Year, Longitudinal, Prospective Study of the Effects of Eltrombopag on Bone Marrow in Patients with Chronic Immune Thrombocytopenia." Acta Haematologica 137, no. 2 (December 23, 2016): 66–72. http://dx.doi.org/10.1159/000452992.
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Background: The long-term effects of eltrombopag on bone marrow (BM) reticulin and/or collagen deposition in previously treated adults with chronic immune thrombocytopenia (ITP) were assessed. Methods: Three BM biopsies were collected at baseline and after 1 and 2 years of eltrombopag treatment. Specimens were centrally processed, stained for reticulin and collagen, independently reviewed by 2 hematopathologists, and rated according to the European Consensus 0-3 scale of marrow fibrosis (MF). Results: Of 162 patients enrolled, 93 completed all 3 protocol-specified BM biopsies. All patients with a baseline assessment were negative for collagen. Of 159 patients assessed at baseline, 150 (94%) had normal reticulin (MF-0) and 9 (6%) had minimally increased reticulin (MF-1). After 2 years, 83/93 patients (89%) with BM biopsies had MF-0, 10 (11%) had MF-1, and none had MF-2 or MF-3. Five out of 127 patients (4%) at 1 year and 1 out of 93 (1%) at 2 years had collagen deposition. None of the patients had clinical symptoms typical of BM dysfunction or abnormalities of clinical concern based on white blood cell count or peripheral blood smear. Conclusion: For most patients with chronic ITP, eltrombopag is not associated with clinically relevant increases in BM reticulin or collagen formation.
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Vidula, Neelima, Andrzej Niemierko, Katherine Hesler, Steven J. Isakoff, Dejan Juric, Laura Spring, Therese Marie Mulvey, et al. "Comparison of the cell-free DNA genomics in patients with metastatic breast cancer (MBC) who develop brain metastases versus those without brain metastases." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): 1094. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.1094.
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1094 Background: The genomics of patients with metastatic breast cancer (MBC) who develop brain metastases (BM) is not well understood given the difficulty in obtaining brain tumor for genotyping. We compared tumor genotyping results via cell-free DNA (cfDNA) collected at MBC diagnosis in patients who developed BM after MBC diagnosis with those who did not develop BM (non-BM). Methods: Patients at an academic institution who had cfDNA testing (Guardant 360/Next generation sequencing, 73 gene assay) at MBC diagnosis between 1/2016-12/2017, with ≥ 6 months of follow-up post testing, were identified. A chart review was done to identify tumor subtype, demographics, cfDNA results, and development of BM at or after MBC diagnosis. Pearson’s chi-squared and Wilcoxon rank sum tests were used to determine differences in clinical and cfDNA characteristics in BM vs. non-BM (p<0.05 for statistical significance). Results: CfDNA results were available for 49 patients, of whom 13 (27%) developed BM (4 with BM at MBC diagnosis). The median time to BM development was 11 months. While patients with BM were younger at MBC diagnosis than non-BM (median age BM 53 vs. non-BM 61, p=0.05), they had similar subtype (BM vs. non-BM: HR+/HER2- 62% vs. 69%, HER2+ 8% vs. 14%, TNBC 23% vs. 17%, unknown 8% vs. 0%, p=0.3), de-novo vs. recurrent disease (BM vs. non-BM: de-novo 8% vs. 14%, recurrent 92% vs. 86%, p=0.6), and visceral disease (BM vs. non-BM: 77% vs. 56%, p=0.2) distributions. All patients with BM had ≥1 detectable cfDNA mutation vs. 88% of non-BM. While the median mutant allele frequency of the most common mutation was similar in BM vs. non-BM (2.4% vs. 3.7%, p=0.5), the mutation pattern varied. Patients with BM more often had mutations in BRCA1 (15% vs. 3%, p=0.1), APC (15% vs. 0%, p=0.02), and CDKN2A (15% vs. 0%, p=0.02), compared to non-BM. In 4 patients with BM at MBC diagnosis, mutations in APC (50%), CDKN2A (50%), and BRCA 1/2 (25%) were noted; 1 had coexisting APC and BRCA1/2 mutations and another had coexisting APC and CDKN2A mutations. Conclusions: Patients with MBC who develop BM may have different cfDNA genomics, particularly BRCA1, APC, and CDKN2A mutations. Further research is needed to determine the predictive value of cfDNA at MBC diagnosis in the identification of patients at higher risk of developing BM. [Table: see text]
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Diaz-Perez, Juan Carlos, W. Keith Jenkins, Dharmalingam Pitchay, and Gunawati Gunawan. "Detrimental Effects of Blood Meal and Feather Meal on Tomato (Solanum lycopersicon L.) Seed Germination." HortScience 52, no. 1 (January 2017): 138–41. http://dx.doi.org/10.21273/hortsci11192-16.
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There is limited information on the effect of organic fertilizers on seed germination and subsequent transplant growth. The objective of this study was to determine the effects of application rate of blood meal (BM) and feather meal (FM) fertilizers on germination of tomato seeds. Both organic fertilizers were applied as amendments to peat-based organic substrates at rates ranging from 0 to over 50 g·kg−1 N. Tomato ‘Brandywine’ seed were sown in trays. Seed germination was recorded daily until the germination percentage remained unchanged. Ammonia concentration in the substrates (Pro-Mix and Miracle-Gro) increased with increasing rate of substrate N concentration. Ammonia concentration also increased with increasing time after incorporation of BM and FM reaching maximum values (16 ppm) at day 9. Tomato seed germination was little affected at BM and FM rates lower than ≈3 g·kg−1 N (4% w/w for BM or FM), but declined above 3 g·kg−1 N reaching 0% germination rate at ≈14 g·kg−1 N for both BM and FM. Substrates pH was 5.9 in the absence of BM or FM and increased to about pH 7 with addition of low rates of BM (2.7 g·kg−1 N) and FM (2.6 g·kg−1 N). Substrate electrical conductivity (EC) increased with increasing substrate N concentration as supplied by BM and FM; FM, however, had a stronger effect on increasing EC compared with BM. In conclusion, BM and FM had inhibitory effects on tomato seed germination when applied at more than 3 g·kg−1 N (4% w/w for BM or FM). High ammonia concentration in the substrates for the first 2 weeks after incorporation of BM or FM likely caused, at least partially, inhibition of tomato seed germination. Thus, substrate mixed with BM or FM should be allowed to incubate for at least 2 weeks before planting tomato seed.
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Jordan, Emmet, Thomas Joseph Kaley, Marinela Capanu, Hayley Estrella, Steven D. Leach, Olca Basturk, David S. Klimstra, et al. "Brain metastases (BM) in pancreatic ductal adenocarcinoma (PDAC): Clinical and molecular characteristics." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): e15728-e15728. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e15728.
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e15728 Background: BM from PDAC represents a rare clinical entity (<0.6%) of PDAC cases for which the clinical and molecular features are not well described. We reviewed detailed clinical characteristics and molecular profiling performed in a cohort of PDAC pts with BM evaluated at MSKCC. Methods: Patients (pts) with BM from PDAC diagnosed from 01/1990-08/2016 were identified from a prospectively maintained database, following IRB approval. Clinicopathological data including time to BM development, overall survival (OS) from PDAC diagnosis (dx) and OS from BM dx was recorded. Molecular profiling was performed by MSK-IMPACT testing (>340 key cancer genes) or via Seqeunom testing (8 gene panel). Results: We identified n= 24 pts with BM from PDAC. Twenty-three/24 pts had imaging for symptoms. Mean no. of systemic regimens was 3 (range 0-7). Three/24 (13%) had BM at initial dx. Median time from PDAC dx to BM development was 17 months (mths) (range 0-79). Median survival from BM was 50 days (range 7-975). BM treatment included; surgery; n=4, RT; n=13 or supportive care; n=7. Two pts had survival of 21 & 31 months post BM, both had resection. Median OS from PDAC dx was 18 mths (0-82). 10 pts had consent/pathology for molecular testing (MSK-IMPACT n=7, Sequenom n=3). Results are available for 6 pts, 3 by IMPACT. 6/6 pts had KRAS mutations (MUT); G12D (4), G12V (1), Q61K (1). 0/6 pts had ERBB2 AMP or MUT. One tumor arising from an IPMN had concurrent GNAS and KRAS MUT. By MSK-IMPACT; 2/3 pts had MYC AMP, 2/3 TP53 MUT, 1/3 ARID1A loss, 1/3 CDKN2A loss. 5/24 pts had germline testing, 3 had BRCA MUT; BRCA1 (2), BRCA2 (1). Conclusions: The presence of BM portends a poor prognosis. In general pts who develop BM are younger at initial PDAC dx and may have a better OS from dx [median OS 18 mths (all pts); OS de novo stage IV pts; 17 mths]. Somatic profiling identified KRAS MUT in all resulted pts with alterations in TP53 and MYC also detected. Although speculative, germline BRCA MUT occurred in 13% (60% of pts tested). See table. [Table: see text]
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Ando, Kiyoshi, Yoshihiko Nakamura, Takashi Yahata, Yukari Muguruma, Tadayuki Sato, Hideyuki Matsuzawa, Tomoko Uno, Shunichi Kato, and Tomomitsu Hotta. "Angiopoietin-1 Supports SRC Activity Acquisition of Human CD34-Bone Marrow Cells." Blood 108, no. 11 (November 16, 2006): 1672. http://dx.doi.org/10.1182/blood.v108.11.1672.1672.
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Abstract CD34 negative hematopoietic stem cells (CD34− HSCs) were identified in mice and humans. Human HSCs are evaluated as severe combined immunodeficient mouse (SCID)-repopulating cells (SRCs), originally identified by the ability to reconstitute hematopoiesis in nonobese diabetic (NOD)/SCID mouse. CD34− cord blood (CB) cells have been hard to engraft in NOD/SCID mice until recent report of successlul engraftment by intra-bone marrow transplantation (iBMT). However, CD34− bone marrow (BM) cells have not been analyzed precisely. We prepared lineage negative CD34 negative (Lin-CD34−) cells by negative selection using CD2,3,7,14,16,19,20,33,34,36,41,56,127, and GlyA antibody. Lin-CD34− BM cells did not engraft in NOD/SCID mice even by using iBMT (0/6). In the previous study, we reported that Lin-CD34− BM cells were able to differentiate into CD34+ cells accompanied by the emergence of colony forming activity after 7 days of stroma-dependent culture, while SRC activity was not detected. (BMT 28, 587–595, 2001) Here we cultured Lin-CD34− BM cells on stroma cells transfected with human angiopoietin-1 cDNA (AHESS-5), since we detected Tie-2 expression on Lin-CD34− BM cells. AHESS-5 supported induction of CD34 much better than HESS-5 cells or empty vector transfected control cells (EVHESS-5), and the effect was blocked by anti-Tie-2 antibody (Fig.1). Furtheremore, CD34+ cells produced from CD34− BM cells engrafted in NOD/SCID mice (11/12). As previously reported, CD34− CB cells differentiate CD34+ cells and acquire SRC activity by stroma-dependent culture without angiopoietin-1. These results highlighted the characteristic differences of CD34− HSCs of BM from CB and the unique role of BM niche for CD34− HSCs. Fig. 1 CD34 expression on Lin − CD34 − BM cells after 7 days of culture Fig. 1. CD34 expression on Lin−CD34− BM cells after 7 days of culture
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Udi, Josefina, Martina Kleber, Dagmar Wider, Ralph Wäsch, and Monika Engelhardt. "Higher Vascular Endothelial Growth Factor (VEGF) and Endothelial Progenitor Cells (EPCs) in Multiple Myeloma (MM) Patients (pts) as a Reflection of Their Governing Role in Pathological Angiogenesis: Comparison of VEGF and EPC Levels Between Healthy Donors (HD), MGUS and MM Pts and Correlation Analysis with MM Activity." Blood 112, no. 11 (November 16, 2008): 5132. http://dx.doi.org/10.1182/blood.v112.11.5132.5132.
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Abstract Introduction: In MM pathogenesis, angiogenesis and growth factors have a governing role. VEGF, secreted by malignant bone marrow (BM) plasma cells (PCs) and stroma, acts as an important mediator of tumor angiogenesis. VEGF has been suggested as an adverse prognostic factor, being elevated in advanced and plasmablastic MM. Circulating as well as BM-residing endothelial cells (ECs) have been shown to contribute to angiogenesis in MM as well as other tumors. Moreover, endothelial progenitor cells (EPC) have been demonstrated to contribute to vascular repair and to be decreased in number and function with end-stage renal impairment (RI). Whereas VEGF and/or EPCs have been described in small former analysis in MM, larger comparisons with MGUS pts and healthy donors (HD) are lacking, differences in various MM subsets (such as BM; peripheral blood and apheresis [AP] samples) have not been addressed, nor the role of EPCs and hemangioblasts in advanced vs. mild RI in MM pts. Methods: We sought to characterize ECs (namely VEGF+ cells, EPCs as VEGFR2+/CD133+/CD34+, hemangioblasts as VEGF+/CD34+) and other subtypes (CD34+, CD45+, CD38+, CD45+/CD38+, CD45−/CD38+) via multiparametric flow cytometry. This was performed in MM pts (n=70), MGUS pts (n=8) and HD (n=14). In MM, BM (n=70), PB (n=14) and AP (n=21) specimens were compared, as well as changes in EPCs and hemangioblasts with and without mild or severe RI. Renal function was determined via estimated glomerular filtration rate (eGFR), classifying mild RI as eGFR <90ml/min/1.73m2 and severe RI as eGFR <30ml/min/1.73m2. Results: MM pts’ age, BM-infiltration and serum creatinine were 63 years (range: 35–84), 15% (0–96) and 0.91mg/dl (0.5–8.6), respectively. BM specimens from MM and MGUS pts showed 4-fold and 2-fold higher VEGF levels, respectively as compared to HD (Table 1). EPCs were also elevated in MM as compared to MGUS and HD (Table 1). Hemangioblasts, CD45+/CD38+ and CD45−/CD38+ were increased in MM BM specimens as compared to MGUS and HD, whereas CD45+ and CD34+ cell numbers were decreased in myeloma specimens (Table 1). Table 1. Median endothelial cells and other subtypes in MM, MGUS and healthy donors BM MM (n=70) BM MGUS (n=8) BM healthy donors (n=14) VEGF+ (%) 0.38 (0 – 12.9) 0.18 (0 – 0.7) 0.09 (0 – 0.6) EPCs (%) 0.03 (0 – 0.4) 0.02 (0 – 0.07) 0.01 (0 – 0.2) VEGF+/CD34+ (%) 0.21 (0 – 2.2) 0.11 (0 – 0.4) 0.04 (0 – 0.5) CD34+ (%) 0.65 (0 – 6.6) 1.23 (0.02 – 4.0) 1.50 (0.07 – 2.8) CD45+ (%) 39.54 (2.8 – 99.1) 39.34 (13.8 – 69.7) 51.70 (10.3 – 90.9) CD45+/CD38+ (%) 24.61 (0.9 – 89.7) 21.68 (1.4 – 49.4) 17.20 (2.6 – 56.9) CD45−/CD38+ (%) 1.54 (0 – 77.7) 1.15 (0 – 2.4) 0.62 (0.1 – 5.6) The comparison of BM, PB, AP specimens in MM showed similar VEGF levels in BM and PB with 0.38% which were increased in AP specimens with 0.5%. This was similarly observed for EPCs with 0.03% in BM and PB as compared to 0.04% in AP samples. Other markers showed similar values for CD34, CD45, CD38+ cells in BM and PB; similar hemangioblast numbers in all 3 subsets, and higher CD34+ and CD45+ cells, and lower CD45−/CD38+ cells in AP specimens. Correlation of EPCs and hemangioblasts with renal function revealed that EPCs decreased with RI, whereas hemangioblasts remained comparable (Table 2). Table 2. Median EPCs and hemangioblasts (VEGF/CD34) with and without RI EPCs (%) VEGF+/CD34+ (%) eGFR >90 (n=41) 0.050 (0 – 0.41) 0.195 (0 – 0.86) eGFR <90 (n=46) 0.025 (0 – 0.41) 0.230 (0 – 0.8) eGFR >30 (n=81) 0.030 (0 – 0.41) 0.210 (0 – 2.23) eGFR <30 (n=6) 0.025 (0 – 0.41) 0.190 (0 – 2.23) Conclusions: These results demonstrate that all ECs, namely VEGF+ cells, EPCs and hemangioblasts are higher in MM than MGUS and HD. Lower CD34+ and CD45+ cells in MM suggest this as a result of the disease and most likely also due to anti-MM therapy. We observed differences in BM, PB and AP specimens in MM pts. RI influenced EC numbers. These results suggest that elevated ECs in MM may reflect disease activity and may be useful as MM biomarkers. The quantification of ECs in MM may also be informative to monitor the efficacy of anti-angiogenic treatment, such as thalidomide and lenalidomide. Further analyses will evaluate the prognostic significance of EPCs, hemangioblasts and other markers in MM, their role in mild and severe RI is ongoing, as well the correlation with disease outcome.
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Chen, Qixuan, and Edmund T. S. Li. "Reduced adiposity in bitter melon (Momordica charantia) fed rats is associated with lower tissue triglyceride and higher plasma catecholamines." British Journal of Nutrition 93, no. 5 (May 2005): 747–54. http://dx.doi.org/10.1079/bjn20051388.
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Slower weight gain and less visceral fat had been observed when rats fed a high-fat diet were supplemented with freeze-dried bitter melon (BM) juice; the metabolic consequences and possible mechanism(s) were further explored in the present study. In a 4-week experiment, rats were fed a low-fat (70 g/kg) or a high-fat (300 g/kg) diet with or without BM (7·5 g/kg or 0·75%). BM-supplemented rats had lower energy efficiency, visceral fat mass, plasma glucose and hepatic triacylglycerol, but higher serum free fatty acids and plasma catecholamines. In the second experiment, 7-week BM supplementation in high-fat diet rats led to a lowering of hepatic triacylglycerol (P<0·05) and steatosis score (P<0·05) similar to those in rats fed a low-fat diet. BM supplementation did not affect serum and hepatic cholesterol. However, plasma epinephrine and serum free fatty acid concentrations were increased (P<0·05). In the third experiment, BM(7·5 and 15 g/kg) and 1·5 % BM lowered triacylglycerol concentration in red gastrocnemius and tibialis anterior (P<0·05) muscle, but a dose–response effect was not observed. These data suggest that chronic BM feeding leads to a general decrease in tissue fat accumulation and that such an effect is mediated in part by enhanced sympathetic activity and lipolysis. BM or its bioactive ingredient(s) could be used as a dietary adjunct in the control of body weight and blood glucose.
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Gerritsen, WR, and RJ O'Reilly. "Granulocyte colony-stimulating factor (CSF) but not interleukin-1 (IL- 1), IL-3, and granulocyte-macrophage CSF protect bone marrow progenitor cells from suppression by allosensitized cytotoxic T cells." Blood 84, no. 6 (September 15, 1994): 1906–12. http://dx.doi.org/10.1182/blood.v84.6.1906.1906.
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Abstract The major immunological reactions after an allogeneic bone marrow transplantation (BMT) are graft rejection and graft-versus-host disease (GVHD). GVHD can be prevented by T-cell depletion of the allogeneic BM graft, but the beneficial effect of T-cell depletion on the incidence of GVHD is counterbalanced by a higher incidence of graft failure. One option for the prevention of graft rejection after T-cell-depleted BM grafts is the administration of cytokines. Before applying cytokines after an allogeneic BMT, we considered it desirable to learn whether cytokines would alter the susceptibility of donor BM cells to host T cells. An in vitro assay was developed to investigate the role of the cytokines interleukin-1 (IL-1), IL-3, granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage CSF (GM-CSF) on the interaction between allosensitized, cytotoxic-T cells (CTLs) and T-cell- depleted BM cells. CTLs primed against the BM donor suppressed the formation of colonies consisting of granulocytes and macrophages (colony-forming unit GM). Colony formation was not inhibited by CTLs sensitized against a third party. Accordingly, the number of colonies scored in cocultures with CTLs sensitized to third party antigens were designated as 0% inhibition. A 66% inhibition of colony formation was observed for untreated BM cells at an effector:target (E:T) ratio of 1:1. Pretreatment of the BM cells with the cytokines G-CSF, GM-CSF, IL- 1, and IL-3 resulted in a 38% (P = .001), 53%, 66%, and 68% inhibition of colony formation, respectively, at E:T ratios of 1:1. G-CSF reduced the susceptibility of BM cells over a range from 4:1 to 1:16 (E:T ratios). GM-CSF had only significant influence at the lower E:T ratios (1:4 and 1:16). These in vitro data indicate that G-CSF could protect BM cells from killing by allosensitized CTLs and suggest that administration of these cytokines might potentially reduce the susceptibility of T-cell-depleted allogeneic BM grafts to host T-cell- mediated rejection.
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Gerritsen, WR, and RJ O'Reilly. "Granulocyte colony-stimulating factor (CSF) but not interleukin-1 (IL- 1), IL-3, and granulocyte-macrophage CSF protect bone marrow progenitor cells from suppression by allosensitized cytotoxic T cells." Blood 84, no. 6 (September 15, 1994): 1906–12. http://dx.doi.org/10.1182/blood.v84.6.1906.bloodjournal8461906.
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The major immunological reactions after an allogeneic bone marrow transplantation (BMT) are graft rejection and graft-versus-host disease (GVHD). GVHD can be prevented by T-cell depletion of the allogeneic BM graft, but the beneficial effect of T-cell depletion on the incidence of GVHD is counterbalanced by a higher incidence of graft failure. One option for the prevention of graft rejection after T-cell-depleted BM grafts is the administration of cytokines. Before applying cytokines after an allogeneic BMT, we considered it desirable to learn whether cytokines would alter the susceptibility of donor BM cells to host T cells. An in vitro assay was developed to investigate the role of the cytokines interleukin-1 (IL-1), IL-3, granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage CSF (GM-CSF) on the interaction between allosensitized, cytotoxic-T cells (CTLs) and T-cell- depleted BM cells. CTLs primed against the BM donor suppressed the formation of colonies consisting of granulocytes and macrophages (colony-forming unit GM). Colony formation was not inhibited by CTLs sensitized against a third party. Accordingly, the number of colonies scored in cocultures with CTLs sensitized to third party antigens were designated as 0% inhibition. A 66% inhibition of colony formation was observed for untreated BM cells at an effector:target (E:T) ratio of 1:1. Pretreatment of the BM cells with the cytokines G-CSF, GM-CSF, IL- 1, and IL-3 resulted in a 38% (P = .001), 53%, 66%, and 68% inhibition of colony formation, respectively, at E:T ratios of 1:1. G-CSF reduced the susceptibility of BM cells over a range from 4:1 to 1:16 (E:T ratios). GM-CSF had only significant influence at the lower E:T ratios (1:4 and 1:16). These in vitro data indicate that G-CSF could protect BM cells from killing by allosensitized CTLs and suggest that administration of these cytokines might potentially reduce the susceptibility of T-cell-depleted allogeneic BM grafts to host T-cell- mediated rejection.
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Harker-Murray, Paul D., Michael R. Verneris, Avis J. Thomas, Xianghua Luo, Margaret L. MacMillan, Jakub Tolar, K. Scott Baker, John E. Wagner, and Paul J. Orchard. "Hematopoietic Cell Transplantation as Therapy for Pediatric Patients with Relapsed Acute Lymphoblastic Leukemia with and without CNS Involvement." Blood 108, no. 11 (November 16, 2006): 3110. http://dx.doi.org/10.1182/blood.v108.11.3110.3110.
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Abstract Allogeneic hematopoietic cell transplantation (HCT) is the standard of care for pediatric patients with acute lymphoblastic leukemia (ALL) with early bone marrow relapse. However, the role of HCT is less clear in patients with isolated central nervous system (CNS) relapse where intensive chemotherapy followed by craniospinal irradiation is often offered. To determine the potential role of HCT, we evaluated the transplant outcomes of 116 patients with relapsed ALL with and without CNS involvement, 1–18 years of age, treated at the University of Minnesota between 1991 and 2006. Patients not in remission at transplant, and those with isolated extramedullary disease not involving the CNS were excluded. Relapse site prior to HCT was CNS in 14 patients, bone marrow (BM) in 85 patients and both marrow and CNS (BM+CNS) in 17 patients. Forty-eight underwent HCT from 1991–1995, 39 from 1996–2000 and 29 from 2001–2006. There were no significant differences among groups in median age at diagnosis (CNS: 3.7 years, range 1.2–7.7; BM: 4.5, 1–16; BM+CNS 3.7, 1.4–17), median age at transplant (CNS: 8 years, range 3.2–17.3; BM: 8.3, 3.5–17.9; BM+CNS 7.8, 3–17.9), or length of CR1 (CNS: 22.8 months, range 8.6–58; BM: 26.9, 0.8–74; BM+CNS: 34.2, 3.3–74). Remission status was similar in all groups (CNS: 7 CR2, 14 CR3+; BM: 73 CR2, 92 CR3+; BM+CNS: 14 CR2, 17 CR 3+; p=.06). Graft source was also similar between groups with 44 patients (38%) having a related donor and 72 patients having an unrelated donor (36% marrow and 25% umbilical cord blood). The majority of patients received cyclophosphamide 120 mg/kg and total body irradiation 1320–1375 cGy alone (n=69), or with etoposide (n=38) or fludarabine (n=8). Preparative regimen had no effect on outcomes. The incidence of grade II–IV GVHD (CNS 51%, 95% CI 24–68; BM 36%, 26–46; BM+CNS 18%, 1–35; p=.27) and grade III–IV GVHD (CNS 21%, 95% CI 0–42%; BM 16%, 8–24%; BM+CNS 0%; p=.21) was similar between groups. Hazard ratios using Cox multiple regression analysis demonstrated reduced survival in recipients with T cell leukemia or BCR-ABL gene rearrangement, history of marrow relapse, or receipt of HLA mismatched marrow from an unrelated donor. Patients with isolated CNS relapse had the least transplant related mortality at 2 years (CNS: 0%; BM: 35%, 95% CI 11–59%, BM+CNS: 34, 24–44; p=.05) and the lowest incidence of relapse (CNS: 0%; BM: 12%, 95% CI 0–27%, BM+CNS: 30%, 20–40; p=.01). The probability of leukemia-free survival at 5 years was greatest for patients with isolated CNS relapse (CNS: 91%, 95% CI 51–99; BM: 35, 25–45; BM+CNS: 46, 22–.68; p<.05). Similarly, the probability of overall survival was also greatest for the CNS group (CNS 86%, 33–98%; BM: 38, 27–49; BM+CNS: 53, 28–73; p<.01). These data strongly support allogeneic hematopoietic cell transplantation as a viable therapeutic option for pediatric patients with isolated CNS relapse with a very high probability of survival. Furthermore, the data indicate that CNS disease in combination with marrow relapse does not adversely effect transplant outcome compared to results expected in those with marrow relapse alone.
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Purnama, Yugi Hari Chandra, Gondo Mastutik, and Suhartono Taat Putra. "Increased Activity Of Mature Osteoblast from Rat Bone Marrow-Mesenchymal Stem Cells tn Osteogenic Medium Exposed to Melatonin." Folia Medica Indonesiana 54, no. 4 (December 11, 2018): 282. http://dx.doi.org/10.20473/fmi.v54i4.10714.
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Exposure to melatonin in the cultures of Bone Marrow Mesenchymal Stem Cells (BM-MSCs) in osteogenic medium is able to induce mesenchymal stem cells and preosteoblasts into active osteoblasts via several transduction signals such as ERK 1/2. Previous studies used a single dose of 50 nM and a physiological dose of 20-200 pg/ml. The objective of the study was to obtain an optimal dose of melatonin that enhances osteoblast activity by increasing the expression of ERK1/2 and ALP levels in the culture of Rat Bone Marrow Mesenchymal Stem Cells (BM-MSCs) in osteogenic medium. This study was an in vitro experimental laboratory study using BM-MSCs from rat femoral bone grown on osteogenic medium without or with exposure to melatonin in doses of 0, 50, 100, 150 nM for 21 days. BM-MSCs were characterized by immunocytochemical techniques (CD45- and CD 105+) and ERK 1/2 expression was checked 24 hours after exposure to melatonin, while ALP levels were examined on day 21 using ELISA technique. ERK 1/2 expression on BM-MScs exposed to melatonin in doses 0, 50, 100, and 150 nM were respectively 0.087, 0.095, 0.081, and 0.079. Mean ERK 1/2 expression in various groups showed a decrease along with increasing doses of melatonin. Among the four treatment groups, the administration of melatonin in a dose of 50 nM resulted in highest mean ERK 1/2 expression. ALP levels in BM-MSCs exposed to melatonin doses of 0, 50, 100, and 150 nM were 0.128; 0.130; 0.117, and 0.111 ng/ml respectively. Data showed that decreasing mean ALP levels occurred along with the addition of melatonin dose. In conclusion, the administration of melatonin 50 nM is the optimal dose to increase the differentiation of cultured rat BM-MSCs into active osteoblasts.
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Ashman, Jonathan Ben, Gabrielle Welch, Naresh P. Patel, Dawn E. Jaroszewski, David Fleischer, William G. Rule, Harshita Paripati, Francisco Ramirez, and Helen J. Ross. "Incidence of brain metastasis from esophageal cancer." Journal of Clinical Oncology 35, no. 4_suppl (February 1, 2017): 165. http://dx.doi.org/10.1200/jco.2017.35.4_suppl.165.
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165 Background: Distant metastases are common in primary esophageal cancer, but data conflict regarding the rates of brain metastases (BM) ranging from 0% to 13%. We sought to investigate whether the incidence of BM from esophageal malignancies is increasing in the modern era. Methods: After IRB approval, a single institution retrospective review identified 583 patients (pts) treated between 1/1997 and 1/2016 for stage I-IV cancer of the esophagus/esophagogastric junction with at least 3 months follow-up. Data collected included demographic information, primary diagnosis date and staging, histologic subtype, treatment regimens for primary and BM, date of BM diagnosis, status of neurologic symptoms and extracranial disease at BM diagnosis, and date of death. Data were analyzed by Fischer’s exact test and Kaplan-Meier analysis. Results: The overall cohort was comprised of 495 pts (85%) with adenocarcinoma and 82 pts (14%) with squamous cell carcinoma. 492 pts (84%) were male; the median age was 68 years (range 26-90). BM were identified in 22 pts (3.8%) with a median latency of 11 months from the primary diagnosis. Of the pts with BM, the primary histology was adenocarcinoma in 21 pts and squamous cell carcinoma in 1 pt ( P = 0.3). BM developed in 12 pts who were initially treated for locally advanced disease and in 10 pts who presented with distant metastases. Diagnosis of BM was at the time of initial presentation in 4 of these 10 stage IV pts. A solitary BM was identified in 9 pts. Initial treatments of BM were surgical resection followed by stereotactic radiosurgery (SRS; n = 5); surgical resection followed by whole brain radiotherapy (WBRT; n = 1); WBRT alone (n = 13); SRS alone (n = 3). Overall survival (OS) following diagnosis of BM was 18% at 1 year with a median of 4 months. OS was superior for pts who had surgical resection as initial treatment of BM compared to pts treated with WBRT or SRS alone (1-year OS 67 vs. 0%; median OS 13.5 vs. 3 months; P = 0.003). Conclusions: The incidence of BM is low in esophageal cancer with no statistically significant increased rate of BM developing in patients with adenocarcinoma compared with squamous cell carcinoma. Outcomes were poor overall for pts who developed BM, but pts who were appropriate for neurosurgical resection had improved survival.
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Fujiwara, Hiroshi, Joseph J. Melenhorst, Frank El Ouriaghli, Sachiko Kajigaya, Matthias Grube, Giuseppe Sconocchia, Katayoun Rezvani, et al. "In Vitro Induction of Myeloid Leukemia Specific CD4 and CD8 T-Cells by CD40 Ligand Activated B Cells Gene-Modified to Express Primary Granule Proteins." Blood 104, no. 11 (November 16, 2004): 1351. http://dx.doi.org/10.1182/blood.v104.11.1351.1351.
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Abstract The closely-related primary granule proteins are a source of multiple antigens with immunotherapeutic potential for myeloid leukemias. To further explore the possibility of generating leukemia-specific T cell responses, DNA vectors encoding the primary granule proteins proteinase 3 (PR3), human neutrophil elastase (HNE) and cathepsin-G (CathG) were transfected into autologous CD40-activated B (CD40-B) cells and used to stimulate T cell responses from peripheral blood T cells of five patients with myeloid malignancies and three ALL patients three months post-bone marrow transplantation (BMT), and one patient with CML-BC pre-transplant. T-cell responses were measured by flow-based intra-cytoplasmic IFN-g assay and cytotoxic assay. CD8 and CD4 cell response to PR3 and HNE were observed in CD8+ and CD4+ T-cells in 6/6 patients with myeloid leukemias with various degrees. T-cell response against CathG were found in both myeloid and lymphoid leukemias. We conclude that gene-transfected CD40-activated B cells are fully capable of expanding functionally-competent primary granule protein-specific CD4 and CD8 T cells, making this approach a valuable means of expanding leukemia antigen-specific T cells for adoptive immunotherapy. PGP-DNA primed T cells showed CTL activity to CML cell (case#5, post transplant) CTL activity % ( E:T ratio ) CML cell; recipient BM cell, normal BM; HLA identical DNR BM cells Effector cells Target 50:1 25:1 12.5:1 PR3-primed CML cell 63.8 54.6 30.4 normal BM 15.5 13.1 5.9 HNE-primed CML cell 43.9 38.3 32.1 normal BM 0 4.1 2.3 CathG-primed CML cell 43.1 29.1 27.5 normal BM 0 0 1.7 mock-primed CML cell 33.3 34.2 29.5 normal BM 5.5 12.9 0
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Hidalgo Lopez, Juliana, Rashmi Kanagal-Shamanna, Bryce Macek, Adrian Carballo-Zarate, Rafael Rojas Sáurez, Steven Reyes, Chong Zhao, and Carlos E. Bueso-Ramos. "Splicing Factor Pathway Is Rarely Mutated in Myeloid Blast Phase of PV with Dysmyelopoiesis and Ring Sideroblast." Blood 132, Supplement 1 (November 29, 2018): 4309. http://dx.doi.org/10.1182/blood-2018-99-116589.
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Abstract Introduction: BP of PV presents with dyserythropoiesis, including ring sideroblasts, and bilineage dysplasia in most cases. Clonal evolution or acquisition of new cytogenetic clone(s) plays a critical role in progression to BP of PV. SF3B1 mutation is associated with 75% of MDS with ring sideroblasts (RS). We hypothesized that an increase in ring sideroblast counts is an early event in the BP evolution. We postulate that genomic lesions other than in splicing factors genes are implicated in RS development in PV during BP evolution. Methods: We identified all cases in the last 14 years (2004 - 2018) with a diagnosis of PV in the MDACC files. We collected demographic, clinical, morphological, cytogenetic, and NGS information from 61 patients who developed BP progression from PV. We did an assessment and scoring of all bone marrow (BM) samples available at BP evolution. Results: A total of 61/477 (13%) patients with diagnosis of BP of PV were identified. Median age at BP diagnosis was 67 yrs. (32-82). This included 34 (56%) men and 27 (44%) women. At BP presentation, median BM blast percentage was 28%; 51 (84%) patients had BM dysplasia; 35 patients (69%) with dyserythropoiesis, 22 (43%) cases showed bilineage dysplasia. At BP, 43 pts had complex CG, 9 were were normal karyotype, 3 had double and 5 had single abnormalities. Prussian blue stain for Iron evaluation was available in 54 patients (89%); 24 patients (44%) had 0% RS; 19 patients (35%) had 1-14% RS; and 11 pts (20%) had >15% RS. Mutation analysis for splicing factor was performed on 13 patients. Of these, 2 patients with >15% RS had SRSF2 mutation and 1 patient with 6% RS had SF3B1 mutation. The other patients were wild type for SF3B1, SRSF2, U2AF1 (5 patients: >15% RS, 2 patients: 1-14% RS and 3 patients: 0% RS). Twenty-four (39%) patients had BM available before the BP diagnosis; median time between first BM at MDACC and BP BM diagnosis was 35 months (range, 1-135). At Baseline BM assessment, median BM blast was 3%; 13 (54%) patients had BM dysplasia. Prussian blue stain for Iron evaluation was available in 13 pts (55%): 10 pts (77%) had 0% RS and 3 pts (23%) had 1, 3, and 60% RS, respectively. To evaluate the level of RS during disease evolution we identified 10/26 pts who had at least 1 BM sample available between the first BM and the BP. 5/10 pts were in spent phase with increased blast, multilineage dysplasia and complex CG (RS: 6%, 25%, 0%, 1% and 50%) median time between samples 5 months. 4/10 pts had 1-4% blast, isolated dyserythropoiesis and normal diploid CG (RS: 12%, 5%, 2% and 0%). The median time between samples was 56 months. The last pt. had 0% blast, no dysplasia, del(20q) on CG and no RS. Pt. developed BP of PV 41 months after this follow up sample. Ten pts with PV chronic phase and were used as control group, median follow up of 14,5 yr. None of the patients had RS at baseline or at last follow up BM. Median time between samples 6 yrs. RS increase during PV evolution were statistically significant more frequent in pts who develop BP than in pts who remain in chronic phase of PV (7/10 vs. 0/10. P=0.003) Conclusion: Splicing factor gene mutation is infrequent in BP of PV despite the presence of dyserythropoiesis and frequent RS in 55% of patients. When present , RS may identify disease evolution and correlate with the disease phase of PV before BP. Dyserythropoiesis and the acquisition of RS is an early event BP of PV that precede other markers of disease progression like CG. Disclosures No relevant conflicts of interest to declare.
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Ghanem, Ismael, Carlos Castañeda, Ana Perez-Campos, Oscar Toldos, Blanca Sancho Perez, Luis Manso, Jose Luis Rodriguez-Peralto, et al. "Molecular biomarkers as predictive factors of pCR for early triple-negative breast cancer." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 1041. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.1041.
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1041 Background: Early triple-negative breast cancer (TNBC) patients (p) without pathologic complete response (pCR) after neoadjuvant chemotherapy (NCT) have unsuccessful prognosis. Predictive factors for pCR are necessary in order to improve the treatment choice. The aims of the study are to determine the expression of different biomarkers (BM) in the initial biopsy (IB) of TNBC, to analyze the relationship between the BM expression and pCR, and to determine the expression changes of BM after NCT. Methods: We reviewed retrospectively the medical records of 49 TNBC p treated with NCT between 2001 and 2011 at two institutions. Expression of 14 BM in the IB and after NCT was independently analyzed by inmunohistochemistry by two pathology specialists. Staining intensity 0-1 + was considered as negative expression, and 2-3-4 + as positive. Ki 67>13% was interpreted as positive. Results: Forty-nine p with a median age of 47 years (27-79) were evaluated. Twenty-seven p (55%) had grade 3. Tumor stages were T1(2%), T2(26%), T3(39%), and T4(33%). 38p (77%) were node positive. Five p (10%) received anthracyclines and 42p (86%) anthracyclines plus taxanes. Fourteen p (29%) presented pCR, 27p (55%) partial response, 4p (8%) stable disease, 2p (4%) progressive disease, and 2p (4%) were not evaluable. The BM expression in the IB was: CD44 (88%), CK 5/6 (27%), EGFR ( 0%), Ki 67 (73%), Wt-1 (10%), p-Akt (24%), HER2 (19%), NY-ESO-1 (11%), MAGE A1 (0%), HER3 (14%), BRCA1 (84%), PTEN (12%), IGFR1 (12%) and AR (14%). Diferentially expressed BM in IB for p with and without pCR, respectively, were p-Akt 0/8(0%) vs 5/13(38%) p=0.11, CK 5/6: 4/9 (44%) vs 2/15 (13%) p=0.15 and Ki 67: 7/7(100%) vs 10/17(59%) p=0.06. The Table shows the BM expression before and after NCT for p without pCR. Conclusions: Tumor samples of TNBC show high expression of CD44, ki67, and BRCA1. Most of BM has a decrease in expression after NCT. CK 5/6, Ki 67, and p-Akt could be predictive factor for pCR, although larger prospective studies are needed. [Table: see text]
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Ogiya, Rin, Naoki Niikura, Nobue Kumaki, Hiroyuki Yasojima, Tsutomu Iwasa, Chizuko Kanbayashi, Risa Oshitanai, et al. "Immune microenvironment in brain metastases of breast cancer." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): 1081. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.1081.
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1081 Background: In patients with brain metastasis (BM) of melanoma or lung cancer, significant activity of immune checkpoint inhibitors has been reported. However, details of the immune microenvironment in BM has not been unveiled. In this study, we used immunohistochemistry (IHC) to compare primary breast tumors and BM tumor samples with respect to tumor infiltrating lymphocytes (TILs) and tumor characteristics related to the immune system. Methods: We retrospectively identified 107 patients with breast cancer, diagnosed with BM, who had undergone surgery between 2001 and 2012 at 8 institutions. We collected 191 samples which included both BM samples alone and pair-matched samples (primary and BM). Hematoxylin and eosin (H&E) stained slides were evaluated for stromal TILs in 10% increments (0–1%, > 1– < 10%, 10%–100%). IHC was performed using the following primary antibodies: CD4, CD8, Foxp3, PD-L1, PD-L2 and HLA class I. The cells positive for each antibody signal were counted automatically using ImageJ (NIH). The expression of PD-L1, PD-L2, and HLA on the tumor cells was scored as 0 (negative), 1 (weak or focal), or 2 (strong). Results: The median category of TILs of BM tumors was > 1– < 10% (range: 1–30%). Forty-six pair-matched samples were analyzed and the percentage of TILs in the primary breast tumor was significantly higher than that in BM samples (paired t-test, P < 0.01). The number of CD4/CD8/Foxp3 positive cells in primary breast tumor was also significantly higher than in BM samples (paired t-test, P < 0.05 for all categories). The negative/positive conversion occurred with the expression of HLA/PD-L2 on tumor cells (paired t-test, P = 0.03/0.06, respectively). No significant difference was observed in the overall survival (OS) of patients, from initial BM, based on high or low TILs (log-rank test, P = 0.131). However, triple negative breast cancer patients with low TILs had significantly shorter OS compared with patients with high TILs (log-rank test, P = 0.04). Conclusions: We demonstrated that TILs in BM tumors was significantly lower as compared to primary breast tumors. The expression of immune related molecules on tumor cells was converted in BM tumors.
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Lee, Michael R. F., and John K. S. Tweed. "Isomerisation of cis-9 trans-11 conjugated linoleic acid (CLA) to trans-9 trans-11 CLA during acidic methylation can be avoided by a rapid base catalysed methylation of milk fat." Journal of Dairy Research 75, no. 3 (August 2008): 354–56. http://dx.doi.org/10.1017/s0022029908003518.
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This study investigated the evolution of trans-9 trans-11 conjugated linoleic acid (CLA) from cis-9 trans-11 CLA during methylation and its avoidance through a rapid base methylation of milk fat. The study examined three conditions shown to result in loss of cis-9 trans-11 CLA during methylation namely: temperature, methylation time, water contamination in old reagents and acidic conditions. Three techniques currently used for the conversion of milk fat into fatty acid methyl esters for analysis of CLA content by gas liquid chromatography and a fourth procedure designed to eliminate acidic conditions and to limit methylation temperature and time were used. The four methods were: (i) acidic methylation (AM); (ii) acidic and basic bimethylation with fresh reagents (FBM); (iii) acidic and basic bimethylation with pre-prepared reagents (PBM) and (iv) basic methylation (BM). Each regime was carried out on six milk samples over two periods and methylated 1 ml freeze-dried milk (n=12 per regime). Total CLA was not different across methylation regimes (0·30 mg/ml). Isomer cis-9 trans-11 was higher (P<0·01) with BM than the other regimes and lowest with AM: 21·2, 17·8, 18·8 and 14·7 mg/100 ml for BM, FBM, PBM and AM, respectively. The inverse relationship was shown for trans-9 trans-11 with higher (P<0·001) amounts with AM than the other regimes and lowest with BM: 0·57, 2·55, 2·36 and 3·69 mg/100 ml for BM, FBM, PBM and AM, respectively. The trans-10 cis-12 isomer was also shown to alter with methylation procedure being higher (P<0·001) with AM than the other regimes: 0·43, 0·47, 0·29 and 1·20 mg/100 ml for BM, FBM, PBM and AM, respectively. Validation with known CLA free fatty acid and triacylglycerol standards confirmed that AM resulted in conversion of cis-9 trans-11 to trans-9 trans-11, and also elevated trans-10 cis-12 whilst BM of triacylglycerol CLA did not isomerise cis-9 trans-11 and was comparable to FBM.
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Giona, Fiorina, Maria Caterina Putti, Maria Luisa Moleti, Mauro Nanni, Anna Maria Testi, Stefania Varotto, Enrico Marco Gottardi, et al. "Imatinib Mesylate Induces High Complete Cytogenetic and Molecular Response Rates in Children and Adolescents with Philadelphia Chromosome-Positive (Ph+) Chronic Myelogenous Leukemia (CML) in Chronic Phase (CP)." Blood 112, no. 11 (November 16, 2008): 4273. http://dx.doi.org/10.1182/blood.v112.11.4273.4273.
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Abstract Imatinib mesylate (IM), a BCR-ABL tyrosine kinase inhibitor, is an effective therapy for CML in adults and has shown efficacy in children with Ph+ leukemias. The aim of this study was to evaluate the efficacy of IM in Ph+ CML patients (pts) in CP aged <18 years at diagnosis, previously untreated or resistant to Interferon (IFN). In all pts, IM therapy, started at a dose of 340 mg/m2/day, was modulated according to the hematologic parameters. Cytogenetic studies were performed on bone marrow (BM) cells at baseline and, during IM therapy, every 3 months (mo). Complete cytogenetic response (CCyR) was also confirmed by FISH. BCR-ABL transcripts were measured in the peripheral blood (PB) cells every mo and in the BM cells every 3 mo by real-time quantitative PCR (RQ-PCR). Molecular response (MolR) was defined as major in the presence of a BCRABL: ABL ratio <0.05% and as complete with a ratio <0.001. Between February 2001 and October 2007, 13 Ph+ CML pts (9 M and 4 F; median age 128/12 years) in CP were recruited from 2 pediatric centers (Rome and Padua). Eight of the 13 pts (7 M and 1 F; median age 11 years) received IM at diagnosis and 5 (3 F and 1 M; median age 146/12 years) after IFN therapy given at a mean dose of 6.000.000 UI/day for a median of 18 mo. All but 1 pt tolerated well IM treatment. The mean dose of IM administered was 326 mg/m2/day for untreated pts and 227 mg/m2/day for those resistant to IFN. The characteristics and followup of the pts are summarized in the Table: Sex/Age at diagn/Age at treat (yrs) IFN duration/%Ph+ IM mg/m2/day CCyR/time (mo) Max Bcr-Abl:Abl (%)/time (mo) (BM) Max Bcr-Abl:Abl (%)/time (mo) (PB) CCyR duration (mo) Follow-up .F/11/146/12 40 mo/100 193.5 4 0/60 0/4 +80 Alive CCyR, Bcr-Abl:Abl (%)BM 0 PB 0.0023 F/179/12/1810/12 9 mo/100 182 6 1.27/9 0.89/9 +7 Lost to follow-up in CCyR at + 13 mo M/91/12/117/12 26 mo/50 208 3 0/36 0/12 +65 Alive CCyR, Bcr-Abl:Abl (%)BM 0 PB 0 F/89/12/910/12 13 mo/50 350 3 0/44 0/66 +66 Alive CCyR, Bcr-Abl:Abl (%)BM 0.009 PB 0 M/172/12/189/12 18 mo/80 205 9 0.029/68 0.114/72 +82 Alive CCyR, Bcr-Abl:Abl (%)BM 0.05 PB 0.15 M/126/12 −/100 310 4 0/42 0/30 +66 Alive CCyR, Bcr-Abl:Abl (%): BM 0 PB 0 M/161/12 −/100 327 n.e. n.e. n.e. n.e. IM tox; alive CCyR after SCT (sibl) (+40 mo) M/144/12 −/100 291 4 0/42 0/24 +61 Alive CCyR, Bcr-Abl:Abl (%) BM 0 PB 0 M/811/12 −/100 357.5 6 0.044/9 0.057/9 CyRel/33 Alive CCyR after SCT (+ 8 mo) M/95/12 −/100 326 3 0.013/12 0.028/9 +12 Alive CCyR,Bcr-Abl:Abl (%) BM 0.013 PB 0.15 M/410/12 −/100 328.5 3 0.02/9 0/12 BMT/+13 SCT (sibl) in CCyR->Alive in CCyR +43 mo M/137/12 −/100 349 6 0.012/30 0.025/30 +32 Alive CCyR, Bcr-Abl:Abl (%) BM 0.012 PB 0.025 F/94/12 −/100 320 3 0.009/9 0.003/9 +7 Alive CCyR, Bcr-Abl:Abl (%) BM 0.02 PB 0.003 Twelve of the 13 pts (92%) achieved a CCyR after a median of 4 mo (range 3–9). Eleven of the latter 12 pts were evaluated for MolR: 11/11 (100%) pts achieved a MolR, 6 major (54.5%) and 5 complete (45.5%), on BM cells after a median of 36 mo (range 9–68) and 9/11 pts (82%) on PB cells, 4 major (44.4%) and 5 complete (55.6%), after a median of 12 mo (range 4–66). To date, 12 evaluable pts are alive in CCyR: 3 after a stem cell transplantation (SCT) and 9 still receiving IM for a median time of 68 mo (range 10–89). MolR persists on BM cells in 9/9 pts (100%), 4 complete (44%), and on PB cells in 7/9 pts (78%), 4 complete. Our experience indicates that IM is highly effective in children and adolescents with Ph+ CML in CP, capable also of inducing high and persistent CCyR and MolR rates also in pts resistant to IFN.
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Leeming, D. J., M. Koizumi, P. Qvist, V. Barkholt, C. Zhang, K. Henriksen, I. Byrjalsen, and M. A. Karsdal. "Serum N-Terminal Propeptide of Collagen Type I is Associated with the Number of Bone Metastases in Breast and Prostate Cancer and Correlates to Other Bone Related Markers." Biomarkers in Cancer 3 (January 2011): BIC.S6484. http://dx.doi.org/10.4137/bic.s6484.
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Background A number of biomarkers have been proven potentially useful for their ability to indicate bone metastases (BM) in cancer patients. The aim of this study was to investigate the relative utility of a newly developed N-terminal propeptide of collagen type I (PINP) human serum assay for the detection of BM in cancer patients. This assay has a corresponding rat PINP assay which in the future might help in translational science between rodent and human trials. Methods Participants were 161 prostate, lung and breast cancer patients stratified by number of BM(Soloway score). PINP was assessed and correlated to number of BM. Additionally, the PINP marker was correlated to bone resorption of young (ALPHA CTX-I)- and aged bone (BETA CTX-I); number of osteoclasts (Tartrate-resistant acid phosphatase 5b, TRACP5B) and osteoclast activity (CTX-I/TRACP5B). Results PINP was significantly elevated in breast- and prostate cancer patients +BM, compared to –BM ( P < 0.001), however not in lung cancer patients. A strong linear association was seen between PINP and the number of BMs. Significant elevation of PINP was observed at Soloway scores 1–4 (<0 BM) compared with score 0 (0 BM) ( P < 0.001). The correlation between bone resorption of young bone or aged bone and bone formation was highly significant in patients +BM and –BM ( P < 0.0001). Conclusions Data suggest that the present PINP potentially could determine skeletal involvement in patients with breast or prostate cancer. Correlations suggested that coupling between bone resorption and bone formation was maintained in breast- and prostate cancer patients.
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Styczynski, Jan, Myriam Labopin, Nabila Elarouci, Adriana Balduzzi, Lidia Gil, Karoline Ehlert, Franca Fagioli, et al. "Pediatric Sibling Donor Complications of Hematopoietic Stem Cell Collection: EBMT Pediatric Diseases Working Party Study." Blood 114, no. 22 (November 20, 2009): 806. http://dx.doi.org/10.1182/blood.v114.22.806.806.
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Abstract Abstract 806 Objective: The analysis of donor safety and early side effects related to hematopoietic stem cells (HSC) collection from bone marrow (BM) or peripheral blood (PB) in pediatric HLA-identical sibling donors. Methods: From 2005 to 2009, data regarding pediatric (<18 years) sibling donors undergoing HSC collection from 38 participating EBMT Centers were registered on specific forms sent to the PDWP Office. Data were centrally analyzed as of July 2009. A multiple logistic regression was performed to express an estimate of the relative risk of BM versus PB donation for the following variables: pain, blood transfusion, prolonged hospital stay, and need for iron supplementation. Results: A total number of 410 pediatric sibling donors with median age of 9 (range; 0.3-18) years were enrolled into the study; including 12% aged <4 yrs and 64% with body weight <40 kg. Children donated BM in 272 (66%), and PB in 138 (34%) cases. The criteria used by transplant centers for PB-HSC collection in children were: discrepancy between donor and recipient body weight, parents decision, undergoing clinical trial (pediatric centers), or transplant protocol (adult centers). Consents for donation were given by parents (49%), court (23%), ethical committee (28%) or social board (0.4%). All BM and 56% of PB donors had general anesthesia (PB donors for central catheter placement), for a median 90 (range; 30-300) and 30 (range 8-285) minutes, respectively. One (0.2%) serious adverse event (SAE) was reported (pneumothorax+hydrothorax) after catheter placement for PB collection. Tachycardia, decrease of blood pressure, sore throat or vomiting after anesthesia occurred in 5-11% cases. Autologous blood transfusion was done in 26% of BM and 7% of PB donors, at median age of 12 years (range 2.8-18). Erythropoietin was administered in 23 BM donors. BM was collected in median volume 18.8 (range; 2-49) ml/kg of donor weight and no severe complications of BM collection were observed. G-CSF priming was performed in all PB donors with median G-CSF dose of 10 (range; 5-20) mcg/kg/day. Median WBC count before collection was 46 (range; 24-101) G/L. Muscle/bone pain, fever, headache, abdominal or back pain, nausea or vomiting related to G-SCF were reported only in 6% of PB donors. Median number of apheresis was 1 (range; 1-3), which lasted for a median of 4 (range; 2-8) hrs. 21% donors experienced hypocalcemia. Thrombocytopenia <70G/L occurred in 3% of PB donors, however platelet transfusion was not required in any case. Blood allotransfusion was done in 23% of BM and 2.6% of PB donors. Iron was supplemented in 73% of BM and 31% of PB donors (p<0.001). Pain after collection occurred in 64% of BM and 15% of PB donors (p<0.001) and persisted for median of 1 day (range; 1-21 for BM and 1-3 for PB donors, respectively). No infections or thrombotic events were reported. Median number of nights spent in hospital before collection was 1 (range; 0-14) for BM and 3 (range; 0-7) for PB donors; while after collection 1 (range; 0-7) for BM and 0 (range; 0-6) for PB donors (p<0.001). Donors felt helpful, happy and proud in most cases, irrespectively of stem cell source. They felt responsible for recipient in 58% of BM and 53% of PB of donors (ns). Willingness to donate again was expressed by 86% and 71% of the BM and PB of donors, respectively (p=0.007). In multiple logistic regression analysis following complications and risk factors were determined: pain (BM collection, OR=12.3, p<0.001; age >4 yrs, OR=9.9, p<0.001), blood allotransfusion (BM collection, OR=22.7, p<0.001; body weight <40 kg, OR=4, p=0.004), prolonged hospital stay (BM collection, OR=3.5, p<0.001), and need for iron supplementation (BM collection, OR=6.9, p<0.001). Conclusions: BM or PB HSC collection in pediatric sibling donors is safe, however there is a risk of mild, short-term and easy to prevent or control early side effects. The risk of SAE in healthy pediatric donors exists, although it is small. Donors and parents must be informed about the risk of possible complication. There is a need of donor outcome and follow-up registry. Disclosures: No relevant conflicts of interest to declare.
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Hawley, John A., Louise M. Burke, Damien J. Angus, Kieran E. Fallon, David T. Martin, and Mark A. Febbraio. "Effect of altering substrate availability on metabolism and performance during intense exercise." British Journal of Nutrition 84, no. 6 (December 2000): 829–38. http://dx.doi.org/10.1017/s0007114500002440.
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The purpose of this study was to determine the effect of altering substrate availability on metabolism and performance during intense cycling. Seven highly trained men ingested a random order of three isoenergetic meals 90 min before cycling at 80 % maximal oxygen uptake (VO2max) for 20 min (about 310 W), followed by a 600 kJ time trial lasting about 30 min. Meals consisted of either 1·2 g saturated fat/kg body mass (BM) with 3500 U heparin intravenously (HIFAT) to elevate circulating plasma free fatty acid (FA) concentration, 2·5 g carbohydrate/kg BM (CHO) to elevate plasma glucose and insulin concentrations or 2·5 g carbohydrate+20 mg nicotinic acid/kg BM (NA) to suppress lipolysis and reduce free FA concentration. HIFAT elevated free FA concentration (HIFAT 1·3 (SEM 0·2), CHO 0·2 (sem 0·1), NA 0·1 (sem 0·1) mm; P<0·001), lowered the RER (HIFAT 0·94 (sem 0·01), CHO 0·97 (sem 0·01), NA 0·98 (sem 0·01); P<0·01) and increased the rate of fat oxidation (HIFAT 24 (sem 3), CHO 12 (sem 2), NA 8 (sem 3) μmol/kg per min; P<0·01) during the 20 min ride. Marked differences in fat availability and fuel utilisation, however, had little effect on performance in the subsequent time trial (HIFAT 320 (sem 16), CHO 324 (sem 15), NA 315 (sem 13) W). We conclude: (1) increased fat availability during intense cycling increases the rate of fat oxidation; but (2) the reduction in the rate of carbohydrate oxidation in the presence of high circulating plasma free FA is unlikely to enhance intense exercise performance lasting about 1 h; (3) substrate selection during intense (about 80 % VO2max) exercise is dominated by carbohydrate oxidation.
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Xu, Xingwei, Xin Gao, Xiaofan Zhao, Yannian Liao, Wu Ji, Qiurong Li, and Jieshou Li. "PU.1-Silenced Dendritic Cells Induce Mixed Chimerism and Alleviate Intestinal Transplant Rejection in Rats via a Th1 to Th2 Shift." Cellular Physiology and Biochemistry 38, no. 1 (2016): 220–28. http://dx.doi.org/10.1159/000438623.
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Background/Aims: Intestinal transplantation is an effective treatment for end-stage bowel failure; however, graft rejection and the toxicity associated with non-specific immunosuppression are major limitations of this procedure. Studies have shown that mixed chimerism can produce post-transplantation immune tolerance. Here, we demonstrate that in rat intestinal transplantation, PU.1-silenced dendritic cells (DCs) plus bone marrow (BM) cell transfusion results in mixed chimerism, and we investigate the mechanisms responsible for the effects of mixed chimerism rejection. Methods: In a model of intestinal transplantation, male Brown Norway rats were the donors, and female Lewis rats were the recipients that were randomly divided into 4 groups: control, BM, BM-imDCs and BM-PU.1. The dynamic changes in graft morphology, rejection scoring and serum concentrations of Th1/Th2-related cytokines were investigated on postoperative days 0, 7, 14, 21, and 30. Results: The BM-PU.1 group had better graft health, milder pathologic injuries, and lower rejection grades compared with the other groups. The rates of mixed chimerism were significantly highest in the BM-PU.1 group and correlated with decreases in serum IL-2 and increases in serum IL-10. Conclusion: Transfusion of PU.1-silenced DCs and BM cells induces stable mixed chimerism and has the potential to reduce pathologic injuries via a pro-Th2 shift in the Th1/Th2 balance.
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Manganaro, Rosa, Lucia Marseglia, Carmelo Mamì, Antonella Palmara, Antonina Paolata, Saverio Loddo, Romana Gargano, Maurizio Mondello, and Marina Gemelli. "Breast milk sodium concentration, sodium intake and weight loss in breast-feeding newborn infants." British Journal of Nutrition 97, no. 2 (February 2007): 344–48. http://dx.doi.org/10.1017/s0007114507280572.
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Elevated breast milk (BM) Na concentration is regarded as responsible for elevated Na intake. To verify the clinical significance of milk Na concentration, we studied the relationship between BM Na+ concentration and infants' daily Na+ intake, infants' daily BM intake (DBMI) and percentage weight loss (%WL) in healthy newborn infants. All mothers who gave birth to a single healthy infant, between February and March 2004 at the Obstetric Clinic of University of Messina (Italy), were invited to participate if they were willing to attempt to breastfeed exclusively. BM Na+ concentration, DBMI, Na+ intake and %WL were determined on the third day after delivery. Statistical analysis was performed by Spearman's correlation test, classification and regression trees and the generalised linear model. Of the 270 eligible mothers, 208 participated in the study. The results showed that on the third day postpartum BM Na+ concentration was 23·05 (sd 1·10) mmol/l, mean DBMI was 202 (sd 68·9) g/d, and mean Na+ intake was 4·36 (sd 0·22) mmol/d and 1·36 (sd 0·07) mmol/kg per d. BM Na+ concentration was inversely related to infant DBMI, and Na+ intake was directly related to infant DBMI and not to BM Na+ concentration. %WL was significantly correlated only to DBMI. In conclusion, the present data demonstrate, for the first time, that when lactogenesis is suboptimal, BM Na+ concentration is higher, but infants' Na+ intake is lower. Finally, the present data probably suggest that for the clinical assessment of breast-feeding, evaluation of milk intake remains the best method.
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Ghoual, Ouda, Stéphanie Jouve, Véronique Salaun, Stéphane Cheze, Michele Malet, Xavier Troussard, and Dina Istasi. "Evaluation of the Interest of BRAF –V600E Mutation Detection By Arms-qPCR in Hairy Cell Leukemia Diagnosis and Treatment Monitoring." Blood 124, no. 21 (December 6, 2014): 2956. http://dx.doi.org/10.1182/blood.v124.21.2956.2956.
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Abstract Background: The discovery of BRAF V600E (Tiacci et al. N.Eng J Med, 2011), has introduced molecular biology in the management of Hairy cell leukemia (HCL). Various techniques for BRAF detection with a specificity of 100% were developed. According to literature, BRAF mutation has been reported in one case of CLL and one B-prolymphocytic leukemia (Langabeer et al. Leukemia research, 2012). The development of BRAF inhibitors for refractory HCL to purine nucleoside analogues (PNA) renders the detection of BRAF mutation indispensable for the diagnosis and monitoring of the minimal residual disease (MRD). Objectives: To test a quantitative PCR on HCL patients at diagnosis, during relapse and at MRD monitoring compared to flow cytometry (FCM), then evaluate its usage on peripheral blood (PB) versus bone marrow (BM) sampling. Methods: We developed a relative quantitative amplification refractory mutation PCR technique (ARMS-qPCR). A retrospective study on a total of 99 samples between 1998 and 2014 was conducted. These samples were previously analyzed by a 4 colors FCM. 38 patients with HCL were tested at diagnosis (21 samples from PB and 17 from BM). 36 patients with other hematologic malignancies were studied, 5 other hairy cell proliferations (3 HCL-Variant (HCL-V) and 2 splenic lymphocyte villous lymphomas SLVL) and 31 non hairy cell proliferations (13 chronic lymphocytic leukemias (CLL), 13 atypical CLL, 3 large B-cell non Hodgkin lymphomas, 2 mantle cell lymphomas, 1 marginal zone lymphoma, 1 acute myeloid leukemia, 1 mastocytosis). Subsequently, we studied 14 patients in relapse (8 samples from PB, 5 from BM and 1 from a diaphragm nodule). Among these patients, 9 had received PNA, 3 interferon (IFN), 1 PNA + rituximab and 1 patient with unknown treatment. We monitored 11 patients for MRD (6 samples from PB and 5 from BM), 6 were treated with PNA, 1 with IFN and 1 with PNA + rituximab and 3 patients with unknown treatment. Results: The sensitivity of our ARMS-qPcr technique attained 0.001%. At diagnosis, the tumor cells ranged from 0.5% to 91% in PB and 3% to 73% in BM. All patients diagnosed as HCL by FCM were also detected by our PCR technique. The average mutated BRAF allele was 8% (0.02-18%) at diagnosis in the PB and 6% (2.5 -14%) in BM. The mutation was not detected for any of the patients harboring other hairy cell proliferations. Of the 36 patients with other hematologic malignancies, no signal was detected except for a weak one for 2 CLL patients with atypical morphology and 1 mixed type CLL/prolymphocytic leukemia (mutated allele: 0.03%, 0.21% and 1% respectively). This tempers the total specificity of BRAF detection in HCL described in earlier publications. At relapse, tumor cells ranged from 0.3% to 81% in PB and 3% to 30% in BM. The average mutated BRAF allele was 5.4% (0.09% -20%) in PB and 3.4% (0.6% -7.5%) in BM. Concerning evaluation of MRD, tumor cells ranged from 0% to 3% in PB and 0% to 2% in BM. All patients having malignant cells detected by FCM were detected by ARMS-qPCR. 2 patients were undetectable by both methods, 1 was treated by PNA + rituximab and the treatment was unknown for the other. The average mutated BRAF allele was 0.5% (0% -1%) in PB and 0.3% (0% -1%) in BM. Patients treated by PNA or IFN and tested in our study were positive for the MRD. DNA was obtained simultaneously from PB and BM for 3 patients (2 diagnosis and 1 relapse). The BRAF mutated allele was similar in PB and BM for 2 patients (4% and 11% in PB, 4% and 14% in BM respectively) and the circulating tumor cells were 60% and 61%. As for the 3rd patient, a lower mutated allele percentage (0.09%) was detected with 1% of tumor cells in blood, where 4% of the mutated allele was found in BM with 25% of tumor cells. Conclusion: This ARMs-qPcr allowed the HCL diagnosis of 100% of tested patients and the differential diagnosis with other hairy cell proliferations though a weak signal was detected in 3 atypical CLL cases. Using this PCR for relapse detection and MRD monitoring is as performing as the FCM. PB sampling which is less invasive than BM puncture seems to be adequate for HCL molecular study. BM aspirate may be considered in case of diagnostic difficulties or very few tumor cells. All patients treated by PNA or IFN and tested in our study were positive for the MRD suggesting that a complete molecular response is hardly achieved with these drugs. This should be confirmed on a larger number of patients as well with the emerging therapies. Disclosures No relevant conflicts of interest to declare.
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Maunglay, S. T., W. J. Fulp, A. Chiappori, and G. R. Simon. "Predictive scoring systems for brain metastasis at diagnosis and at recurrence in non-small cell lung cancer." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): e19020-e19020. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.e19020.
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e19020 Background: Brain metastasis (BM) is a major cause of mortality and morbidity in Non Small Cell Lung Cancer (NSCLC) but large studies analyzing potential factors that could be predictive of BM at diagnosis or recurrence are lacking. We have developed 2 predictive scoring models to identify the patients at risk. Methods: A retrospective analysis on 4,294 NSCLC cases, seen between 1994 and 2006, at the Moffitt Cancer Center and Research Institute, Tampa, FL was performed utilizing the cancer center's registry data. 477 (11.12%) patients had BM at the time diagnosis and additional 252 (5.82%) patients developed new BM as first recurrence. Results: For patients with BM at diagnosis, age younger than 63 years, non squamous histology and current or never smoking status were all significant in both univariate and multivariate analysis (N= 4174). Based on calculated odds ratios, a scoring system of 0 to 6 points was developed for these patients. Higher scores predicted higher risk for BM (0- 2=3.38%, 3- 4=9.93%, 5=13.65% and 6=21.03%; p <.0001). For patients with new BM at first recurrence, age younger than 63 years, non squamous histology, and the stage at diagnosis (i.e., BM risk in stage III>IV>II>I), were all significant in both univariate and multivariate analysis (N=4291). Based on calculated odds ratios, a scoring system of 0 to 7 points was developed for these patients. Higher scores predicted higher risk for BM (0–1=3.38%, 2–3=4.72%, 4–5= 8.76%, and 6–7=11.83%; p<.0001). Similar risk percentage results were seen after testing the 2 scoring systems in 3 chronologically divided patient groups. Conclusions: The 2 scoring systems developed based only on clinical data were predictive of BM in NSCLC at diagnosis and recurrence. These scoring systems should be helpful for establishing initial and follow up cranial imaging schedules in NSCLC patients. [Table: see text] No significant financial relationships to disclose.
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Durer, Seren, Ceren Durer, Faiza Jamil, Insija Ilyas Selene, Mustafa Nadeem Malik, Abdul Rafae, Muhammad Abu Zar, et al. "The Comparison of Unmanipulated Bone Marrow Versus Peripheral Blood Haploidentical Stem Cell Transplantation in Adult Acute Leukemia: A Systematic Review and Meta-Analysis." Blood 132, Supplement 1 (November 29, 2018): 5768. http://dx.doi.org/10.1182/blood-2018-99-109924.
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Abstract Background: The use of peripheral blood stem cell source (PBSC) continues to grow in the setting of haploidentical hematopoietic stem cell transplantation (haplo-SCT), mainly due to the ease of collection and rapid peripheral blood count recovery. We conducted a systematic review and meta-analysis of the published literature to evaluate the outcomes of unmanipulated bone marrow (BM) and PB haplo-SCT for adult leukemia patients. Method: A comprehensive literature search of electronic databases (Medline, Embase, and Cochrane library) for studies published between 1 January 2004 to 24 June 2018 was conducted. We included the studies of unmanipulated BM and/or PB haplo-SCT in adult acute myeloid leukemia (AML) and acute lymphoblastic leukemia ( ALL) . We excluded the studies which combined PB and BM stem cell sources and the studies which did not report the results of BM and PB haplo-SCT for ALL and AML separately. CMA software v.3 was used for the analysis. Heterogeneity among studies was assessed using the I2 test. Random-effect model was applied. Publication bias was assessed using funnel plots. Primary endpoints were engraftment, 2-year overall survival (OS), disease-free survival (DFS), relapse incidence (RI); grade II-IV, III-IV acute and chronic GVHD. Results: Out of 1548 publications, 3 studies (n = 672 patients; retrospective; multi-center) met our inclusion criteria. The sample size of the studies varied between 71 and 451 patients. The median follow-up ranged from 18 to 46 months. PB haplo-SCT was used in 191 patients (Ruggeri, A. et al. 2018) and BM haplo-SCT was used in 481 patients (Arcese, W. et al. 2015; Ruggeri, A. et al. 2018; Chiusolo, P. et al. 2018). Myeloablative (MA) conditioning was used in majority of patients. The pooled (95%CI) engraftment rate was 93% (88-95) in BM group and 95% (91-97) in PBSC group. The pooled estimates (95%CI) of BM studies showed a 2-year OS rate of 56.1% (51.6-60.4), 2-year DFS of 48.9% (43.5-54.2) and 2-year cumulative RI of 24.6%(20.7-29).There was no heterogeneity in BM group (I2=0%) for 2-year OS, DFS and RI. For PBSC group, the pooled estimates (95%CI) for 2-year OS, DFS and RI were 56 % (48.9-62.9; I2=0%), 54% (46.9-60.9; I2=0%) and 22% (16.7-28.4; I2=0%), respectively. Incidences of grade II-IV, grade III-IV aGVHD and cGVHD from a pooled analysis (95%CI) were 23.1% (17.2-30.3; I2=55%), 5.4% (3.4-8.3; I2=16%) and 19.5% (9.7-35.3; I2=88%) for BM group in comparison to 38% (31.4-45.1; I2=0%), 14% (9.8-19.7; I2=0%) and 32% (25.8-38.9; I2=0%) for PBSC group. Pooled estimates were shown in figure 1. Conclusions: In this analysis, higher pooled rates of grade II-IV aGVHD (38% vs 23.1%), III-IV aGVHD (14% vs 5.4%) and cGVHD (32% vs 19.5%) were observed in PBSC group vs BM group, respectively. Based on comparable OS, DFS and RI, PB haplo-SCT appears to be a good alternative option for adult AML and ALL patients. Large prospective randomized controlled trials are required to confirm these results. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.
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Andre, Fabrice, Erika P. Hamilton, Sherene Loi, Peter Schmid, Carey K. Anders, Tinghui Yu, Sarice Boston, Celina M. D'Cruz, Pia Herbolsheimer, and Komal L. Jhaveri. "Trastuzumab deruxtecan (T-DXd) combinations in patients with HER2-positive advanced or metastatic breast cancer: A phase 1b/2, open-label, multicenter, dose-finding and dose-expansion study (DESTINY-Breast07)." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): TPS1096. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.tps1096.
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TPS1096 Background: HER2-targeted therapies have improved survival in patients (pts) with HER2+ advanced/metastatic breast cancer (mBC) but challenges remain, including resistance to current HER2-targeted therapies. Also, additional treatment options are needed in pts with brain metastases (BM). In the phase 2 DESTINY-Breast01 trial, T-DXd demonstrated efficacy, with an objective response rate (ORR) of 61.4% and median progression-free survival (mPFS) of 19.4 mo in pts with previously treated HER2+ advanced/mBC (Modi SABCS 2020); data from an earlier cutoff of this trial supported approval of T-DXd in the US, Europe, and Japan. In a subgroup analysis of 24 pts with stable BM, T-DXd showed preliminary efficacy, with mPFS of 18.1 mo (Jerusalem ESMO Breast Cancer 2020). Here, we describe a phase 1b/2 trial evaluating the safety and preliminary antitumor activity of T-DXd monotherapy and combinations in pts with HER2+ advanced/mBC, including pts with stable and active BM. Methods: DESTINY-Breast07 (NCT04538742) is a global, multicenter, open-label, phase 1b/2 trial designed to evaluate the safety, tolerability, and preliminary antitumor activity of T-DXd monotherapy and combinations in pts with HER2+ advanced/mBC. This study consists of a T-DXd monotherapy module (module 0) and 5 combination modules of T-DXd plus (1) durvalumab, (2) pertuzumab, (3) paclitaxel, (4) durvalumab + paclitaxel, or (5) tucatinib, all in pts with no or stable BM. Two additional modules consisting of (6) T-DXd + tucatinib and (7) T-DXd monotherapy will include pts with untreated BM not requiring local therapy or previously treated BM that have progressed since local therapy (active BM). The need for chronic steroids or local therapy to manage BM symptoms is exclusionary. Modules 2 to 5 will each consist of 2 parts: dose finding (part 1) and dose expansion (part 2). Modules 0, 1, 6, and 7 will include part 2 only. Part 1 of individual modules will enroll pts who have had disease progression while receiving ≥1 prior line of therapy in the metastatic setting. In part 2, pts who have received no prior therapy (modules 0 to 5) or ≤1 prior therapy (modules 6 to 7) for metastatic disease will be randomized to receive a T-DXd combination regimen or monotherapy. The primary endpoints are determination of the recommended phase 2 doses (part 1 only) and safety and tolerability of T-DXd and combinations (parts 1 and 2). Secondary endpoints include ORR, PFS, PFS2, duration of response (DoR), and overall survival (all assessed in part 2 only) and pharmacokinetics and immunogenicity (parts 1 and 2). To assess central nervous system (CNS) activity, exploratory endpoints were added, including CNS-ORR, CNS-DoR, and CNS-PFS (by RECIST version 1.1 and RANO-BM criteria) as well as cognitive and symptom assessment using CANTAB, MDASI-BT, and NANO. Clinical trial information: NCT04538742 .
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Detko, Eva, John P. O'Hara, Peter E. Thelwall, Fiona E. Smith, Djordje G. Jakovljevic, Roderick F. G. J. King, and Michael I. Trenell. "Liver and muscle glycogen repletion using 13C magnetic resonance spectroscopy following ingestion of maltodextrin, galactose, protein and amino acids." British Journal of Nutrition 110, no. 5 (February 7, 2013): 848–55. http://dx.doi.org/10.1017/s0007114512005818.
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The present study evaluated whether the inclusion of protein (PRO) and amino acids (AA) within a maltodextrin (MD) and galactose (GAL) recovery drink enhanced post-exercise liver and muscle glycogen repletion. A total of seven trained male cyclists completed two trials, separated by 7 d. Each trial involved 2 h of standardised intermittent cycling, followed by 4 h recovery. During recovery, one of two isoenergetic formulations, MD–GAL (0·9 g MD/kg body mass (BM) per h and 0·3 g GAL/kg BM per h) or MD–GAL-PRO+AA (0·5 g MD/kg BM per h, 0·3 g GAL/kg BM per h, 0·4 g whey PRO hydrolysate plus l-leucine and l-phenylalanine/kg BM per h) was ingested at every 30 min. Liver and muscle glycogen were measured after depletion exercise and at the end of recovery using 1H-13C-magnetic resonance spectroscopy. Despite higher postprandial insulin concentations for MD–GAL-PRO+AA compared with MD–GAL (61·3 (se 6·2) v. 29·6 (se 3·0) mU/l, (425·8 (se 43·1) v. 205·6 (se 20·8) pmol/l) P= 0·03), there were no significant differences in post-recovery liver (195·3 (se 2·6) v. 213·8 (se 18·0) mmol/l) or muscle glycogen concentrations (49·7 (se 4·0) v. 51·1 (se 7·9) mmol/l). The rate of muscle glycogen repletion was significantly higher for MD–GAL compared with MD–GAL-PRO+AA (5·8 (se 0·7) v. 3·7 (se 0·6) mmol/l per h, P= 0·04), while there were no significant differences in the rate of liver glycogen repletion (15·0 (se 2·5) v. 13·0 (se 2·7) mmol/l per h). PRO and AA within a MD–GAL recovery drink, compared with an isoenergetic mix of MD–GAL, did not enhance but matched liver and muscle glycogen recovery. This suggests that the increased postprandial insulinaemia only compensated for the lower MD content in the MD–GAL-PRO+AA treatment.
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Field, Gill, Uthoff, and Plews. "Acute Metabolic Changes with Lower Leg-Positioned Wearable Resistances during Submaximal Running in Endurance-Trained Runners." Sports 7, no. 10 (October 11, 2019): 220. http://dx.doi.org/10.3390/sports7100220.
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The aim of this study was to determine the acute metabolic effects of different magnitudes of wearable resistance (WR) attached to the lower leg during submaximal running. Fifteen endurance-trained runners (37.8 ± 6.4 years; 1.77 ± 0.7 m; 72.5 ± 9.8 kg; 58.9 ± 7.4 L/min VO2max; 45.7 ± 5.8 min 10 K run time) completed seven submaximal running trials with WR loads of 0, 0.5, 1, 1.5, 2, 2.5 and 3% body mass (BM). Based on regression data, for every 1% BM increase of additional load, oxygen consumption (VO2) increased by 2.56% and heart rate increased by 1.16%. Inferential based analysis identified that ≤1% BM were enough to elicit responses in VO2, with a possible small increase (effect size (ES), 90% confidence interval (CI): 0.22, 0.17 to 0.39), while 3% BM loads produced a most likely very large increase (ES, 90% CI: 0.51, 0.42 to 0.60). A training load score was extrapolated using heart rate data to determine the amount of internal stress. An additional 1% BM resulted in an extra 0.39 (0.29 to 0.47) increase in internal stress over five minutes. Lower leg WR elicited substantial increases in lactate production from the lightest loading (0.5% BM), with a likely moderate increase (ES, 90% CI: 0.49, 0.30 to 0.95). Lower-leg positioned WR provides a running-specific overload with loads ≥ 1% BM resulting in substantial changes in metabolic responses.
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Alzer, Horst, and Chao-Ping Chen. "Inequalities involving gamma and digamma functions." Studia Scientiarum Mathematicarum Hungarica 51, no. 4 (December 1, 2014): 520–29. http://dx.doi.org/10.1556/sscmath.51.2014.4.1285.
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We prove: (A) Let \documentclass{aastex} \usepackage{amsbsy} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{bm} \usepackage{mathrsfs} \usepackage{pifont} \usepackage{stmaryrd} \usepackage{textcomp} \usepackage{upgreek} \usepackage{portland,xspace} \usepackage{amsmath,amsxtra} \usepackage{bbm} \pagestyle{empty} \DeclareMathSizes{10}{9}{7}{6} \begin{document} $$\Delta _c (x) = \log \frac{{\Gamma (x + 1)}}{{\sqrt {2\pi } (x/e)^x }} - \frac{1}{2}\psi (x + c) (x > 0; c \geqq 0).$$ \end{document} (i) −Δc is completely monotonic on (0, ∞) if and only if c ≧ 2/3. (ii) Δc is completely monotonic on (0, ∞) if and only if c = 0. (B) The inequalities \documentclass{aastex} \usepackage{amsbsy} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{bm} \usepackage{mathrsfs} \usepackage{pifont} \usepackage{stmaryrd} \usepackage{textcomp} \usepackage{upgreek} \usepackage{portland,xspace} \usepackage{amsmath,amsxtra} \usepackage{bbm} \pagestyle{empty} \DeclareMathSizes{10}{9}{7}{6} \begin{document} $$\frac{1}{2}\psi (x + a_0 ) < \log \frac{{\Gamma (x + 1)}}{{\sqrt {2\pi } (x/e)^x }} < \frac{1}{2}\psi (x + b_0 )$$ \end{document} hold for all x > 0 with the best possible constants a0 = 0.52660… and b0 = 2/3.
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Gallagher, Robert E., Esther L. Schachter Tokarz, Lawrence E. Morris, Tianna Dauses, Ivana Gojo, Marcel P. Devetten, Katarzyna Jamieson, et al. "Effectiveness of Peripheral Blood (PB) Molecular Monitoring by Quantitative RT-PCR (Q-PCR) in Phase II Acute Promyelocytic Leukemia (APL) Trial J0422." Blood 112, no. 11 (November 16, 2008): 1502. http://dx.doi.org/10.1182/blood.v112.11.1502.1502.
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Abstract Bone marrow (BM) is the accepted source for monitoring post-therapy minimal residual disease (MRD) in APL. PB is easier and less painful to obtain but variable, sometimes contradictory evidence has been presented for its efficacy in MRD monitoring. In this study, PB vs BM monitoring, as well as conventional, qualitative RT-PCR (C-PCR) vs Q-PCR were directly and prospectively compared for their effectiveness as part of an intensive MRD monitoring schedule applied as a safety measure to an investigative Phase II trial (J0422) designed to test the efficacy of minimizing chemotherapy exposure and treatment duration. This trial consisted of one cycle of induction with all-trans retinoic acid (ATRA) and daunorubicin, followed by consolidation with single-agent arsenic trioxide (ATO), followed by a maintenance phase of intermittent ATRA alone or with 6-mercaptopurine and methotrexate for patients (pts) with a presenting white blood cell count (WBC) of >10,000 WBC/uL. The MRD monitoring schedule was as follows: BM and PB after the induction and consolidation treatment modules (modules 1 & 2), then, PB every month and BM every 3 months during 2 years of maintenance therapy. C-PCR and Q-PCR were performed according to published procedures for monitoring the APL-specific fusion gene PML-RARα by the BIOMED-1 Concerted Action and the North American Cooperative Oncology Groups, respectively. Criteria for positive assays were: C-PCR, confirmed visualization of an appropriate-sized gel band after conventional, double-nested PCR amplification; Q-PCR, demonstration of a CT value <40 cycles by real-time PCR amplification in ≥2 of triplicate assays. Positive dilution controls to document detection with approximately 1 in 104 sensitivity were included in all experiments. Test samples were available from 26 patients with 3 to 38 months (mo) post-module-2 follow-up (median, 16 mo). After module-1 induction, 4 pts were positive by C-PCR (3 BM-only; 1 PB-only) and 9 pts were positive by Q-PCR (7 BM & PB, 2 PB-only). All 4 C-PCR and 4 Q-PCR positives occurred in pts with WBC <1,000 (6 pts), while 0 C-PCR and 2 Q-PCR positives occurred in pts with WBC >10,000 (7 pts), suggesting an association of pretreatment WBC with a difference in the initial dynamics of treatment response. After module-2 consolidation, 0 pts were positive by C-PCR and 3 by Q-PCR (1 BM & PB, 1 BM-only, 1 PB-only). During maintenance at the 3 mo shared BM/PB checkpoints, 0 C-PCR and 5/114 Q-PCR assays were positive (2 BM & PB, 1 BM-only, 2 PB-only), distributed among 3 pts. At monthly PB-only checkpoints, an additional 12/252 assays were positive by Q-PCR, none in a progressive pattern suggestive of impending molecular relapse. Overall, 1 – 3 Q-PCR assays were positive in 9 patients during the maintenance and follow-up periods. Among 8 pts who completed 24 mo maintenance, only 1/6 positive Q-PCR assays occurred at >12 mo, suggesting continued reduction of MRD during first 12 mo of maintenance therapy. No C-PCR assays were positive beyond module-1. In 1 exceptional pt, excluded from the above maintenance analysis, the Q-PCR assays became recurrently positive in BM and/or PB after 6 mo maintenance at a level below the criterion for molecular relapse (normalized quotient relative to the housekeeping gene GAPDH, NQGAPDH, ≥10−5). After 18 mo, the C-PCR became repeatedly positive in PB but not BM with Q-PCRs positive (2 BM & PB, 1 PB-only at shared checkpoints) in the NQGAPDH 4×10−7 to 4×10−6 range, which was associated with relapse in the central nervous system but not the BM. These results indicate that molecular monitoring of PB or BM was equally effective in detecting MRD and that Q-PCR was a more critical measure of MRD than C-PCR on protocol J0422 after single-cycle ATO-based consolidation therapy. The results further suggest that PB monitoring may be more effective in detecting extramedullary relapse, a relatively increasing cause of disease relapse with improved overall therapy for APL.
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Prebet, Thomas, Kaddour Chabane, Isabelle Tigaud, Eric Wattel, Mauricette Michallet, and Franck E. Nicolini. "Hematopoietic Progenitor Cell Response to SDF-1 alpha and SDF-1 alpha Production Are Impaired in Chronic Phase Chronic Myeloid Leukemia at Diagnosis." Blood 106, no. 11 (November 16, 2005): 1384. http://dx.doi.org/10.1182/blood.v106.11.1384.1384.
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Abstract SDF-1 alpha and its cognate receptor CXCR-4 are involved in normal Hematopoietic Progenitor Cells (HPC) regulation of adhesion, migration and survival. In Chronic Phase (CP) Chronic Myeloid leukaemia (CML), HPC exhibit a deregulation of all of those phenomena. Here, we investigated by different ways, the involvement of SDF-1 alpha in the pathogenesis of CP CML. Samples of bone marrow (BM) and peripheral blood (PB) from normal donors (ND) (n=10), CP CML (100% Ph1+ metaphases, all selected for Ph1+ LTC-IC) patients at diagnosis (n=35) and CP CML patients in Complete Cytogenetic Response (CCR) (0% Ph1+) (n=10) were explored. First, SDF-1 alpha concentrations were determined by ELISA assays in PB and BM samples, and showed higher yields for CP CML PB (2060±700 pg/ml) compared to CCR PB [1570±300 pg/ml (p=0.002)] and lower concentrations for CP CML BM (3080±1015 pg/ml) compared to CML in CCR BM [3990±680 pg/ml (p=0.01)] and ND BM [4060±1020 pg/ml (p=0.03)]. CCR BM and PB, and ND BM and PB SDF-1 alpha concentrations were not different. Further, we analyzed CD34+Lin− HPC migration in a 4h-Transwell™ assay, in SFM conditions ± SDF-1 alpha or ± one of its specific inhibitors SDF-1(G2) vs control. After migration, median percentages of migrating cells were consistently higher for CML vs ND BM (32±9 vs 20±1, p=0.002) in control arm, but equivalent for CML samples with SDF-1 alpha (39±10) vs control (32±9) indicating a relative insensitivity of CML HPC to this chemokine. In addition, SDF-1(G2) significantly inhibited the migration of CML HPCs (28±7) vs SDF-1 alpha (p=0.01). The proportion of CFC and LTC-IC in the migrating fraction was equivalent in the 3 experimental arms (SDF-1 alpha vs SDF-1(G2) vs control). As assessed by FACS, CD34+Lin− cells CXCR-4 surface expression was equivalent for CP CML (31±2.3%) and ND BM (43±2%) before migration, and there was no modification of the CXCR-4 expression after migration for CP CML. As SDF-1 alpha is involved in the regulation of the proliferation of normal HPC, we assessed CP CML CD34+Lin− cells in 3H-Thymidine cycling assays after 14 days culture on M210B4 murine feeder cell line (producing residual concentrations of SDF-1 alpha). CP CML HPC (CFC and LTC-IC) cycling status was not modified either after SDF-1 alpha or SDF-1(G2) exposure whereas ND BM cycling was paradoxically up-regulated by SDF-1(G2) vs control, suggesting a specific functional defect of CP CML HPCs in response to SDF-1 alpha. Taken together, all these results suggest that SDF-1 alpha production by stromal cells is impaired in CP CML, and that migratory and proliferative responses of CP CML HPCs to SDF-1 alpha are likely to be perturbed. This results might illustrate some pathologic interactions between BCR-ABL and signal transduction pathways activated through CXCR-4 ligation to its sole ligand SDF-1 alpha.
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Ashkar, Ryan, Sandra K. Althouse, Clint Cary, Timothy A. Masterson, Richard Foster, Nasser H. Hanna, Lawrence H. Einhorn, and Nabil Adra. "Model to predict brain metastasis (BM) in patients with metastatic germ-cell tumors (mGCT)." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): 5057. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.5057.
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5057 Background: BM is an independent adverse prognostic factor that can lead to treatment complications and failure in pts with mGCT. We aimed to establish an effective and practical model for prediction of BM in mGCT. Methods: 2,256 consecutive pts with mGCT treated at Indiana University between January 1990 and September 2017 were identified. Pts were divided into 2 categories: BM present (N = 144) and BM absent (N = 2112). Kaplan-Meier methods were used to analyze progression free survival (PFS) and overall survival (OS). Logistic regression was used to determine a predictive model for whether BM was present. The data was separated 50/50 into training and validation datasets with equal numbers of events in each. Results: Baseline characteristics for 2 groups are listed in Table. 2-yr PFS and OS for pts with vs without BM: 17% vs 66% (p < 0.001) and 62% vs 91% (p < 0.001) respectively. Among the 144 pts with BM, 64 (44%) had radiation only (whole-brain radiotherapy or gamma knife), 21 (15%) had BM-surgery only, 14 (10%) had both radiation and BM-surgery. 45 pts (31%) did not receive local therapy for BM. A stepwise selection was used to determine the best model with p < 0.15 as the entry and staying criteria. The model with the largest ROC AUC was used moving forward. The model was tested in the validation dataset. A model was generated including age at diagnosis≥40 (1 point), presence of pulmonary metastases (3 points), bone metastasis (1 point), pre-chemotherapy hCG≥5000 (1 point), and choriocarcinoma predominant histology (1 point). Patients with 0 points had a 0.4% probability of BM, 1 point: 1%, 2 points: 2.6%, 3 points: 7%, 4 points: 16%, 5 points: 32%, 6 points: 56%, and 7 points: 77%. Details regarding analysis in training and validation datasets will be presented. Conclusions: The prediction model developed in this study demonstrated discrimination capability of predicting BM occurrence and can be used by clinicians to identify high-risk pts. [Table: see text]
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Greco, N. J., V. J. Pompili, H. M. Lazarus, D. Adler, T. Lasser, R. Fox, L. Solchaga, et al. "Correlative Cellular Analyses in a Phase I Trial (Safety and Efficacy of Autologous Intracoronary Stem Cell Injections in Total Coronary Artery Occlusions (SEACOAST)) of Autologous Bone Marrow-Derived CD133 Cells." Blood 108, no. 11 (November 16, 2006): 1689. http://dx.doi.org/10.1182/blood.v108.11.1689.1689.
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Abstract Correlative laboratory studies were developed in a phase I trial to evaluate the safety of intracoronary injection of escalating doses of bone marrow (BM) CD133+ cells in patients with chronic coronary ischemia. Concurrent with patient cellular therapy, CD133+ cells were phenotyped and tested functionally with endothelial cell colony formation and in vitro and in vivo transmigration. BM (194 ± 11 ml) was isolated from patients meeting study inclusion criteria. CD133+ cells (20 ± 13 x 106, 84 ± 7% purity and 76 ± 7% viability (7AAD)) were isolated using the CliniMACS device (Miltenyi). Contaminating cells following the CliniMACS selection were: < 5% of CD3, CD3neg/CD56, CD19 (immature/mature), CD14, and CD71 cells with 5% CD61, 8% CD13+ SSChigh. BM, PB (peripheral blood), cord blood (CB)-derived endothelial progenitor cells (EPC) were assessed by a culture assay (StemCell Technologies) scoring early outgrowth CFU-EC. SEACOAST patients yielded significantly less colonies compared to controls of matched PB and BM (donors 28–48 yrs) and CB: normal donor (ND) PB, 65; ND BM, 40; CB, 43; SEACOAST patient PB, 2, SEACOAST patient BM, 1. Transmigration assays were used to evaluate the functionality of selected CD133+ cells to chemotactic agents stromal derived factor-1 (SDF-1) and vascular endothelial growth factor (VEGF). Selected CD133+ cells were recovered, resuspended in DMEM/1% HSA media and after a 37°C incubation for 16–20 hrs, 5 x 104 CD133+ cells were added to transwells (5 mm) for 3 hours. Transmigrated cells were quantitated by flow cytometry using anti-CD45, anti-CD133 antibodies, and Fluorosphere beads. Surface expression on ND BM CD133+ cells of CXCR4 and VEGF-R2 was 0–16.4% and 1.2–4.3%, respectively. Transmigration was effected by 200 ng/ml (range of 16–62%) but not to 10 ng/ml VEGF. For CD133+ cells devoid of the expression of CXCR4, SDF-1-induced transmigration was absent. Expression of CXCR4 and VEGF-R2 on clinical trial patient-selected CD133+ cells was 0–5% and 0–2%, respectively, and transmigration was 5–19% to 200 ng/ml SDF-1 but not to 10 ng/ml VEGF. Patient selected CD133+ cells or PB mononuclear cells (PBMC), ND CD133+ cells, or a vehicle control were injected via a left intraventricular route into NOD/SCID mice with a femoral artery ligation immediately after injury. Doppler flow measurements were obtained weekly for 6 weeks comparing the perfusion ratio of ischemic/healthy limbs. At 28 days, perfusion ratios were statistically higher in study groups receiving ND CD133+ cells (0.51 ± 0.06) compared to controls (0.37 ± 0.03, p=0.025). Mice receiving patient CD133+ cells (0.46 ± 0.04) or PBMC (0.37 ± 0.08) did not show statistically significant improvement over control animals (p= 0.07, p= 0.94, respectively). BM was harvested to assess human engraftment by cytometric analysis. Mice injected with 0.5 x 106 patient BM CD133+ cells showed <0.2% huCD45+ cells compared to 1.6 ± 0.4% ND BM huCD45+. Beyond the demonstrated safety of the delivery of CD133+ cells (>70% purity and >70% viability) to chronic ischemic patients via an intracoronary route, important correlative in vitro and in vivo assays has demonstrated the diminished potency of BM-derived CD133+ cells as compared to CB and ND PB and BM-derived cells.
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Sousa, J. P. L., K. F. Rodrigues, L. F. T. Albino, R. G. M. V. Vaz, G. F. da Silva, J. C. Siqueira, E. R. Santos Neta, I. P. Parente, A. F. Amorim, and M. C. da Silva. "Bagaço de mandioca com ou sem complexo enzimático em dietas de frangos de corte." Archivos de Zootecnia 63, no. 244 (September 29, 2014): 657–64. http://dx.doi.org/10.21071/az.v63i244.514.
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Objetivou-se avaliar a utilização de bagaço de mandioca (BM) em rações suplementadas com complexo enzimático (CE) para frangos de corte em duas fases. Foram avaliados o ganho de peso (GP), consumo de ração (CR) e conversão alimentar (CA) de frangos de corte nas fases de 1 a 21 e 22 a 40 dias, alimentados com rações contendo 0 e 20 % de inclusão de BM com e sem adição de CE. Os experimentos foram realizados num delineamento experimental em blocos casualizados com 4 tratamentos utilizando um arranjo fatorial 2x2 (0 e 20 % de BM, com e sem CE) com 8 repetições e 20 aves por unidade experimental. Não foi observada interação entre os tratamentos, inclusão de BM e CE. A inclusão do BM diminuiu o CR e o GP em ambas as fases de criação. Enquanto que a inclusão do CE melhorou o GP e a CA das aves na fase inicial, não afetando o desempenho na fase de 22 a 40 dias de idade, já menor custo de ração por quilograma de ganho de peso e os melhores índices de eficiência econômica e de custo para ambas as fases foi encontrado para os animais que foram submetidos a rações com 0 % de inclusão de bagaço de mandioca com adição de complexo enzimático.
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Cermak, Jaroslav, Dana Mikulenková, Jana Brezinova, and Kyra Michalova. "A reclassification of Myelodysplastic Syndrome (MDS) patients of RAEB-1 subgroup according to IPSS-R improves discrimination of high risk patients and better predicts overall Survival. A retrospective analysis of 49 Patients." Blood 120, no. 21 (November 16, 2012): 4957. http://dx.doi.org/10.1182/blood.v120.21.4957.4957.
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Abstract Abstract 4957 Refractory anemia with excess of bone marrow (BM) blasts up to 10% (RAEB-1) has been generally considered a MDS subgroup with moderate prognosis and most of the patients are not indicated for immediate intensive treatment. In our retrospective study, 27 out of 49 patients with RAEB-1 had intermediate-1 (IM-1) risk and 22 patients were classified as intermediate-2 (IM-2) risk group according to the IPSS. Nevertheless, median survival of untreated patients with RAEB-1. was only 5. 0 months compared to 36. 3 months in untreated patients with ≤ 5% BM blasts at the time of diagnosis (P<0. 0001). After reclassification of patients according to revised IPSS (IPSS-R) only 14 patients remained in the intermediate (IM) risk group and 3 patients were even shifted to the low (L) risk group. On the other hand, 14 patients have fulfilled criteria for high (H) risk group and 18 out of 49 patients (37%) had very high (VH) risk score. Median survival of patients treated with low dose chemotherapy (9. 0 months) or hydroxyurea (8. 8 months) was not significantly different from that in patients who received supportive care only. A significant benefit in median survival was observed after combination chemotherapy (14. 0 months) or after stem cell transplantation (SCT) (17. 0 months). SCT was the only treatment connected with prolonged survival, nevertheless, estimated 5 years overall survival of 31. 2 months was significantly inferior (P=0. 02) to that of transplanted patients not only with ≤ 5% BM blasts (62. 2 months) but also with > 10% BM blasts (55. 6 months). Univariate analysis using Kaplan-Meier curves and log-rank2 test revealed as significant variables affecting overall survival: poor cytogenetics IPSS subgroup (P=0. 001), ECOG > 2 (P=0. 001), IM-2 IPSS risk group (P=0. 001), treatment with SCT (P=0. 003), platelet (PLT) count < 20×109/l (P=0. 004), high or very high IPSS-R risk group (P=0. 01) and age > 60 years (P=0. 03). The most important independent variable for determining overall survival (studied by Cox regression multivariate analysis) was poor cytogenetics according IPSS (P=0. 0001, χ2=52. 623), followed by PLT count < 20×109/l (P=0. 001, χ2= 10. 382), and ECOG > 2 (P=0. 002, χ2= 9. 794). Our data suggest that RAEB-1 represent a poor prognostic MDS subgroup with similar outcome as advanced MDS with > 10% BM blasts. The analysis confirms the usefulness of IPSS-R for prediction of survival and for better discrimination of high risk patients in subgroups of patients with less advanced disease. Moreover, the results of regression analysis justify the high scoring value of cytogenetic abnormalities used in IPSS-R. SCT represents the only treatment enabling a long-term survival of RAEB-1 patients, nevertheless, our results of SCT were inferior to that achieved in patients with advanced MDS. Thus, more extensive clinical trials validating efficiency of hypomethylating agents and other new drugs in the treatment of RAEB-1 patients are needed. Disclosures: No relevant conflicts of interest to declare.
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Hamid, Anis, Kathryn P. Gray, Grace Shaw, Laura E. MacConaill, Carolyn Evan, Brandon David Bernard, Atish Dipankar Choudhury, and Christopher Sweeney. "Tumor suppressor aberrations and outcomes in localized and metastatic hormone sensitive prostate cancer (PrCa)." Journal of Clinical Oncology 36, no. 6_suppl (February 20, 2018): 184. http://dx.doi.org/10.1200/jco.2018.36.6_suppl.184.
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184 Background: Aberrations of tumor suppressors (TS) TP53, PTEN and RB1 are recurrent genomic events in PrCa and associated with adverse clinical outcomes. Preclinical data suggest that cooperative functional loss of these genes drives development of even more aggressive disease phenotypes. Methods: We identified a retrospective cohort of men with PrCa who underwent DFCI Oncopanel targeted sequencing (NGS) on prostate gland (n = 230) or metastatic tissue (n = 7) for TP53, PTEN and RB1. Biomarker(BM)-positive was defined as copy number loss or likely deleterious mutation of ≥1 TS. For pts presenting with localized disease, Kaplan-Meier method estimated time from biopsy preceding local therapy to PSA relapse/metastasis/death (EFS), castration resistance (CRPC) and death (OS). Cox model assessed association of BM status and outcomes, adjusted for age, clinical stage and Gleason score in multivariate analyses (MVA). For M1 disease, time from ADT start to CRPC and death was estimated. We explored the association of cumulative BM-positive gene hits (0 vs 1 vs 2/3) with EFS (local disease) and OS (M1 disease). Results: Of pts presenting with localized disease (n = 205), 39% were BM-positive and 73 (36%) relapsed after median follow-up of 3.1 years. BM positivity was associated with significantly shorter EFS (driven by PSA relapse) (median 2.6 years, HR 1.95, 95% CI 1.22-3.13) and time to CRPC (HR 3.36, 95% CI 1.01-11.16). MVA confirmed the association with EFS (HR 1.84, p = 0.029). More gene hits lead to incremental risk of relapse (1 gene: HR 1.8, 95% CI 1.09-2.99; 2/3 genes: HR 2.68, 95% CI 1.27-5.63; both vs 0 hits) and this remained significant in MVA (1 gene: HR 1.75, p = 0.05; 2/3 genes: HR 2.74, p = 0.04). 43 patients had relapsed or de novo M1 disease. BM positivity (enriched at 63% of M1) was associated with poorer OS (10 deaths [of 27 BM-pos] vs 0 deaths [of 16 BM-neg] at median follow-up 3.3 years, HR not eval). A trend to incremental worse survival with cumulative gene hits was again observed. Conclusions: Deleterious TP53, PTEN and RB1 variants are associated with a short time to PSA relapse in localized disease, occur at a higher frequency in M1 disease and confer poorer OS. Worse outcomes are seen with cumulative gene hits.
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Rizqan, Bakr Hussein, H. E. Darwish, and A. Y. Lashin. "On certain subclass of p-valent meromorphically starlike functions with alternating coefficients." Tamkang Journal of Mathematics 45, no. 2 (June 30, 2014): 149–63. http://dx.doi.org/10.5556/j.tkjm.45.2014.1406.
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A certain subclass Bm(p,α,λ,ℓ,A,B) consisting of meromorphic p-valent functions with alternating coefficient in U∗={z:z∈C:0<|z|<1} is introduced. In this paper we obtain coefficient inequalities, distortion theorem, closure theorems and class preserving integral operators for functions in the class Bm(p,α,λ,ℓ,A,B) are obtained .
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Masarova, Lucia, C. Cameron Yin, Jorge E. Cortes, Marina Konopleva, Gautam Borthakur, Kate J. Newberry, Hagop M. Kantarjian, Carlos E. Bueso-Ramos, and Srdan Verstovsek. "Histomorphological Responses after Therapy with Pegylated Interferon Alpha-2a in Patients with Essential Thrombocythemia (ET) and Polycythemia Vera (PV)." Blood 128, no. 22 (December 2, 2016): 4266. http://dx.doi.org/10.1182/blood.v128.22.4266.4266.
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Abstract Introduction: We previously reported the long-term efficacy and safety of pegylated interferon alpha-2a (PEG-IFN-a-2a) in 83 patients with ET and PV after a median follow-up of 83 months. Here, we present the bone marrow (BM) response assessment according to modified International Working Group for-Myeloproliferative Neoplasms Research and Treatment (IWG-MPN). Objective: To identify histomorphological BM responses in patients with ET and PV treated with PEG-IFN-a-2a as part of a prospective phase II study. Methods: All patients had BM assessment done prior to their enrollment, and then every 6-12 months while on study if possible, and in some patients after treatment discontinuation. Complete BM remission (BM-CR) required absence of > grade 1 reticulin fibrosis and disappearance of megakaryocyte hyperplasia in ET or trilinear hyperplasia with age-adjusted normocellularity in PV. An incomplete, partial response (BM-PR), was defined when fibrosis grading had consistently improved by at least one grade level on at least 2 consecutive samples > 12 months apart, yet with persistent MPN morphological features. Hematologic (HR) and molecular response (MR) assessments were previously reported (ASH 2015, abstract #60). Results: Among 83 enrolled patients (43 PV, 40 ET), 58 patients (70%) had evaluable BM samples for histomorphological response assessment, with median number of 8 samples per patient (range, 3-12). Among the remaining 25 patients, 18 were treated ≤12 months, and 7 did not have representative samples. Median age was 52 years (range, 19-75), and 29% (n=17) were males. Median disease duration prior to enrollment was 31 months (range, 1-350), and the median exposure to PEG-IFN-a-2a was 80 months (range, 15-107). After a median follow-up of 84 months (range, 36-107), 32 patients are on study. Forty-two patients were JAK2 positive, 6 CALR positive, 2 MPL positive and 8 triple negative (TN). Hematologic and molecular (JAK2V617F mutation only) responses were seen in 54 (93%) and 29 (69% of JAK2V617F positive) patients, including complete HR and complete MR in 52 (90%) and 9 (31%) patients, respectively. In total, 29 evaluable patients (50%) had BM response, including 13 patients (22%) with BM-CR (MF-0 in 11, example in Figure 1). Among 16 patients with BM-PR, 3 had resolution of dense collagen bundles as well as decreased reticulin fibrosis. Except for increased platelets in those with BM-PR (p<0.001), likely due to the higher proportion of ET patients in that group, no other differences in basic demographic or clinical parameters were present among different response groups (Table 1). Patients with BM response (PR & CR) had lower discontinuation rate, higher duration of response (HR & MR) with longer time on therapy; 13 patients with BM-CR had higher probability of complete MR (Table 1). Median time to BM-CR was 48 months (range, 30-72), median duration was 30 months (24-52), and has been maintained in 9 patients (69%). Two patients who lost their BM-CR are still on active therapy with persistent complete MR. Interestingly, 4 patients achieved BM-CR after being off therapy for a median of 18 months (range, 2-30), and 3 of them have sustained the BM-CR for 24, 50 and 52 months. Conclusions: Histomorphological BM responses (including complete response) can occur in ET/PV patients treated with PEG-IFN-a-2a, and generally correlate with more durable treatment benefit. Complete BM responses may be sustained even after treatment discontinuation, or be seen after therapy discontinuation. Despite this, we could not identify a uniform correlation between hematologic, histomorphological and molecular response. Table Patients with BM assessment stratified by response, N=58 Table. Patients with BM assessment stratified by response, N=58 Figure BM assessment of a PV patient with BM-CR. A & C: Before treatment: increased cellularity and abnormal megakaryocytes number/morphology; MF-2. B & D: After treatment: normocellular BM, normal morphology, MF-0. Figure. BM assessment of a PV patient with BM-CR. A & C: Before treatment: increased cellularity and abnormal megakaryocytes number/morphology; MF-2. B & D: After treatment: normocellular BM, normal morphology, MF-0. Disclosures Cortes: ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. Konopleva:Reata Pharmaceuticals: Equity Ownership; Abbvie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Stemline: Consultancy, Research Funding; Eli Lilly: Research Funding; Cellectis: Research Funding; Calithera: Research Funding.
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Bakanidze, G., M. Roinishvili, E. Chkonia, M. H. Herzog, A. Brand, and I. Puls. "FC19-06 - Visual backward masking - an excellent endophenotype for Schizophrenia ?" European Psychiatry 26, S2 (March 2011): 1920. http://dx.doi.org/10.1016/s0924-9338(11)73624-0.
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Due to the complexity of psychiatric diseases, endophenotypes are of primary interest in psychiatric research. They are stable markers which are assumed to be related to a small number of genes involved in the pathophysiology of the disease. Visual backward masking (BM), like other parameters measuring early information processing, was proposed to be a reliable marker for schizophrenia. Performance deficits in BM are considerably more pronounced in schizophrenic patients and their unaffected relatives compared to controls. As shown before, in the present study BM performance was significantly worse in schizophrenic patients compared to controls; healthy relatives of schizophrenic patients performed intermediately.Several candidate genes for schizophrenia including nicotinic receptor α7 subunit (CHRNA7), catechol-O-methyltransferase (COMT), dystrobrevin-binding protein 1 (dysbindin, DTNBP1) and metabotropic glutamate receptor 3 gene (GRM3) were investigated for their association with schizophrenia and BM in two independent samples. A strong and reproducible association was observed for CHRNA7 with both diagnosis of schizophrenia and BM performance. In conclusion, BM is an excellent endophenotype which will likely support the search for further candidate genes and related pathophysiological pathways in schizophrenia. Moreover, CHRNA7 has further supported its important role as one of the main candidate genes for schizophrenia.
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Biewen, Carter, Angela R. Smith, Jakub Tolar, and Weston P. Miller. "Outcomes after Donor Lymphocyte Infusion for Insufficient Donor Chimerism Following Hematopoietic Cell Transplantation for Non-Malignant Disorders." Blood 126, no. 23 (December 3, 2015): 1969. http://dx.doi.org/10.1182/blood.v126.23.1969.1969.
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Abstract Background: Little is reported of the utility of donor lymphocyte infusion (DLI) following HCT for non-malignant disorders (NMD). We describe outcomes after DLI for insufficient donor chimerism after HCT in a large NMD cohort. Patients/Methods: We queried the Institutional BMT Database for patients with NMD receiving DLI for insufficient post-HCT donor chimerism. HLA typing, graft selection and conditioning were per institutional guidelines. The use, timing and dosing of DLI was at the discretion of the treating physician. Donor chimerism values on the myeloid fraction of peripheral blood at pre-DLI and most-recent time-points were reviewed. Patients were considered best DLI responders if donor chimerism improved (pre-DLI to most-recent) and most recent chimerism was ³ 80%. Results: Twenty-three patients (43% female) were identified. Table 1 shows patient, disease, transplant and DLI characteristics. The median zenith chimerism post-HCT (but pre-DLI) was 84% (IQR, 39 - 99%), observed at a median 28 days post-HCT. The median chimerism just prior to first DLI was 40%. The median time to first DLI was 90 days. Patients underwent a median 2 cycles (IQR, 2 - 3; maximum, 5) of DLI; the median cumulative per-patient CD3+ dose was 11.5 x 106/kg. Post DLI, two patients developed aGvHD and 2 patients developed cGvHD. Five patients (22%) were best DLI responders. At a mean 3.6 years post-HCT, they retained mean chimerism of 94% (mean increase from pre-DLI of 37%). Of the 18 non-best responders (78%), median chimerism at last follow-up was 10% (IQR, 2 - 25%). Seven patients underwent repeat HCT. Best response to DLI did not depend on HCT total nucleated cell dose, donor relatedness, serotherapy agent of HCT regimen, chimerism prior to DLI, or total DLI CD3+ dose. Best responders tended to have undergone myeloablative conditioning, be HLA-matched to the donor and receive first DLI later post-HCT (median 102 days, versus 83 days). Conclusions: In a large NMD cohort undergoing DLI after HCT, sustained high donor chimerism response was observed in 22%. Ongoing analyses aim to assess those with intermediate response (many of whom also enjoy improved or stable NMD), as well as the impact of peri-DLI immune suppression on outcomes. Table 1. Patient, Disease and Transplant Characteristics. ID Dx Age (y) at HCT Conditioning/ Serotherapy Donor / Graft HCT TNC(x 108 /kg) Days# to DLI DLI@ CD3+ (x106 /kg) % Chimerism Pre/MRFU aGvHD (grade) / cGvHD Re-HCT? Survival (y#) Notes / Cause of Death 1 ALD 8.1 MA / ATG R / BM 2.16 508 6 92 / 100 n/n n A (10) SD 2 ALD 8.3 NMA / C R / BM 3.17 73 9 59 / 27 n/n n A (6) SD 3 ALD 8.4 NMA / C R / BM 3.97 51 45 44 / 23 n/n n A (4.6) SD 4 ALD 9.9 NMA / C R / BM 2.13 44 17 43 / 17 n/n n A (7.2) SD 5 HLH 18 NMA/ Unk U / BM 1.94 102 1 75 / 100 Y(4)/n n D (0.6) Viral; Resp Failure 6 HLH 1 NMA / C U / BM 9.39 181 3 3 / 4 n/n Y D (1.9) Sepsis 7 Hurler 2.5 MA / ATG R / BM 5.05 193 16 67 / 58 n/n n A (8.3) SD 8 Hurler 1 MA / C R / BM 4.25 305 1 64 / 80 n/n n A (6.7) SD 9 IPEX 1.3 NMA / Unk U / BM 4.99 160 13 44 / 56 n/n n A( 6.4) SD 10 JEB 0.5 NMA / ATG U / BM 5.22 81 6 25 / 13 n/n n D (0.4) Sepsis 11 RDEB 2.8 NMA / ATG R / BM 6.21 274 11 17 / 25 n/n n A (2.1) SD 12 RDEB 6.3 NMA / ATG R / BM 7.28 167 Unk 17 / 6 n/n n A (3.1) SD 13 RDEB 0.9 NMA / ATG U / BM 9.91 98 16 12 / 87 n/n n A (2.7) SD 14 RDEB 3.3 NMA / ATG R / BM 3.53 48 16 10 / 0 n/n Y A (1.6) SD 15 RDEB 0.9 NMA / ATG R / BM 3.35 90 65 40 / 100 n/Y n A (1) SD 16 RDEB 4.9 NMA / ATG R / BM 4.27 133 65 41 / 25 n/n n A (0.8) SD 17 RDEB 0.5 NMA / ATG R / BM 5.5 85 30 71 / 45 n/n n A (0.7) SD 18 SCD 9.1 NMA / ATG U / BM 3.19 34 0.5 0 / 0 n/n n D (13.7) Progressive SCD 19 SCD 10.2 NMA / ATG U / PBSC 0.13 57 12 69 / 4 n/n Y A (10) Rejected re-HCT 20 Thal 2.3 NMA / ATG R / BM 3 84 Unk 15 / 0 n/n Y A (7.3) E, SD 21 Thal 2.8 NMA / ATG U / PBSC 0.22 48 1 40 / 0 Y(2)/Y Y D (2.2) cGvHD 22 Thal 1.7 NMA / C U / PBSC 0.17 69 5 11 / 2 n/n Y A (7.6) E, SD 23 Thal 2.6 MA / ATG R / BM 6.23 159 Unk 17 / 4 n/n Y A (5.3) E, SD # = time referenced to HCT; @ = cumulative CD3+ cell dose; ALD = adrenoleukodystrophy; HLH = hemophagocytic lymphohistiocytosis; IPEX = immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome; JEB = junctional epidermolysis bullosa; RDEB = recessive dystrophic epidermolysis bullosa; SCD = sickle cell disease; Thal = thalassemia; y = years; MA = myeloablative; NMA - non-myeloablative; ATG = anti-thymocyte globulin; C = alemtuzumab; Unk = unknown; R = related; U = unrelated; BM = marrow; PBSC = peripheral blood stem cell; TNC = total nucleated cell dose; Pre = just prior to DLI; MRFU = most recent follow-up; n = no; Y = yes; A = alive; D = dead; SD = stable disease; E = engrafted. Disclosures No relevant conflicts of interest to declare.
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Joensuu, Heikki, and Mahmoud Ould Kaci. "LUX-breast 3: Randomized phase II study of afatinib alone or with vinorelbine versus investigator’s choice of treatment in patients (pts) with HER2-positive breast cancer (BC) with progressive brain metastases (BM) after trastuzumab or lapatinib-based therapy." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): TPS647. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.tps647.
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TPS647 Background: Approximately 1/3 of pts with HER2-positive, advanced BC will develop BM with a poor prognosis. Efficacy of systemic therapies is limited since few drugs can readily cross the blood-brain barrier. BC BM represents a high unmet medical need for which novel targeted therapies are needed. Afatinib is a small molecule, irreversible ErbB Family Blocker that has shown preclinical activity in trastuzumab-resistant cell lines and HER2-positive tumor xenografts. Its clinical efficacy has been demonstrated in pts with heavily pre-treated, HER2-positive metastatic BC, who progressed after trastuzumab therapy, with partial responses in 10% and clinical benefit in 46% of pts. In a Phase I afatinib trial a sustained PR was observed in a NSCLC pt with BM, and in a phase II trial in NSCLC, pts with or without BM achieved comparable outcome on afatinib. The purpose of this study (NCT01441596) is to investigate whether afatinib alone or in combination with vinorelbine has any effect on HER2-positive BC with BM after failure of prior trastuzumab or lapatinib. Methods: Key eligibility criteria: histologically confirmed HER2-positive BC; recurrent/progressive BM during/after prior trastuzumab or lapatinib therapy; ≥1 measurable BM (≥10 mm on T1-weighted, gadolinium-enhanced MRI); extra-CNS lesions allowed; prior surgery, whole brain radiotherapy or stereotactic radiosurgery allowed; ECOG 0–2. Eligible pts are stratified by: ECOG score 0–1 vs 2; No of BM ≤ 3 vs >3; prior lapatinib therapy. Pts are randomized to (n = 40/arm): Arm A: afatinib (40 mg/d oral); Arm B: afatinib (40 mg/d oral) + vinorelbine (25 mg/m2/ week); Arm C: investigator’s choice of medical treatment approved for metastatic BC. Primary endpoint: pt benefit at 12 weeks (i.e. absence of CNS/extra CNS disease progression as per RECIST 1.1) and no tumour-related worsening of neurological signs/symptoms or increase in steroid dosage. Secondary endpoints: PFS, OS, safety and afatinib concentration in plasma/cerebrospinal fluid in ≥12 pts. The study began in October 2011 and enrollment is ongoing.
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Kvasnicka, Hans Michael, Juergen Thiele, Carlos E. Bueso-Ramos, William Sun, Ahmad Naim, Smitha Svaraman, Jessy Gao, et al. "Effects of Long-Term Ruxolitinib (RUX) on Bone Marrow (BM) Morphology in Patients with Myelofibrosis (MF) Enrolled in the COMFORT-I Study." Blood 128, no. 22 (December 2, 2016): 1949. http://dx.doi.org/10.1182/blood.v128.22.1949.1949.
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Abstract Background: MF is a life-shortening complication of myeloproliferative neoplasms associated with ineffective hematopoiesis, splenomegaly, cytopenias, debilitating symptoms, and progressive BM fibrosis The 2 phase 3 COMFORT studies have shown that RUX, an oral Janus kinase (JAK) 1/JAK2 inhibitor, improves splenomegaly, constitutional symptoms, and overall survival in patients with MF. Accumulating evidence suggests that RUX may also modulate the BM microenvironment. Aims: We evaluated the effects of long-term RUX treatment on changes in BM fibrosis in patients with intermediate-2 or high-risk primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF who were enrolled in the phase 3 COMFORT-I study. Methods: BM biopsies were obtained at baseline (BL), Weeks 48 and 72, and approximately every 48 weeks thereafter for up to 5 years of RUX treatment. Biopsies were reviewed independently in a blinded fashion (blinded for patient and treatment) by 3 hematopathologists (HMK, JT, and CEB-R). The final grading was based on consensus; no disagreements were recorded. The WHO grading system was used to grade BM fibrosis density based on a scale of 0-3 (Thiele et al, Haematologica 2005;90). Other details on the patient population and study design for the COMFORT-I study have been published previously (Verstovsek et al, N Engl J Med 2012;366). Biopsies from 59 patients were included in this exploratory analysis; patients who failed screening or received only 1 BM measurement were excluded. Three subgroups were defined for the analysis: 1) originally randomized to RUX (n=36); 2) randomized to placebo with BM measurements at BL and Week 48 (n=15); and 3) crossover to RUX with BM measurements at BL and ≥1 post-BL measurement after crossover (n=21). Changes from BL in BM fibrosis grades at various time points were categorized for each patient as improvement (-1 to -3), stabilization (0), or worsening (1 to 3). Patients with a BL score of 0 for improvement and 3 for worsening were excluded from the analysis. Patients who received placebo for ≥36 weeks were included in the crossover group, with Week 48 used as the BL BM measurement. RUX and crossover groups were combined for evaluation of RUX effect. Placebo effect in the crossover group was assessed by analyzing change from BL to Week 48. Change from BL was evaluated using a signed rank test. Change from BL to last grade, and time to the first occurrence of a ≥1 grade improvement from BL was assessed for RUX and crossover groups. KM analysis was used to estimate time to improvement in BM fibrosis for a subgroup of patients who had a BM fibrosis grade of ≥1 at BL. Results: BL characteristics for age, gender, International Prognostic Scoring System risk, spleen volume, hemoglobin, and platelet counts were similar between the 3 groups. At BL, of 36 patients originally randomized to RUX, 17% (n=6) presented with WHO-defined fibrosis grade 1, 39% (n=14) with grade 2, and 36% (n=13) with grade 3 (3 patients were grade 0). Of the 15 patients randomized to placebo, 20% (n=3) presented with grade 1, 40% (n=6) with grade 2, and 27% (n=4) with grade 3 WHO-defined fibrosis at BL (2 patients were grade 0). Mean exposure to RUX in the RUX and crossover groups was 136.0 (SD, 67.4) weeks and 129.1 (SD, 67.7) weeks, respectively. The proportion of evaluable patients with an improvement in BM fibrosis from BL to Week 48 was 26% (n=27) in the RUX group and 15.4% (n=13) in the placebo group. When evaluating all patients who received RUX (including placebo crossover), a significant shift was observed from BL to the last change in BM fibrosis grade (P=0.0119; signed rank test). For all RUX-treated patients (n=57), 33% (grade -1, n=11; -2, n=7; -3, n=1) had an improvement, 49% had no change or stabilization, and 18% had a worsening in BM fibrosis from BL to the last grade (Figure). At the final grading, 82% (n=47) of patients had improvement or stabilization while on RUX. Median time to a ≥1 grade improvement in BM fibrosis grade was approximately 3.5 years (95% CI, 2.5 to 4.5; n=51). Conclusions: This analysis from the COMFORT-I study showed that treatment with RUX was associated with improvement and stabilization in WHO-defined BM fibrosis in the majority of patients with MF in this study cohort. These results support evidence from other studies, suggesting that RUX treatment may contribute to disease-modifying effects in MF. The clinical effect of improvement and stabilization in BM fibrosis requires further study. Disclosures Kvasnicka: Novartis: Consultancy, Honoraria; Incyte Corporation: Consultancy, Honoraria; AOP Pharma: Consultancy, Honoraria. Thiele:Novartis: Consultancy, Honoraria; Incyte Corporation: Consultancy, Honoraria. Sun:Incyte Corporation: Employment, Equity Ownership. Naim:Incyte Corporation: Employment, Equity Ownership. Svaraman:Incyte Corporation: Employment, Equity Ownership. Gao:Incyte Corporation: Employment, Equity Ownership. Gotlib:Incyte Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Gupta:Incyte Corporation: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Dao:Incyte Corporation: Research Funding. Talpaz:Incyte Corporation: Other: Travel expense reimbursement, Research Funding; Novartis: Research Funding; Ariad: Other: Expense reimbursement, travel accomodation expenses, Research Funding; Pfizer: Consultancy, Other: travel accomodation expenses, Research Funding. Winton:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding. Verstovsek:AstraZeneca: Research Funding; Roche: Research Funding; Celgene: Research Funding; Lilly Oncology: Research Funding; Galena BioPharma: Research Funding; NS Pharma: Research Funding; Promedior: Research Funding; CTI BioPharma Corp: Research Funding; Geron: Research Funding; Gilead: Research Funding; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Genentech: Research Funding.
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Sehn, Laurie H., Mukesh Chhanabhai, Suman Singh, Wayne Saville, Dan Matso, John J. Spinelli, Joseph M. Connors, and Randy D. Gascoyne. "Both Discordant and Concordant Bone Marrow (BM) Involvement Predict for a Poorer Outcome Independent of the IPI in Patients with Diffuse Large B-Cell Lymphoma (DLBCL) Treated with R-CHOP." Blood 110, no. 11 (November 16, 2007): 1559. http://dx.doi.org/10.1182/blood.v110.11.1559.1559.
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Abstract Recently, it has been suggested that concordant but not discordant BM involvement is a negative predictor of outcome in DLBCL patients treated with CHOP (Chung et al, Blood 2007). The significance of BM involvement in pts treated in the current era of therapy including rituximab has not been fully examined. We evaluated the prognostic impact of BM involvement in DLBCL patients treated with the current standard of care, R-CHOP. Patients: We identified 282 patients with biopsy proven de novo DLBCL treated in British Columbia (BC) with an R-CHOP regimen between 01/01/2001 and 01/01/2005 with complete clinical information and staging bone marrows available for review. Cases were identified using the Lymphoid Cancer Database of the BC Cancer Agency. Median follow-up is 44 mos (range 1–77). Results: 234/282 (83%) had a negative staging BM, 27 pts (10%) had a positive BM with concordant histology (Con-BM) and 21 (7%) had a positive BM with discordant histology (Dis-BM) with predominantly small B-cells present. Clinical characteristics for the entire cohort were as follows: median age 64 y (range 18–88); 66% male; 65% stage III/IV; 39% PS>1; 51% elevated LDH; 31% >1 extranodal site. IPI risk factors: 10% 0; 42% 1–2; 48% 3–5. In addition to higher stage and greater extranodal involvement, pts with a positive BM were more likely to have a higher LDH and a poorer PS than pts with a negative BM. Compared to pts with Con-BM, pts with Dis-BM were more likely to be elderly, but otherwise exhibited a similar distribution of clinical prognostic factors. The Kaplan-Meier 4-year PFS was significantly worse for pts with both Dis-BM (32%) and Con-BM (46%) involvement compared to pts with a negative BM (75%) (p<0.0001) (see Figure). Similarly, 4-year overall survival was significantly worse for pts with Dis-BM and Con-BM involvement (53% and 54%) compared to pts with a negative BM (74%) (p=0.005). All patients with Dis-BM involvement who developed progressive or relapsed disease were believed to have progression of their aggressive lymphoma based on clinical behavior or biopsy proof. In a multivariate analysis controlling for the IPI, BM involvement (Dis-BM and Con-BM) remained an independent predictor of PFS (p=0.03). Conclusions: In DLBCL pts treated with R-CHOP, both discordant and concordant BM involvement predict for a poorer outcome independent of the IPI. It is possible that pts with DLBCL and discordant BM involvement represent a subset of pts with transformed disease which is inherently less treatment-sensitive. Figure Figure
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Benevolo, Giulia, Maura Nicolosi, Francesca Palandri, Laura Godio, Andrea Evangelista, Elena Crisà, Elena Sabattini, et al. "Bone Marrow Reticulin Fibrosis in 579 Patients with Polycythemia Vera and Essential Thrombocythemia: Effect on Clinical Outcome." Blood 128, no. 22 (December 2, 2016): 3130. http://dx.doi.org/10.1182/blood.v128.22.3130.3130.
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Abstract Background: Prognostic value of bone marrow (BM) fibrosis grading in myeloproliferative neoplasm (MPN) is still debated. Polycythemia Vera (PV) and Essential Thrombocythemia (ET) are long term outcome MPN; however, they could evolve to adverse secondary myelofibrosis-MF or acute leukemia-AL. Aims and Methods: We retrospectively analyzeda cohort of 579 World Health Organization-defined PV (n=180) and ET (n=399) patients, and examined the prevalence and prognostic relevance of BM reticulin fibrosis. All patients were diagnosed between 1990 and 2013 and were recruited in Turin (n= 436) and Bologna (n=143), Italy. BM biopsy sample were reviewed by local pathologist and fiber scoring was performed according to a 3-graded system. Eligibility criteria included the availability of BM samples at diagnosis. Patients with grade 2 or 3-fibrosis were excluded. Overall survival (OS) was evaluated from diagnosis to death using Kaplan Meyer method and Hazard Ratio were estimated with the Cox Model. Cumulative incidence of MF and AL evolution were estimated considering death from any cause as a competing event and compared between groups using the Gray's test. Results: Overall, we observed 115 (63%) grade 0 and 65 (36%) grade 1 fibrosis and 291 (72%) grade 0 and 108 (27%) grade 1 among PV and ET patients, respectively (p= 0.028) We analyzed effect on clinical outcome separately. PV With a median follow up of 110 months (IQR:70-170), 5 and 10-years OS were 96% and 87%, respectively. Stratifying patients based on fibrosis degree, we observed 15 (13%) and 16 (25%) deaths for grade 0 and 1 fibrosis respectively, with 5 and 10-years OS of 98% vs 90% and 92% vs 82% for grade 0 and grade 1, respectively (p 0.076). Neither clinical findings nor thrombosis were significantly different between fibrosis degree. JAK2 V617F or exon 12 mutation status and allele burden was similar into subgroup. Cumulative incidence of MF evolution at 5 and 10-years was 2,8% and 7,2% vs 3,8% and 18,7% for grade 0 and grade 1 respectively (p 0.123). Cumulative incidence of AL evolution at 10- year was 4,2 % for both grade whereas at 15-years was 4,2% vs 19% for grade 0 and 1, respectively. ET At a median follow up of 75 months (IQR:39-120), 5 and 10-years OS were 98% and 90%, respectively. We observed 22 (8%) and 16 (55%) deaths for grade 0 and 1 respectively, with 5 and 10-years OS of 98% and 90% for grade 0 vs 97% and 89% for grade 1, respectively (p 0.358). The mutation status was analyzed in 379 patients and showed: 62% JAK2V617F, 19% CALR (type-1/1-like 14% and type2/2-like 5%), 3% MPLW515, 63 patients were triple negative for the above mutations. During follow-up, patients with grade 0 fibrosis showed more thrombotic events, 41 cases (14%; the 71% JAK2V617F-positive) vs 17 (16%). At multivariate analysis MPL mutation showed a higher risk of MF evolution compared to triple negative with an HR of 5,8 (p 0.0014) and to JAK2V617 mutation with an HR of 9,5 (p 0.002). Cumulative incidence of MF evolution was at 5-years 0,5% and 9% and at 10-years 6,2% and 18% for grade 0 and 1, respectively (p 0.0001). Cumulative incidence of AL evolution at 5 and 10-years was 0% for grade 0 and 13% and 7,3% for grade 1, respectively (p 0.096). However grade 0 showed a higher cumulative risk of AL evolution at 15-years (6,9% vs 10% for grade 0 and 1, respectively) (p=0.096). Conclusion: According to data recently published, in ET patients grade 1 BM fibrosis seems to correlate with a higher cumulative risk of MF and AL evolution, whereas in PV patients seems to correlate to a trend of higher mortality, even if not statistically significantly. Data reaffirm the importance of BM examination as part of diagnostic criteria in all MPN. Disclosures Cavo: Janssen-Cilag: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Millennium: Consultancy, Honoraria. Vitolo:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Gilead: Honoraria; Celgene: Honoraria; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.
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Rosti, Vittorio, Margherita Massa, Elisa Bonetti, Rita Campanelli, Valentina Meli, Claudia Castelnovi, Daniela Lisini, et al. "Reconstitution of Endothelial Progenitor Cells after Allogeneic Bone Marrow Transplantation in Children with Malignancies." Blood 106, no. 11 (November 16, 2005): 3026. http://dx.doi.org/10.1182/blood.v106.11.3026.3026.
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Abstract Evidences have been reported that bone marrow (BM)-derived endothelial progenitor cells (EPCs) circulate in peripheral blood (PB) of healthy subjects. These EPCs seem to play an important role in maintaining homeostasis of vessel walls, participating in both neo-angiogenetic processes and re-endothelization of the wall of injured vessels. The aim of this study was to assess the number and origin of circulating EPCs in PB and BM of children who underwent allogeneic BMT for malignancies. Thirty-five patients with acute lymphoid leukemia (n=18), acute myeloid leukemia (n=13), non Hodgkin lymphoma (n=1), myelodysplastic syndrome (n=1), chronic myeloid leukemia (n=1), and rabdomyosarcoma (n=1) were enrolled in this study. We evaluated PB samples at 21 days, and either PB or BM samples at 45, 60, 90, 120, 180, and 365 days after transplantation. The number of EPCs was evaluated as CD34+VEGFR-2+ or CD34+CD133+VEGFR-2+ cells by cytofluorimetric analysis, and by in vitro culture. PB (n=10) and BM (n=10) samples from age-matched BM donors were analyzed as controls. Donor or recipient origin of EPCs was assessed, by micro-satellite analysis, on at least 10 individually-picked endothelial colonies. The percentage of circulating CD34+VEGFR-2+ cells was significantly lower (p=0.02) in patients tested 21 days after transplant (median 0.01%, 0–1.0) than in PB from controls (median 0.06%, 0–1.3). At the same time point, the percentage of CD34+ co-expressing the CD133 and VEGFR-2 antigens, representing a restricted subset of immature EPCs, was lower, although still not-statistically significant, in patients (median 0.0%, 0.0–4.6) than in controls (median 0.6%, 0.0–15.1); the number of EPC-derived colonies was also significantly lower (p<0.002) in patients at 21 days from BMT (median 4/106 MNC, 0–15) than in controls (median 22/106 MNC, 11–43). Neither the percentage of circulating cell subsets, nor the number of EPC-derived colonies, showed significant modifications during 1-year follow up (ANOVA test). Similar results were obtained when BM samples were analyzed. The percentage of CD34+VEGFR-2+ and CD34+CD133+VEGFR-2+ EPCs was lower in patients tested at 45 days after transplantation than in controls (p=0.03 and p<0.04, respectively). The number of EPC-derived colonies was also lower (p= 0.001) than that found in BM from controls. At subsequent time points, no significant variation of these parameters was found (ANOVA test). Conditioning regimen, or occurrence of GvHD did not influence the percentage of EPCs in either PB or BM. Microsatellite analysis was performed on EPC-derived colonies of 4 patients, at time points ranging from 45 days to 9 months after the allograft. All the analyzed colonies were of donor origin. In conclusion, circulating and BM EPCs are detectable in children given BMT from 21 days up to 1 year after transplant. These cells are derived from donor BM indicating that EPCs are transferred with the graft into the recipient. More cases and longer follow up studies are needed to assess whether these cells can be correlated with clinical outcome of the transplanted patients.c
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Skeie, Bente Sandvei, Per Øyvind Enger, Paal-Henning Pedersen, and Geir Olve Skeie. "RADI-23. CLINICAL RISK ASSESSMENT SCORE TO ESTIMATE THE LIKELIHOOD OF PSEUDOPROGRESSION VERSUS TUMOR RECURRENCE FOLLOWING STEREOTACTIC RADIOSURGERY FOR BRAIN METASTASES." Neuro-Oncology Advances 1, Supplement_1 (August 2019): i26. http://dx.doi.org/10.1093/noajnl/vdz014.115.
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Abstract OBJECTIVE: A major challenge in the follow-up of patients managed with stereotactic radiosurgery (SRS) for brain metastases (BM) is to differentiate pseudoprogression (PP) from tumor recurrence (TR). A clinical score based on tumor and treatment related factors would be valuable when selecting appropriate treatment. MATERIAL AND METHODS: Follow-up images of 97 consecutive patients treated with SRS for 406 BM were analyzed. Of these 100 (24.6 %) BM in 48 (49.5 %) patients responded either with TR (delayed growth; 53 (13.1 %) BM) or PP (temporary volume increase; 47 (11.6 %) BM). Differences between the 2 groups were analyzed and used to develop a PP risk assessment score (PP-RAS). RESULTS: Significant factors associated with a higher incidence of PP versus TR were: primary lung cancer vs. other primaries, BM volume ≤ 2cc (or BM ≤ 1.5 cm in diameter), Target cover ratio > 98 % and prior radiation SRS or WBRT. Based on the presence (0) or not (1) of these 5 parameters, a risk assessment score for PP versus TR was established. A PP-RAS score of 0 corresponds with high likelihood of PP vs. TR, whereas a score of 5 corresponds with a high risk of TR. A score of ≤ 1 point was associated with 100 % PP, 2 points with 57 % PP and 43 % TR, 3 points with 57 % TR and 43 % PP, whereas ≥ 4 points were associated with 84 % TR and 16 % PP, π=24.57, df =4, p < 0.001). CONCLUSION: Based on these 5 parameters at the time of SRS our risk assessment score could robustly differentiate between PP versus growth following SRS. The score is user-friendly and may be a useful tool to guide the decision making whether to retreat or observe at appropriate follow-up intervals.
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Shide, Kotaro, Takuro Kameda, Ayako Kamiunten, Masaaki Sekine, Keiichi Akizuki, Haruko Shimoda, Tomonori Hidaka, Yoko Kubuki, Akira Kitanaka, and Kazuya Shimoda. "Therapies Targeting the MAPK Pathway Improve Bone Marrow (BM) Fibrosis Induced By JAK2V617F." Blood 124, no. 21 (December 6, 2014): 162. http://dx.doi.org/10.1182/blood.v124.21.162.162.
Full textAbstract:
Abstract In primary myelofibrosis patients, somatic mutations such as JAK2V617F(JAKVF) and MPLW515 that activate JAK-STAT signaling are often seen. Small-molecule JAK2 inhibitors are effective for organomegaly and constitutional symptoms, but the drugs have little effect on BM fibrosis. To clarify the mechanism by which MPN cells with JAK2 mutations cause BM fibrosis, we compared the gene expression patterns of Lin−Sca1+ BM cells in JAK2VF transgenic mice (JAK2VF-TG), which develop myelofibrosis (MF), with that in WT mice. We found that TGFb1 and HOXB4, the target genes of transcription factor USF1 were highly expressed. TGFβ1, which is secreted by hematopoietic cells, is essential for fibrotic development in a murine model of MF (Chagraoui et al. Blood 2002), and increased expression of HOXB4 enhances human megakaryocytic development (Zhong et al. BBRC 2010). To investigate the mechanism of the high expression of these genes downstream of JAK2 signaling, USF1 and a cytokine receptor gene (MPL, EPOR or CSF3R) were co-transfected into 293T cells along with either a TGF-β1/HOXB4 promoter-driven or a STAT5 response element-driven luciferase reporter. Stimulation of MPL with TPO enhanced USF1 transcriptional activity about 3 fold, but stimulation of EPOR with EPO or of CSF3R with G-CSF did not change this activity. However, stimulation with any of the 3 types of cytokines enhanced STAT5 transcriptional activity. JAK2VF upregulated USF1 and STAT5 much more highly than JAK2WT without TPO stimulation. This USF1 upregulation specifically to TPO/MPL signaling was suppressed by a dominant negative mutant of USF1, JAK2 inhibitors (AG490, NS-018) or MEK inhibitors (U0126, PD325901). Inhibition of PI3K or p38MAPK did not affect the USF1 activation. Co-treatment with JAK2 and MEK inhibitors showed a synergistic effect in blocking both USF1 upregulation and STAT5 activation induced by JAK2VF. Next, we tested the MEK inhibitor, PD325901, in combination with the JAK2 inhibitor, NS-018, in the JAK2VF-TG mice. After disease was established 12 weeks after birth, JAK2VF-TG mice were divided into the following 4 groups: vehicle control; PD325901 monotherapy; NS-018 monotherapy; and combined therapy. PD325901 (5 mg/kg) and NS-018 (50 mg/kg) were orally administered once and twice daily, respectively. After 12 weeks of treatment, we evaluated the effect on BM fibrosis. The grading of MF in each group (n = 5-6) was as follows: vehicle control (MF-0: 0/6, MF-1 or 2: 6/6); PD325901 monotherapy (MF-0: 4/5, MF-1 or 2: 1/5); NS-018 monotherapy (MF-0: 0/6, MF-1 or 2: 6/6); and combined therapy (MF-0: 3/6, MF-1 or 2: 3/6). In the 2 groups treated with PD325901, 50~80% of mice showed MF-0. In contrast, in vehicle-treated or NS-018 monotherapy groups, all mice showed MF-1 or 2. Consistent with the MF grading, BM cellularity was significantly increased in the PD325901 monotherapy or combined therapy groups compared with the vehicle-treated group. A significant reduction was seen in the plasma TGFβ1 concentration in the PD325901 monotherapy and combined therapy groups compared with the vehicle-treated group (9.7 ng/ml, 8.1 ng/ml vs. 18.2 ng/ml, respectively). The TGFβ1 concentration in the extracellular fluid of BM (Wagner et al blood 2007) was also significantly reduced (5.6 ng/ml, 6.8 ng/ml vs. 9.1 ng/ml, respectively). BM cellularity and the TGFβ1 concentration in the NS-018 monotherapy group were comparable to those in the vehicle-treated group. Interestingly, megakaryocytes in the PD325901 monotherapy and combined therapy groups were decreased in number and were smaller than those in the vehicle-treated or NS-018 monotherapy groups. Regarding the effect on splenomegaly, spleen weight was significantly reduced in the NS-018 monotherapy and combined therapy groups compared with the vehicle-treated group (0.83 g, 0.69 g vs. 1.18 g, respectively). PD325901 monotherapy had little effect on splenomegaly. It is known that MEK-ERK1/2 pathway is critical in normal megakaryocyte development. In vitro data suggest that JAK2VF activates this pathway downstream of MPL and may contribute to TGFβ1 overproduction and dysmegakaryopoiesis, causing BM fibrosis via transcriptional enhancement of USF1. In vivo data suggest that MEK inhibition has the potential to improve dysmegakaryopoiesis and BM fibrosis. The combined therapy of JAK2 inhibitors with MEK inhibitors might be a promising therapy for improving both splenomegaly and BM fibrosis. Disclosures No relevant conflicts of interest to declare.