Articles de revues sur le sujet « TJ 7.5 UL 2003 »

Abstract PBSC mobilization for auto transplantation of NHL pts with multiple regimens of prior chemotherapy is hard to achieve and 25%–30% of patients experience mobilization failure. AMD is a small bicyclam compound which specifically binds to CXCR4 receptor and blocks signaling through SDF-1. Previous studies in normal donors suggested clear dose dependent CD34+ cell mobilization as a single agent as well as additively with G-CSF with little toxicity (ASH meeting, 2002; 2003). Similarly, previous studies with NHL and Myeloma patients resulted with a dose-dependent augmentation of CD34+ cell mobilization in pts receiving G-CSF with little toxicity. The exact mechanism of AMD-induced mobilization of CD34+ cells was not studied in patients and AMD was not used before for PBSC mobilization in hard to mobilize NHL patients. Furthermore, its effect on mobilization of DCs and lymphoma cells was not studied before. On November 2003, we initiated a phase II study of 10, hard to mobilize NHL patients, receiving 16ug/kg of G-CSF for 4 days and G-CSF followed by 240ug/kg of AMD on day 5, 9 hours before apheresis collection. G-CSF and AMD were continued for additional day or 2, as needed, in order to collect the target dose of ≥ 2x106 PBSC/kg. Ten liters of blood were exchanged in ~4hours of apheresis. Median age was 54 years (44 to 63 years). Of the 10 patients enrolled, 6 pts had diffuse large cell lymphoma and 3 had follicular histology with 8/10 received 2 regimens of chemotherapy, 2 of which received also radiation prior to mobilization. At mobilization, 5/9 pts were primary refractory, 3 pts were in 1st relapse, 1 pt in 2nd relapse and 1 pt in 2nd CR. We determined percent CD34+ cells and percent DC1 and DC2 cells as well as percent lymphoma cell mobilization (by Real time DNA-PCR) at baseline (before administration of G-CSF) and before and after AMD, in the blood and in the apheresis product. To date 7 pts were transplanted. Five pts collected in 1 day and 5 pts collected in 2 days. No adverse events were observed during mobilization. All patients collected ≥ 2x106 PBSC/kg and 7 pts have been transplanted with a dose of 2-7x106 PBSC/kg. All transplanted pts engrafted with a mean of 10 days (9 to 12 days) for ≥ 500ANC and with a mean of 13 days (12–14 days for 6/7 pts) to reach 20K of plts. One pt had a delayed plt engraftment and was engrafted on day 27. Addition of AMD to G-CSF, prior to the first or 2nd PBSC collection resulted in a mean increase of percent CD34+ cells from 0.11% to 0.17% ( p=0.017), with a similar mean increase in CD34+ cells/ul (35/ul to 81/ul; p=0.0001) followed by normalization of CD34+ cells/ul within 24 hours. Similarly, addition of AMD to G-CSF resulted in an increase in the mean of DC1 cells from 79/ul to 156/ul (p=0.009) and from a mean of 62/ul to164/ul (p=0.006) for DC2 cells. One pt had 0.08% lymphoma cells at baseline by DNA-PCR for the major breakage point of the Bcl-2 translocation sequence, with no detectable lymphoma cells in the blood or apheresis collection post AMD. All other pts were negative for lymphoma pre and post AMD by this test. Adverse events and sever adverse events related to study were minimal. We conclude that AMD is a safe drug with clinical benefit in increasing PBSC and DC mobilization with no detectable mobilization of lymphoma cells.

Abstract Backgrounds/Aims: Hepatic veno-occlusive disease (VOD) is a life-threatening complication associated with allogenic stem cell transplantation (SCT). Although some risk factors including the intensified conditioning regimen, the second SCT, and liver dysfunction have been implicated on the pathogenesis of VOD, its etiology remains undetermined. Plasma von Willebrand factor (VWF) is produced in vascular endothelial cells (ECs) as unusually-large VWF multimers (UL-VWFMs) and released into circulation, where UL-VWFMs are cleaved into the small multimers with a specific metalloprotease ADAMTS13. Thus, the elevated level of plasma VWF, together with UL-VWFMs, has been thought in part to be a reflection of vascular EC injuries. Previously, we reported that plasma ADAMTS13 activity significantly decreased in patients with VOD during the first 4 weeks after SCT, compared with those without VOD (BMT2002, 29:789). Since ADAMTS13 down-sizes UL-VWFM by its proteolytic cleavage and reduces its thrombogenicity, we have here performed multicentric, prospective randomized study as to whether the infusion of fresh frozen plasma (FFP), a source of ADAMTS13, can prevent the occurrence of VOD in high-risk group patients with SCT. Methods: The study was conducted at 10 hospitals between April 2001 and March 2003. Patients for allogenic SCT were enrolled to participate in the study, if they were high-risk for VOD abovementioned. Forty-three patients enrolled in this study were randomly divided into two groups: 23 patients with FFP infusion and 20 patients without. FFP was infused twice a week during conditioning regimen and until day 28 after SCT. The amount of FFP infused depends on body weight as follows; 1 unit (=80 ml) for patients under 10 kg, 2 units for 10–20 kg, 3 units for 20–30 kg, 4 units for 30–40 kg, and 5 units for over 40 kg. Plasma ADAMTS13 activity was measured by a novel monoclonal antibody-based highly sensitive ELISA (Transfusion2006, 46:1444). Results: Three patients with hepatic VOD occurred within 20 patients who did not receive the FFP infusion, but none were observed in 23 patients who received the FFP infusion. We analyzed both the groups with special references to plasma levels of VWF and ADAMTS13. A significant difference was found in plasma levels of VWF:Ag, where the patients received FFP infusion had the lower values at day 0, day 7, and day 28, than those without receiving FFP infusion. However, no clear difference of plasma levels of ADAMTS13 activity was observed in both the groups. Most interestingly, however, a heightened degradation of VWFM (a total lack of the high ~ intermediate molecular size multimers) was found in patients with VOD who did not receive FFP infusion, but this finding was not seen in those without VOD who received FFP infusion. Conclusions: FFP infusion apparently reduces plasma levels of VWF:Ag, together with the disappearance of UL-VWFMs, and thereby prevents the occurrence of VOD. On the other hand, in the patients with hepatic VOD, prior to the disease progression the high~intermediate multimers including UL-VWFMs were already consumed, by which platelet aggregation/thrombi might occur, as evidenced by VWFM analysis.

Abstract Introduction: Traditional prognostic factors for adult acute lymphocytic leukemia (ALL) include age, white blood count at diagnosis, and cytogenetic (CG) risk. We sought to identify a more detailed prognostic risk score for newly diagnosed adult patients (pts) based on these and other pre-treatment characteristics. Methods: 82 newly diagnosed ALL pts given induction chemotherapy (IC) at our institution between the years 2003-2011 were included, and data were obtained by chart review. Institutional review board approval was obtained. Variables examined included: gender, age, immunophenotype, CG risk, pre-IC body mass index (BMI), pre-IC and day 28 serum albumin, absolute lymphocyte (ALC) and neutrophil (ANC) counts, positive culture (blood or other) during IC, positive imaging suggestive of infection (during IC), and allogeneic hematopoietic cell transplant (AHCT). CG risk was ascribed by CALGB criteria (Blood 1999; 93: 3983). BMI was defined by: underweight (≤ 18.5), normal (> 18.5-25.0), overweight (> 25.0-30.0), moderately obese (> 30.0-35.0), severely obese (> 35.0-40.0), and very severely obese (> 40.0). The primary endpoint was overall survival (OS) which was measured from IC to death or last follow-up. Proportional hazards models were used for univariable and multivariable analyses. In the multivariable analysis stepwise variable selection was used to identify independent predictors. Results were internally validated using a bootstrap algorithm. For convenience measured factors were discretized using a recursive partitioning algorithm. Prognostic groups were formed by assigning “points” to each factor that were based on the magnitude of the estimated regression coefficients of the final model, and then summing the total number of points present. Results: Median age at diagnosis was 43 yrs (range 18-78); 58% male. 71% of pts (58/82) had a B-cell immunophenotype. CG risk included: normal: 15 pts (18%), high: 41 pts (50%), miscellaneous: 9 pts (11%), and unknown: 17 pts (21%). Twenty-four pts (29%) were Ph+. The majority of pts (70%: 57/82) received the CALGB 19802 regimen (Cancer 2013; 119: 90) for IC +/- a tyrosine kinase inhibitor (if they were Ph+). 27% of pts (22/ 82) received AHCT in CR1. Estimated median OS is 41.5 months (95% CI: 15.5-N/A). In univariable analysis age, pre-induction BMI, Day 28 ALC, pre- and Day 28 albumin, Day 28 ANC, Day 28 platelet count, evidence of infection, and CG risk were all seen to impact outcome. In multivariable analysis pre-IC BMI and albumin, age, and Day 28 ALC were identified as independent predictors. Assigning 1 “points” each for age >50, albumin prior to IC ≤ 3.2 g/dL, or Day 28 ALC ≤ 50 /uL and 2 points for BMI ≥ 35, 3 prognostic groups were defined: favorable (0 points) 32% of pts (26/80): estimated 5-yr OS of 68% +/-11%; intermediate (1 points) (29% of pts, 23/80): estimated 5 yr OS of 39% +/-11%, and unfavorable (≥ 2 points) (39% of pts, 31/80) with estimated 5 yr OS of 17% +/- 7% (Figure 1). Conclusion: We have constructed a simple prognostic model for newly diagnosed adults with ALL. This model will need to be validated in a larger group of uniformly treated patients. Table 1 Prognostic Factors for OS in Univariable and Multivariable Analysis Factor Univariable (HR (95% C.I.)) Multivariable (HR (95% C.I.)) Age at dx (≤50 vs. >50) 3.29 (1.80-5.99), p=.0001 2.83 (1.45-5.53), p=.002 Pre-IC BMI (<35 vs. >35) 2.95 (1.57-5.52), p=0.0008 3.88 (1.84-8.17), p=.0004 Pre-IC albumin (≥ 3.2 vs. < 3.2 g/dl) 2.61 (1.43-4.77), p=0.002 2.66 (1.33-5.30), p=.0006 Day 28 ALC (> 50/uL vs. ≤50/uL) 3.57 (1.61-7.91), p=0.002 3.11 (1.33-7.28), p=.009 CG risk 2.03 (0.98-4.22); p=0.06 ------ Day 28 albumin (>2.3 vs. ≤2.3 g/dl) 3.37 (1.66-6.83), p=0.0008 ------ Day 28 ANC (>200/uL vs. ≤200/uL) 4.51 (1.94-10.51), p=.0005 ------ Day 28 platelets (>75K/uL vs. ≤75K/uL) 2.44 (1.26-4.72), p=.008 ------ Any positive culture (no vs. yes) 2.19 (1.19-4.04), p=0.01 ------ Blood culture positive for bacteria (no vs. yes) 2.34 (1.28-4.30), p=0.006 ------ Positive imaging suggestive of infection (no vs. yes) 2.44 (1.34-4.46), p=0.004 ------ Positive blood culture and image (no vs. yes) 1.96 (1.07-3.57), p=0.03 ------ Figure 1 Prognostic Groups Figure 1. Prognostic Groups Disclosures No relevant conflicts of interest to declare.

8018 Background: WM is an indolent B-cell lymphoma. NA are widely used in the treatment of WM, and are considered as appropriate first line agents for the treatment of WM (Gertz et al, Semin Oncol 2003; Treon et al, Blood 2006). Increased incidences of disease transformation and development of MDS/AML have been observed among patients with indolent B-cell malignancies receiving NA. We therefore sought to delineate the incidence for these events in a large population of WM patients treated at our institution. Methods: 326 previously treated patients with the consensus panel definition of WM, who received treatment with (n=173) or without (n=153) a NA were included in this analysis. Baseline characteristics between NA and non-NA treated patients were not significantly different and were as follows: median age 59 years; male/female ratio 1.4; median B2M 2.9 mg/L; serum IgM 3,000 mg/dL; BM involvement 40%; Hct 34%; WBC 5,100/ul, and PLT count 243,000/ul. For patients receiving NA, treatment consisted of either fludarabine (n=117; 68%), cladribine (n=48; 27%) or both (n=8; 5%). For non-NA treated patients, therapy included chlorambucil, rituximab, CVP, CHOP, thalidomide, and cyclophosphamide alone or in combination with rituximab, and alemtuzumab. Median follow-up of patients was 64 (range 10–270) months. Results: Among NA treated patients, 10 (5.7%) patients had transformation to an aggressive NHL (to DLBCL) (n=7; 4%) or developed MDS/AML (n=3; 1.7%). Disease transformation and development of MDS/AML occurred at a median time of 48 (range 7–114), and 48 (range 38–52) months following NA treatment, respectively. In contrast, among non-NA treated patients, only 1 patient demonstrated disease transformation (to DLBCL) at 10 months and no patients developed AML/MDS (p=0.025). Conclusions: These data demonstrate an increased incidence of disease transformation and development of MDS/AML among WM patients treated with NA. No significant financial relationships to disclose.

Abstract Autologous stem cell transplantation is curative for many patients with hematologic malignancies. Approximately 20% of patients do not have an adequate stem cell mobilization. Recently, work from our laboratories has shown that parathyroid hormone (PTH) increases osteoblast number and expansion of the stem cell compartment in mice. In murine models, the addition of PTH caused an increase in the absolute number of stem cells. Daily PTH injection caused an increase in the absolute number of murine stem cells and improved survival in transplant recipients of limiting numbers of stem cells. (Nature425: 841, 2003). This observation suggested that PTH might be able to increase stem cell numbers in humans. PTH is an FDA approved drug used for treatment of osteoporosis. In this Phase I study, patients who have collected less than 2 million CD34+ cells/kg after 1 or 2 stem cell mobilization attempts received 14 days of sc PTH, in escalating dose cohorts of 40 mcg, 60 mcg, 80 mcg, and 100 mcg per day, with G-CSF 10mcg/kg/day for the last four days. Patients with >5 CD34+/uL on Day +14 proceeded to stem cell apheresis and autologous stem cell transplant. 14 patients have enrolled on this study, now enrolling at the highest dose cohort, and 12 patients have completed treatment for this analysis with 3 patients per dose cohort. The median age was 57 years (range 24–71 years), and 9 (75%) patients are female. In 10 patients (83%) one attempt at stem cell mobilization failed with either growth factor alone or growth factor plus chemotherapy; in the other 2 patients (17%) two attempts at mobilization failed to attain adequate cells. The diagnoses were as follows: non Hodgkin’s lymphoma (7 patients, 58%), Hodgkin’s disease (5 patients, 42%). There were no dose limiting toxicities defined as calcium > 11.5, ionized calcium > 1.5, phosphate <1.0, or systolic blood pressure less than 80mm Hg. 3 patients had a self-limited fever, one patient had an unexplained eosinophilia, and 1 patient required an admission with fever, rigors, and headache. 6 of 12 patients (50%) achieved the target peripheral CD34 level of 5/uL, of whom 4 underwent stem cell apheresis. The median CD34 cells/uL on Day +14 was 4.3 (range 0–18.8). 2 patients who achieved the target peripheral CD34 level of 5/uL did not complete collections, 1 due to access problems, and 1 due to physician preference. The 4 patients who continued with the study collected a median CD34+ dose/kg of 2.2 x 106 (range 0.9–2.7) from stem cell apheresis with a median of 2 collections (range 1–4). These 4 patients proceeded to autologous stem cell transplant, with median days to neutrophil and platelet engraftments of 11 (range 10–12) and 14 (range 12–19), respectively. In conclusion, 1) PTH is well tolerated in this population, even at a dose of 100 mcg; 2) PTH plus G-CSF may be effective in patients that fail primary or secondary stem cell mobilization attempts; 3) PTH plus G-CSF should be tested in a larger Phase II study to improve donor stem cell yield. Future directions may also include the use of parathyroid hormone to improve engraftment efficiency in settings of low stem cell dose such as adult cord blood transplantation.

Abstract Abstract 3063 Background: Dying mammalian cells release danger signals that stimulate antigen presenting cells (APCs) to promote an immune response. It has been demonstrated that uric acid released from injured cells alerts the immune system to cell death, acts as a danger signal to stimulate cytotoxic T cell responses and that elimination of uric acid in mouse models reduces this immune response (Ref: Nature 2003; 425:516–521). Rasburicase is a recombinant urate-oxidase enzyme that catalyzes oxidation of uric acid into an inactive soluble metabolite and is currently used to prevent tumor lysis syndrome. We hypothesized that rasburicase administered during myeloablative conditioning prior to allogeneic HCT will reduce the serum levels of uric acid and thereby may decrease the incidence of acute GVHD via inhibition of danger signal-mediated activation of host APCs. Methods: In this pilot trial at the Massachusetts General Hospital, between 2007 and 2010, 23 patients (median age: 41 years, range: 19–59) with hematologic malignancies in complete remission (AML, n=13; ALL, n=8; MDS, n=1; MPD, n=1;) received myeloablative preparative regimens (Bu/Cy, n=14; Cy/TBI, n=7; Bu/Flu, n=2) followed by GCSF-mobilized HLA-matched (MRD, n=18; MUD, n=5) peripheral blood HCT. GVHD prophylaxis consisted of cyclosporine or tacrolimus and methotrexate for MRD transplants and tacrolimus/MTX and anti-thymocyte globulin (Thymoglobulin) for MUD transplants. Rasburicase was administered beginning on the first day of conditioning therapy, at a dose of 0.20 mg/kg intravenously daily for 5 consecutive days. Outcomes were compared to 44 controls at this institution from the same time period identified using retrospective chart review. Patients in the control group received allopurinol during the conditioning as a part of the institutional guidelines. Associations between categorical variables were evaluated using Fisher's exact test. Overall and disease-free survival (OS and DFS) were estimated using the method of Kaplan and Meier. Results: The mean serum uric acid concentration was 0.2 mg/dl (range, 0–1.7) on 6 consecutive days, beginning the day after the first dose of rasburicase. Engraftment was achieved in all patients, and the median times to neutrophil (at least 0.5 × 109/ul) and platelet engraftment (at least 20 × 109/ul) were 18 days (range, 7–26 × 109/ul) and 16 days (range, 8–57 × 109/ul), respectively. The only serious toxicity caused by rasburicase was intravascular hemolysis in one patient who was found to have G6PD deficiency; this patient received only 2 doses of rasburicase. Greater than or equal to grade II-IV acute GVHD occurred in 5 out of 23 patients (22%), 4/18 in MRD and 1/5 in MUD recipients: grade II, n=1; grade III, n=2; and grade IV, n=2. When compared with 44 patients (AML 28, ALL 5, MDS 4, NHL 5, MPD 1, CML 1), comparable to rasburicase-treated patients with respect to age, gender, disease status, donor sources, conditioning and GVHD prophylaxis, who received myeloablative HCT (MRD, n=32; MUD, n=12) at the MGH during the same time period as the patients in the rasburicase-treated group, there was significantly less grade II or higher aGVHD in the rasburicase group (rasburicase: 22% vs. institutional control: 48% [total 21/44, 13/32 in MRD and 8/12 MUD recipients], Fisher's exact test, p=0.033). There was no significant difference in the incidence and severity of chronic GVHD between the two groups (rasburicase, 61%, control 48%; Fisher's exact test, p=0.721). At 3 years, there was no significant difference in disease-free survival (DFS) or overall survival (OS) between the rasburicase-treated and control groups (DFS: rasburicase vs. control 51.2% vs. 40.4%, p=0.97; OS: rasburicase vs. control 55.3% vs. 44.9%, p=0.88). Conclusion: Rasburicase can be safely administered during myeloablative conditioning, results in a profound lowering of serum uric acid levels and has the potential to reduce the incidence of acute GVHD. Based on these data a prospective randomized phase II trial is planned in order to verify whether rasburicase inhibits acute GVHD after myeloablative HCT and to study the possible mechanisms of protection from GVHD. Disclosures: Off Label Use: Rasburicase for GVHD prevention in allo-HSCT.

Abstract Decitabine, an inhibitor of DNA methyltransferase (DNMT) enzymes, has clinical activity in myeloid malignancies, even at low doses (>1 log below the MTD) which may be optimal for demethylation rather than only cytotoxicity. We designed a two step trial for AML patients (pts) to determine: Step 1) the minimal effective pharmacologic dose (MEPD) of decitabine as a single agent (defined as lowest dose to induce reexpression of genes commonly methylated in AML in 5/6 pts treated at a single dose level) and Step 2) the MTD of the histone deacetylase inhibitor valproic acid given in combination with decitabine at this MEPD. To date, Step 1 is ongoing; decitabine alone has been administered to 14 pts at two dose levels. Pts had relapsed/refractory AML (N=8) or age>60 and ineligible/refused standard induction therapy (N=6). Pts ranged in age from 57–83 years and had received ≥ 2 prior inductions (N=6), 1 prior induction (2), or were untreated (4). 8 pts received decitabine at 15mg/m2/IV over 1 hr daily (d) for 10 consecutive d, and 6 received 20mg/m2/d on the same schedule, every 28 d. Plasma decitabine levels were analyzed by a validated LC-MS/MS method with a sensitivity of 2 ng/ml developed in our laboratory. Plasma drug concentration-time courses on d 1 and 10 achieved a mean Cmax of 93 ng/ml (N=7) and followed a two compartment infusion model. The mean short and long half-lives were 2.7 and 36.9 min, respectively, with a trend of decreasing the longer half-life on d 10. According to published bone marrow (BM) response criteria (Cheson, JCO 2003), 4/10 pts who completed two cycles of therapy responded (2 at each dose level). 3 had complete response with incomplete recovery of counts (CRi), and one achieved CR. Hematologic improvement (HI) or clinical benefit was seen in 3 additional pts: one achieved neutrophils of 2,200/uL, platelets (plts)>100,000/uL, disappearance of circulating blasts, and disappearance of BM blasts except by flow cytometry; one pt achieved plt transfusion independence (plts>100,000/uL); one pt had stabilization of disease for 6 months. Two more pts who remain on study are not yet evaluable for BM response but have already had significant HI with plts of 259,000 and 74,000/uL, respectively, after one cycle of therapy. Two pts were not evaluable for response due to death from sepsis or death related to decitabine-induced differentiation syndrome (first reported by Blum, ASH 2004), respectively. Decitabine was well tolerated, given typically as an outpatient. There were no severe non-hematologic drug related toxicities. Pts with HI or BM response required plt transfusion support when subsequent cycles were administered. At 15mg/m2/d x 10 d: 4/6 pts experienced at least 100% increase in reexpression genes commonly methylated in AML such as p15 or estrogen receptor; immunoblotting demonstrated DNMT1 protein depletion in 4/6 pts lasting 4–42 d. Clinical trial design based on achieving the MEPD is feasible in AML; we demonstrate clinical activity of low dose decitabine associated with changes in levels of the DNMT1 target and reexpression of epigenetically silenced genes. Complete PK and PD studies including gene reexpression by quantitative RT-PCR, DNMT1 protein levels by immunoblotting, and decitabine-induced promoter demethylation by COBRA/bisulfite sequencing will be presented. (NCI U01 CA 76576-05)

Abstract Early response to therapy as determined by Day 8 prednisolone response (PR) and minimal residual disease (MRD) are highly predictive of risk of relapse in childhood ALL. They are currently employed in risk-stratification in modern chemotherapeutic regimens. Leukemia biological factors like hyperdiploidy, oncogene fusions like TEL-AML1, MLL rearrangements and BCR-ABL are widely used for risk stratification but patient’s pharmacogenetic profile has thus far not been utilised for tailoring therapy because of conflicting or equivocal results. We investigated potential candidate genes involved in drug transport and metabolism of steroids, vincristine, L-asparaginase and anthracyclines used in the BFM induction backbone to exploit the plausible pathways of early chemoresistance. We studied 282 children with ALL enrolled in the Malaysia-Singapore 2003 ALL trial. Poor prednisolone response (PPR) is defined as absolute blast count ≥1,000/uL after 7 days of prednisolone and 1 IT MTX. MRD quantification at day 33 induction using IgH and TCR markers based on European MRD Study Group standards. Four potential candidate genes MDR1 3435C>T, GSTT1, GSTM1, NQO1 609C>T were studied using Polymerase Chain Reaction and Restriction Fragment Length Polymorphism. Statistical analysis was carried out using multinomial regression model. We had 241 good prednisolone responders (GPR), and 34 poor prednisolone responders (PPR). There were 112 patients with negative MRD (<10−4) while 129 had positive MRD ≥10−4 (35 had high MRD > 5 × 10−3). Only MDR1 3435TT genotype was strongly associated with poor PR (p=0.011; OR=2.8; 95%CI=1.3–6.4), MRD positive disease ≥10−4 (p=0.011, OR=2.8, 95%CI= 1.3–5.9) and high levels of MRD >5×10−3 as compared to MRD <10−4 (p<0.0001; OR=5.9; 95%CI=2.3–15.1). Interestingly, MDR1 3435CT heterozygosity is significantly associated good early response: with low levels of <MRD10−4 as compared to high MRD levels >5×10−3 (p=0.022; OR=0.4; 95%CI=0.2–0.9). Oral prednisolone and dexamethasone are the most powerful drugs in the treatment of childhood ALL. MDR1 3435C>T although a synonymous SNP, is associated with lower P-glycoprotein because of reduced MDR1 3435T mRNA stability. MDR1 3435 TT homozygote has 4 fold reduced levels of P-glycoprotein in the duodenum and is associated with reduced drug absorption like digoxin. We postulate that TT homozygote; there is reduced absorption of oral steroids in the gut, resulting in low oral bioavailability and poor early response as determined by poor prednisolone response and high MRD. On the other hand, in the CT heterozygote, drug oral bioavailability is not the drug-limiting step. The predominant effect of reduced P-glycoprotein expression in the cells are associated with reduced efflux of drugs, hence higher levels of intracellular drug resulting in good treatment response. MDR1 C3435T polymorphism is highly correlated with early response to therapy in childhood ALL as determined by prednisolone response and MRD levels at the end of induction.

Abstract BACKGROUND. c-kit is a receptor tyrosine kinase for the ligand stem cell factor and a member of the PDGF receptor family. c-kit positivity, as defined by the presence of CD117 by flow cytometry (FC) in > 20% blasts, is detected in up to 90% of patients with AML, and is a potential target for imatinib, a selective tyrosine kinase inhibitor of c-kit as well as of BCR-ABL, PDGFR, and ARG. Previous reports of treatment with single-agent imatinib at 400 mg/day showed no response in AML (Cortes et al, Cancer 2003), while up to 24% of patients treated with 600 mg/day responded (Kindler et al, Blood 2003, Abstract 3242). Little information is available on the response in AML to imatinib as a single agent at 800 mg/day. CASE AND DISCUSSION. A 42-year old Caucasian male with relapsed c-kit expressing AML with del(9q), concurrent secondary high-grade (HG) glioma and few remaining therapeutic options presented to our service. He was initially diagnosed with primary oligodendrioglioma in January 2001 and underwent subtotal tumor resection, followed by whole brain radiation therapy, followed by 6 cycles of procarbazine, CCNU, and vincristine (PCV) chemotherapy, and entered complete remission (CR). In December 2002, he was diagnosed with AML M2 with del(9q) and was treated with cytosine arabinoside (Ara-C) and daunorubicin (7+3), followed by 3 cycles of consolidation with HD Ara-C, and entered CR. In March 2004, he had recurrent abnormal magnetic resonance imaging of the brain and HG malignant glioma was diagnosed by stereotactic biopsy. He was started on temozolamide but was unable to tolerate treatment due to pancytopenia, and a bone marrow (BM) at another institution disclosed relapsed AML with 75% blasts. Upon presentation to our institution, a BM examination showed > 90% blasts, 53% of which expressed CD117 positivity by FC. Imatinib therapy was initiated at a dose of 400 mg/day and escalated to 800 mg/day (HD) after lack of response. (Table 1.) The peripheral blood (PB) white blood cell count (WBC) peaked on Day 9 of treatment with imatinib and declined thereafter. On Day 21, blasts were undetectable in the PB and there was a proportional increase of PB neutrophils (PMN). By Day 25, the BM blasts decreased to 50% and only 12% blasts showed positivity for CD117. The patient experienced severe muscle/bone pains at the start of imatinib therapy, which resolved within five days. Response to HD imatinib was also accompanied by dramatic decline in serum LDH. The patient’s platelet (PLT) count improved to a peak of 70k on Day 14, declined thereafter, and the patient required PLT transfusion support by Day 31. The patient also received dexamethasone 4 mg q6h for his HG glioma, which remained stable during this time of observation. CONCLUSION. Our case demonstrates that HD imatinib 800 mg/day has significant preferential activity against the CD117+ AML blasts, is active in a shorter time span than previously reported at lower doses, and should be studied further in combination with other agents in AML. The patient’s HG glioma may have been partially stabilized by imatinib as PDGFR overexpression has been reported in secondary glioblastomas. Table 1. Imatinib Dose, mg/day Day WBC x 10-3/uL PMN, % PB Blast, % BM Blast,% BM Blasts CD117 +, % PLT x 10-3/uL - −7 1.8 4 15 > 90 53 34 400 1 17.5 3 21 - - 28 600 7 59.6 5 40 - - 50 800 8 71.0 9 21 - - 41 800 9 100.0 9 30 - - 31 800 14 11.0 22 25 - - 70 800 21 6.3 61 0 - - 31 800 25 4.0 49 0–3 50 12 13

Abstract Abstract 2065 Poster Board II-42 Background: Hypomethylating agents have significant clinical activity in myelodysplastic syndromes (MDS) and AML. In AML, we recently demonstrated a novel epigenetic mechanism of action for the proteasome inhibitor bortezomib (Liu, Blood 2008). Bortezomib induced hypomethylation of leukemic cells in vitro and in vivo via depletion of the Sp1/NF-kB transcriptional activation complex on the DNA methyltransferase 1 (DNMT1) gene promoter, which results in down-regulation of DNMT1 mRNA and enzyme, DNA hypomethylation and re-expression of otherwise hypermethylated target genes. Based on this preclinical work, we designed a phase I dose escalation study of 5-azacytidine (AZA) in combination with bortezomib in AML. Methods: Adults with relapsed or refractory AML by WHO criteria and preserved organ function with ECOG ≤2 were eligible. Previous decitabine or AZA was permitted. Patients received AZA at 75mg/m2 IV daily for days (d) 1-7. Bortezomib was gradually dose escalated–dose level 1 (DL 1): 0.7mg/m2 by IV push given immediately after AZA on d 2 and 5; DL 2: 0.7mg/m2 on d 2, 5, 9, and 12; DL 3: 1.0mg/m2 on d 2, 5, 9, and 12; and DL 4: 1.3mg/m2 on d 2, 5, 9, and 12. Cycles were repeated every 28 d, regardless of count recovery or response at least until 3 cycles were administered. Responses were graded by International Working Group criteria for AML (Cheson, JCO 2003). Bortezomib was discontinued after 3 cycles if no objective response of complete remission (CR), CR with incomplete count recovery (CRi), or partial remission (PR) was achieved, but AZA could be continued beyond this timepoint in the absence of disease progression. For responding patients, 12 or more cycles of therapy were permitted. Dose limiting toxicities (DLT) were assigned for cycle 1 of therapy. Given the high likelihood of infection in this population regardless of therapy, infection was not considered a DLT. Six additional patients were treated at the recommended phase 2 dose (RP2D). Results: 23 patients were enrolled with a median age of 65 years (range, 42-81) and had received a median of 2 prior inductions (range, 1-5). Median presenting WBC was 3,700/uL (500-59,100/uL); median BM blast was 26% (2-93%). 14 patients were refractory to last therapy received, including 4 with primary refractory AML. 9 patients had relapsed disease; all but 2 of these had prior CR duration <1 year. Patients received a median of 2 cycles of study therapy (range, 1-12+ cycles). Dose escalation was halted once the target bortezomib dose was reached; the RP2D was AZA at 75mg/m2 d 1-7 plus bortezomib 1.3mg/m2 d, 2, 5, 9, 12. Though no toxicities were considered to be DLT in this study, infection and/or febrile neutropenia were universal. Death within 8 weeks occurred in 5 patients (22%) due to pneumonia (1), sepsis (1), or progressive disease (3). Two patients had discontinuation of bortezomib after 2 cycles due to Grade 3 neuropathy; only 1 patient received bortezomib beyond 3 cycles. In 3 patients without objective response (and with no progression), AZA alone was continued after 3 cycles of combination therapy; each reported a subjective improvement in fatigue without bortezomib. Overall, the objective response rate was 26% (6/23). Responses were as follows: 3- CR, 2- CRi, and 1-PR. One CRi patient (in cytogenetic remission also) who discontinued study treatment after 2 cycles due to unrelated trauma subsequently had complete count recovery, but a repeat marrow examination was not performed. Three patients went on to allogeneic transplantation due to response achieved. Response followed the typical pattern of azanucleoside activity, requiring more than one cycle of therapy; the median number of cycles to initial response was 2 (range, 1-5). 5/6 responders had response to combination therapy; one patient responded following 5 cycles of treatment, the last 2 cycles with AZA as a single agent. Conclusions: The combination of 5-azacytidine and bortezomib is well tolerated and active in this cohort of relapsed or refractory AML patients. Additional studies to further elucidate the role of proteasome inhibition as a mediator of hypomethylating activity in AML are warranted. Correlatives studies are ongoing. Disclosures: Blum: Celgene: Research Funding.

Abstract The combination of thalidomide and dexamethasone (TD) has induced disease remission in 69% of 132 newly diagnosed patients with multiple myeloma (MM) treated at our center, with preventable and/or manageable side effects, and represents our primary treatment of choice. By adding bortezomib (Velcade), the 3-drug combination (VTD) has induced remission in 55% of patients with myeloma resistant to standard therapies, twice the frequency observed with bortezomib alone (Zangari, Barlogie et al, 2003). From 6/03 to 6/04, we combined bortezomib with thalidomide (100–200 mg each evening) and dexamethasone (20 mg/m2 on days 1–4, 9–12, 17–20) with therapeutic anticoagulation for 25 previously untreated patients with MM. Bortezomib was given at a dose of 1.0 (n=2), 1.3 (n=11), 1.5 (n=7), 1.7 (n=4) or 1.9 (n=1) mg/m2 IV on days 1, 4, 8 and 11, every 4 weeks to patients for 2–3 cycles of VTD. Median age was 63 (39–81), median B2M 5.1 mg/L (1.7–19), Hgb <10.5 g/dl in 60%, corrected serum calcium >11.5 mg/dl in 17%, and high tumor mass in 32% of patients. Grade 3 or 4 toxicities included non-neutropenic infection (2), orthostatic hypotension (1), DVT (1), neutropenia (1), thrombocytopenia (1); grade 3 or 4 neuropathy was not seen. Median nadir of ANC was 2360/ul and of platelets 135,000/ul with no correlation between bortezomib dose and myelosuppression. An initial dose of bortezomib of 1.5 mg/m2 IV x 4 was safe unless age > 70 and/or drugs for hypertension were taken concurrently. Responses were confirmed (>75% reduction serum myeloma protein and/or >95% reduction Bence Jones protein) in 19 patients (76%) and when defined by less stringent Blade criteria in 21 patients (84%); median time to remission was 0.6 mo (range 0.3–1.8) by either criteria in comparison with 1.1 mo (range 0.3–8.1) after TD (p<.01). Disease resistance was recognized by one month in 5 of 6 patients rated as unresponsive. Autologous blood stem cells were collected easily with G-CSF alone in 12 patients who were intensified a median 3.6 months after initial therapy; all 4 patients with primary resistant disease who received such therapy achieved partial remission. The frequency of CR to VTD could not be assessed because of early intensification. All patients are alive after median follow-up of 6 months (range 2–14). VTD induced a slightly higher frequency of PR, and significantly more rapid onset of remission, than those observed in similar patients treated previously with TD. No more than 2 courses of therapy were necessary before intensification or maintenance, so that the potential side effects and cost of more therapy were avoided. Results appeared superior to those observed with any prior program for previously untreated patients with MM at our center.

Abstract Sixty-four patients (pts) with chemotherapy-refractory CLL who were ineligible for ablative allogeneic HCT due to age and/or comorbidities were given nonablative-HCT from related (n=44) or unrelated donors (n=20) between 1997-2003 (Table). Median pt age was 56 (range 44–69) years, interval from diagnosis to HCT was 4.4 (3–25) years, and number of prior regimens was 4 (range 1–12). Sixty-one pts were refractory to at least 1 regimen, 56 to fludarabine (FLU), 19 to alkylating agents, 14 to rituxumab and 4 to CAMPATH, and 2 had failed autologous HCT. Twenty-three pts (36%) had disease responsive to last chemotherapy [28% partial (PR) and 8% complete remission (CR)] while 34 were nonresponsive and 7 had untested relapse. Conditioning for HCT consisted of 2 Gy TBI alone (n=11) or combined with FLU (n=53), 90 mg/m2. Postgrafting immunosuppression consisted of mycophenolate mofetil and cyclosporine. Pts received G-CSF mobilized peripheral blood mononuclear cells. After HCT, pts became neutropenic for a median of 11 days. Forty-four percent of pts had thrombocytopenia (&lt;20,000 cells/ul). Three pts had graft rejection; 1 died with aplasia and 2 are alive with disease relapse. Incidences of grades II, III, and IV acute GVHD were 39%, 14%, and 2% respectively, and chronic GVHD was 50% at 2-years. With median follow up of 24 (range 2.8–62.8) months, the overall response rate was 67% (50% in CR). URD-pts had significantly higher CR rate than MRD-pts. All 11 responding patients tested had molecular eradication of their disease. Overall, 39 patients are alive; 25 in CR, 5 in PR, 2 with stable disease, and 7 with relapse/progression. Twenty-five pts died, 10 from progression, 10 from infections ± GVHD, 2 from cardiac causes, 1 from metastatic lung cancer, 1 from cerebral stroke and 1 from rejection and aplasia. Estimated 2-year rates of non-relapse mortality, disease free survival, and overall survival were 22%, 52%, and 60% respectively. In multivariate analysis, high pretransplant comorbidity scores predicted higher non-relapse mortality and worse survival while bulky lymphadenopathy predicted increased risk of progression. CLL appears susceptible to graft-versus-leukemia effects particularly after URD grafts and nonablative-HCT should be explored in phase II trials in pts with FLU-refractory CLL. Table: Results Related (n = 44) Unrelated (n = 20) P Acute GVHD grade II, III, and IV 39%, 11%, and 2% 40%, 20%, and 0% 0.41 2-year chronic extensive GVHD 44% 69% 0.56 Median follow up (range) 31 (3–63) months 12 (3–39) months CR at 2-years 42% 78% 0.005 Relapse/progression at 2 years 34% 5% 0.08 Surviving pts 13 CR, 3 PR, 2 stable, 5 progression, 1 relapse 12 CR, 2 PR, 1 relapse 2-year non-relapse mortality 22% 20% 0.75 2-year disease free survival 44% 75% 0.15 2-year overall survival 56% 74% 0.33

Abstract Abstract 313 Introduction: Peripheral blood progenitor cell (PBPC) mobilization with intermediate-dose cyclophosphamide (3–4 gm/m2) (ID-CY) and G-CSF has been shown to be less toxic than high-dose CY (≥7 gm/m2) -based, and more efficacious than low-dose CY (LD-CY) (1–2 gm/m2) -based mobilization regimens in multiple myeloma (MM) patients following conventional induction regimens. However the relative importance of CY dose intensity in PBPC mobilization following novel induction regimens is not known. Herein we report comparative efficacy of PBPC mobilization in MM patients following novel induction chemotherapies, relative to CY dose intensity. Methods: This multicenter outcomes study includes 123 patients who underwent a planned, single autograft within 1-year of starting induction chemotherapy with novel chemotherapy agents (thalidomide, lenalidomide, bortezomib), from 2003–2010. Consecutive patients undergoing mobilization with ID-CY/G-CSF (3–4 gm/m2) (n=55) at one institution were compared against consecutive patients receiving LD-CY/G-CSF (1.5 gm/m2) (n=68) at a different transplant center. At baseline the two groups were compared for parameters predicting mobilization failure. In order to assess efficiency of PBPC mobilization, we evaluated peak peripheral blood (PB) CD34+ cell counts, CD34+ cell yield on day1 of collection, total CD34+ cell collection, and total number of apheresis sessions. Mobilization failure was defined as failure to collect ≥2 ×106cells/kg body weight. All patients with normal renal function received uniform conditioning with Mel200 (MEL140 if serum creatinine was >2 mg/dl). SPSS version 13.0 was used for statistical analysis. Results: At baseline, the ID-CY and LD-CY cohorts were well balanced respectively in terms of mean age (57-yrs vs. 59-yrs, p=0.3), gender (males; 66% vs. 58%, p=0.4), high-risk cytogenetics (p=0.6), prior radiation (34% vs. 18%, p=0.06), disease stage (p=0.5), number of prior therapies (p=0.5) and remission status (p=0.2). No difference was observed in the types of novel therapies received prior to transplant (p=0.2), except 22% of the patients received lenalidomide in LD-CY vs. 40% in the ID-CY group (p=0.04). Compared to LD-CY, ID-CY use was associated with higher median peak PB CD34+ cell count (35/ul vs. 160/ul, p<0.001), CD34+ yield on day 1 of collection (2.6 ×106/kg vs. 11.6 ×106/kg, p=<0.001), total CD34+ cell yield (7.7 ×106/kg vs. 24.9 ×106/kg, p=<0.001), and a trend towards fewer apheresis sessions (p=0.052). Three patients in the LD-CY group had mobilization failure, while no patient in the ID-CY group had mobilization failure. Significantly higher proportion of patients (27% vs. 3.6%, p=<0.001) were unable to collect >5×106/kg CD34+ cells in LD-CY group. Neutrophil engraftment was significantly faster (15.4 days vs. 9.9 days) in the ID-CY patients, likely because of higher infused CD34+ cell dose. Conclusion: In conclusion, compared with LD-CY, ID-CY produced a more robust PBPC mobilization, in all parameters analyzed. These data caution against the use of LD-CY containing mobilization strategy in MM patients undergoing stem cell collection following novel induction regimens. Disclosures: No relevant conflicts of interest to declare.

Abstract The hypomethylating agent decitabine inhibits DNA methyltransferase (DNMT) enzymatic activity and is approved by the FDA for treatment of myelodysplastic syndromes. We previously performed a phase I trial in AML of decitabine (with or without the histone deacetylase inhibitor valproic acid); the trial was designed to establish a biologically effective dose (BED) of decitabine based on drug-induced re-expression of methylated and silenced genes. With the derived BED of 20mg/m2/day given for 10 days, every 4 weeks, clinical activity was observed in previously untreated older AML patients (pts, CR in 4/12); clinical response correlated with gene re-expression (Blum, JCO 2007). The addition of tolerable doses of valproic acid did not appear to improve clinical results or increase gene re-expression compared to decitabine alone. Therefore, we designed a phase II study of single agent decitabine for previously untreated AML pts of age≥60 who were not candidates for intensive chemotherapy (or who refused it). Performance status was ECOG &lt;3. All pts received induction with decitabine at 20mg/m2 IV over 1 hour on days 1–10 of a 28 day cycle. The schedule for subsequent cycles was customized for each patient based on clinical response and/or toxicity (e.g., myelosuppression). Pts with persistent AML at the end of a cycle received a repeat of the 10 day treatment. In contrast, pts with &lt;5% blasts received decitabine as consolidation for only 5 days/cycle (every 4 weeks for 1 year). For CR/CRi patients, the decitabine schedule could be reduced further to 4 or 3 days/cycle for Grade 4 neutropenia lasting more than 2 weeks, if applicable. 33 pts were enrolled; accrual was completed in 13 months. Pts had a median age of 74 years (range, 60–83); 24 pts were age≥70. 18 pts had de novo AML; 15 had secondary or t-AML. Pts had a median presenting white blood cell count of 2,400/uL (range, 400–58,800/uL) with median marrow blasts of 44% (range, 21–92%). 13 pts had complex karyotype (≥3 abnormalities); 12 had normal karyotype; one patient had t(8;21), and the rest had other abnormalities (with one unknown). This was a high risk group by any comorbidity measure. Scoring was as follows on four high-risk factors of age ≥70, antecedent hematologic disorder, unfavorable karyotype, and ECOG 2: 16 pts had 3+ risk factors; 15 had two, and the other 2 pts had one risk factor. Using the transplant comorbidity index for older AML pts (HCT-CI; Giles, BJH 2007), pts had scores of 3+ (N=18), 1–2 (N=10), or 0 (N=5). The median number of cycles received to date is 3 (range, 1–10); 17 pts continue to receive study therapy. 10 pts have received 4+ cycles. Of the first 22 consecutive pts enrolled, 11 achieved CR (50%); 4 more have achieved CRi by IWG criteria for response (Cheson, JCO 2003). 11 pts are &lt;3 months since entry onto the study, with response evaluations ongoing. The response rate was similar between cytogenetic risk subgroups and in both de novo and secondary AML. 4 pts who achieved CR subsequently relapsed, with CR duration of 9, 6, 6, or 2 months, respectively. The other CR pts have maintained ongoing responses for 2–11+ months. 9/11 pts who achieved CR required only 1 cycle of induction therapy (10 day course) before initial response was achieved (CR, N=2; CRi, N=7). For pts who had CRi as initial response, the median number of additional cycles to achievement of full CR was 1 (range, 1–3). In this high risk group, death within 8 weeks of any cause occurred in 4 pts and was related to infection in each case. Though therapy was often administered in the outpatient clinic, febrile neutropenia and infections in the setting of drug and/or disease-related myelosuppression requiring hospitalization during the induction courses were frequent, occurring in nearly all pts. Post-CR therapy, however, was very well tolerated with no hospitalizations for complications during consolidation courses. In conclusion, decitabine in this novel schedule of induction with outcome-adapted modification of consolidation therapy was highly active and well tolerated by most in this poor risk cohort of older AML pts. Clinical results compare favorably to those seen in this population with low dose clofarabine (Erba, ASCO 2008a) or decitabine-5 day schedule (Cashen, ASH 2006a). Correlative studies including re-expression of epigenetically silenced genes, target gene promoter methylation, and global DNA methylation are ongoing.

Abstract Abstract 3731 Both T cell and natural killer (NK) cell reconstitution have been shown to affect clinical outcomes after hematopoietic stem cell transplantation (HSCT). Killer immunoglobulin-like receptor (KIR) interactions between alloreactive NK cells and their targets can prevent relapse, but may be dysregulated, especially after T cell replete HSCT. T cell recovery is also affected by the stem cell source and T cell content of the graft. To better understand the effects of various NK and T cell subsets we evaluated lymphocyte recovery in 304 adult patients who received either UCB (n=116), Sib (n=84) or Auto (n=94) HSCT for hematologic malignancies between 2003 and 2010 at the University of Minnesota. Peripheral blood mononuclear cells obtained at 3 months after HSCT were stained with CD56, CD3, CD4, CD8, and a cocktail of anti-NK cell KIR antibodies to determine the relative percentage of lymphocyte subsets by flow cytometry. The absolute lymphocyte count (ALC) was measured and used to calculate the absolute (Abs) number of T and NK cells and their subsets. ALC recovery at 3 months was similar among groups (UCB: 901.9 ± 74.5, Sib 890.2 ± 73.0 and Auto 1076.7± 69.4 cells/ul). Abs NK cells were highest in the UCB cohort (375.4 ± 24.9) vs. Sib (183.8 ± 15.4; p<0.0001) or Auto (160.7 ± 11.0; p<0.0001), as were the CD56bright and KIR+ subsets (data not shown). In contrast, Abs T cell recovery was lowest in the UCB group (300.8 ± 39.6) vs. Sib (578.5 ± 57.9; p<0.0001) or Auto (737.3 ± 60.4; p<0.0001). Accordingly, the lowest Abs CD4 count was in the UCB group (158.8 ± 14.7) vs. Sib (272.5 ± 23.5; p<0.0001) or Auto (223.6 ± 20.2; p=0.01), with a similar pattern observed for Abs CD8 counts. We then examined the effect of lymphocyte recovery on clinical outcomes. Multivariate models were constructed for each transplant group with relevant covariates (risk status, conditioning, sex, age, number of UCB units, CMV status, HLA matching (4/6, 5/6, or 6/6), and ABO matching). The most significant effect of lymphocyte recovery on outcomes was observed specifically in the UCB group, where higher ALC was associated with improved OS with a hazard ratio (HR) of 0.86 (95% CI 0.78–0.95) for each unit increase in ALC of 100 cells/ul (p <0.01). A similar trend was observed in Sib recipients but not in the Auto group. Specifically, increases in Abs T cells (HR 0.75 [95% CI 0.58–0.98]; p=0.034), Abs CD4 count (HR 0.63 [95% CI 0.42–0.95]; p=0.03), Abs CD8 count (HR 0.31 [95% CI 0.13–0.73]; p=0.01) and to a lesser extent Abs NK cells (HR 0.85 [95% CI 0.71–1.02]; p=0.085) were associated with improved OS. In the Sib cohort, higher Abs CD4 count was associated with improved OS (HR 0.43 [95% CI 0.20–0.92]; p=0.03) and decreased relapse (HR 0.37 [95% CI 0.37–1.00]; p=0.02), with no other factor having a significant impact. In the Auto group, only Abs NK (HR 0.40 [95% CI 0.16–0.99]; p=0.05) and to a lesser extent Abs KIR+ NK cells (HR 0.17 [95% CI 0.02–1.36]; p=0.09) were associated with improved OS but no other outcomes. The effect of Abs CD4 count on OS in all groups is shown in Figure 1 with survival stratified by quartiles. Figure 1: Figure 1:. In summary, rapid recovery of T cells predicts significantly better survival in patients undergoing UCB and Sib HSCT, while the NK cell effects are less pronounced. In contrast, NK cell effects predominate after Auto HCT. This suggests that more rapid T cell recovery is critical for survival and that defects in NK cell education after allogeneic HSCT may affect their function such that just increasing numbers may not be sufficient for clinical benefit. Appropriate modifications to immune suppression or the use of agents that promote T cell (IL-7) and/or NK cell (IL-15) function and survival may positively influence survival outcomes. Disclosures: No relevant conflicts of interest to declare.

Abstract Background For decades, cytogenetic analysis has played an essential role in AML risk stratification. Among the 50% of AML patients (pts) with normal karyotype (NK), outcome can vary widely. More recently, whole genome sequencing (WGS) and whole exome sequencing (WES) have identified several recurrent mutations that play an important role in AML pathogenesis and impact outcome. Pts with secondary AML (sAML) have a particularly poor prognosis, are not as responsive to standard induction chemotherapy, and often are referred in first complete remission to hematopoietic stem cell transplantation. We hypothesized that different genomic patterns exist between primary AML (pAML) and sAML that can distinguish the two, and can alter treatment recommendations. To negate the impact of chromosomal abnormalities, we focused our analyses on pts with NK. Methods We performed WES and multi-amplicon targeted deep sequencing on samples from bone marrow and peripheral blood of pts diagnosed with sAML at our institution between 1/2003- 1/2013 and who had NK cytogenetics. We compared them to pts with NK primary AML (pAML) whose data were extracted from The Cancer Genome Atlas (TCGA). A panel of 62 gene mutations that has been described as recurrent mutations in myeloid malignancies was included. Mutations were considered individually and grouped based on their functional pathways: RNA splicing (SF3B1, U2AF1/2, SRSF2, ZRSR2), DNA methylation (TET2, DNMT3A, IDH1/2), chromatin modification (ASXL1, EZH2, MLL, SUZ12, KDM6A), transcription (RUNX1, CEBPA, NPM1, BCOR/BCORL1, SETBP1, ETV6), activating signaling (FLT3, JAK2), cohesion (STAG2, SMC3, RAD21), RAS superfamily (K/NRAS, NF1, PTPN11, CBL) and tumor suppressor genes (TP53, APC, WT1, PHF6). Using deep sequencing methodology for resequencing or targeted sequencing, variant allelic frequency (VAF) was measured for each mutation detected. VAF was adjusted by zygosity evaluated by SNP-array karyotyping. For confirmation of clonal architecture, serial sample sequencing and single colony PCR were applied. Differences were compared using Fisher-exact test and Mann-Whitney U test for categorical and continues variables respectively. Results: Of 143 pts included, 101 (71%) had pAML and 42 (29%) had sAML. Compared to pAML, sAML pts were older (59 vs 69 years, p <.001), and had lower white blood cell count (28 vs 3.5 X 109/L, p <.001). Median hemoglobin (10 vs 10) g/dl and platelet counts (57 vs 60) k/uL were similar between the two groups. With a median follow up of 26.4 months (mo, range, .93-95.4), median OS was shorter for sAML than for pAML (12.9 vs 16.2 mo, p= .03). Overall, the most common mutations were: NPM1 (35%), DNMT3A (27%), FLT3 (25%), RUNX1 (14%), IDH1 (12%), IDH2 (12%), STAG2 (12%), TET2 (11%), NRAS (8%), ASXL1 (8%), U2AF1 (8%), PTPN11 (7%), WT1 (6%), BCOR (5%), and PHF6 (5%). Mutations in SF3B1, U2AF1/2, BCOR/BCORL1, ETV6, ASXL1, JAK2, STAG2, and APC were more common in sAML compared to pAML, whereas mutations in DNMT3A, NPM1, CEBPA, and FLT3 were more common in pAML. Mutations in activated pathways in splicing machinery, transcription, chromatin modification, cohesion and RAS pathway were more prominent in sAML, while mutations in DNA methylation and signaling pathways occurred more frequently in pAML. Serial sample analyses at multiple time points demonstrated intra-tumor heterogeneity in most cases of sAML, which was supported by additional cross sectional analyses of VAF in multiple gene mutations in each case. These findings prompted us to evaluate secondary events in the cohort of pts whose sAML originated from an initial MDS stage, defined by ancestral mutations. Among genes frequently affected by mutations, TET2 and ASXL1 were identified as founder events, whereas STAG2, NRAS and PTPN11 were observed in subclonal sAML derived from founder MDS clones. In pAML, however, TET2 and ASXL1 mutations were found to be secondary lesions, while IDH1 and DNMT3A were identified as ancestral events. Conclusion Clear genomic variations exist between sAML and pAML that suggest differences in the pathophysiology of both diseases. Specific therapies should be directed to the activated pathways according to the unique clonal hierarchy in each AML subtype. Disclosures No relevant conflicts of interest to declare.

Abstract Background: Pulmonary function is particularly susceptible to acute and chronic injury occurring in patients with sickle cell anemia (SCA). Acute Chest Syndrome (ACS), a common and potentially fatal complication of SCA, can be the cause or the consequence of abnormal pulmonary function (Siddiqui & Ahmed, 2003). Use of hydroxyurea therapy (HU) is increasing for children with recurrent pulmonary complications, following the findings that HU reduces risk of ACS in adults (Charache et al, 1995). How HU may improve pulmonary function in children with SCA is still ill-defined. The purpose of this study was to assess the change observed on serial pulmonary function tests (PFT) for children prescribed HU for abnormal pulmonary function. Methods: Over 240 children with pulmonary complications, such as acute chest syndrome, reactive airway disease, and chronic hypoxia, have been evaluated in the Sickle Cell Pulmonary Clinic at Children’s Healthcare of Atlanta since beginning in July 2000. As part of the Clinic’s standard of care, PFT were routinely attempted on children over the age of 5. A retrospective review of PFT results was done for the children with SCA and prior abnormal PFT. Children were included in the HU cohort (+HU) if repeat PFTs were available following &gt; 3 months on HU therapy and if time on HU did not include frequent RBC transfusions. Children without history of HU therapy (−HU) were selected for comparison. PFTs were performed on a standard plethysmograph. Paired t-test was used to evaluate observed differences. Results: Thirty-one children with prior abnormal PFT had test before and following prescription of HU. Their mean age was 12.6 (range 6–20) years and mean duration of HU was 21 (range 4–47) months at the time of the repeat PFT. Hematologic changes expected on HU occurred for all 31 children. Twenty-four children followed for abnormal PFT had no history of HU (−HU) and matched the +HU group by gender, age (mean 12.3, range 7–19 years), duration followed at time of repeat PFT (mean 19, range 3–66 months; p=0.36), and initial hematologic parameters. Spirometry findings changed for +HU group, and remained stable for −HU group. Mean FVC and FEV1 values improved significantly on HU, when compared to initial (PreHU) PFT and to −HU controls. Conversion to a normal PFT, as interpreted by a pediatric pulmonologist masked to treatment status, occurred in 18 (58%) and 2 (8%) children in the +HU and −HU groups, respectively. Table 1: Serial PFT and hematologic parameters according to HU exposure −HU (n=24) +HU (n=31) Initial Repeat # PreHU Repeat 1 % predicted value for age, sex and height of subject. 2Mean (SD) #No significant changes compared to Initial, p &gt; 0.05. *P value &lt; 0.001 compared to PreHU; ++P value &lt; 0.001 compared to −HU repeat. PFT parameter 1 TLC 88 (13.6)2 85 (11.7) 85 (13.4) 90 (13.5) FVC 78 (9.8) 79 (9.9) 75 (12.6) 90 (13.2)*,++ FEV1 75 (9.6) 74 (12.2) 72 (11.4) 86 (10.2)*,++ FEF 25-75 75 (22) 72 (28.0) 77 (23.4) 79 (26.8) FEV1/FVC (%) 85(6.7) 82 (9.8) 87 (11.8) 86 (11.1) Pulse oximetry (%) 95 (3.1) 96 (2.4) 94 (4.4) 97 (2.8)* WBC (x103/ul) 14 (3.8) 13 (2.9) 13.02 (2.9) 9.0 (2.1) *,++ Hb (g/dl) 8.0 (0.1) 8.0 (0.9) 7.8 (1.1) 9.1 (1.3) *,++ MCV (fl) 84 (9.2) 85 (10.0) 87.3 (8.1) 101.2 (10.1) *,++ HbF (%) 4.3 (1.5) 5.2 (5.2) 6.0 (3.8) 14.0 (7.3) *,++ Conclusions: Serial PFTs showed improved pulmonary function, following initiation of HU therapy in children with prior abnormal PFT. Routine PFT assessments of children prescribed HU may serve as an objective measure of clinical response in children with SCA and pulmonary complications. These results will help in the design of future prospective studies examining the clinical benefits of HU therapy for children at risk for long-term pulmonary complications.

The aim of the study was to evaluated the effect of giving water hyacinth and fish oil in quail diet on the performance, egg cholesterol and egg fatty acid profile. This study used 200 unsex day old quail divided into 5 treatments and 4 replications that were reared 5 weeks and then selected male or female. The results of sexing quail at week 5 were 95 females and 86 males. Growth period diets (0-5 weeks) contains 24% crude protein and metabolic energy of 2900 kcal kg-1 and production period diets (5-12 weeks) contains 22% crude protein and 2900 kcal kg-1. The experimental design used a completely randomized design with the treatment of using water hyacinth that was 0%,1%, 2%, 3 % and 4% with fish oil which was 0%, 4%, 5%, 6% and 7% in quail diet. The variables measured were quail performance (0-5 week age and 5-12 week age), egg cholesterol, and egg fatty acid profile. The results showed that using of water hyacinth meal 1% -4% and fish oil 4%-5% in the diet of the growth period resulted in higher feed consumption and body weight gain than diet without water hyacinth and fish oil but feed conversion rasio were same. Quail performance of the production period was not affected by all treatments. Unsaturated fatty acids tend to increased in quail eggs. The lowest cholesterol level of quail eggs was by giving 2% of water hyacinth meal and 5% of fish oil in the diet. It was concluded that water hyacinth can be used as local feed ingredients in quail diet until 4%. Key words: Coturnix coturnix japonica, egg cholesterol, egg fatty acid profile, performance, production DAFTAR PUSTAKA Aboul-Enein AM, Al-Abd A, Shalaby EA, Abul-Ela F, Nasr-Allah AA & Mahmoud AM. 2011. Eichornia crassipes (MarT) solm. Plant Signal Behaviour. 6(6): 834-836 Afrose S, Hossain MS & Tsuji H. 2010. Effect of dietary karaya saponin on serum and egg yolk cholesterol in laying hens. British Poultry Science. 51 (6) : 797-804 Adeyemi OA, Adekoya JA & Abayomi R. 2012. Performance of broiler chickens fed diets containing cassave leaf: blood meal mix as replacement for soybean meal. Revista Cientifica UDO Agricola. 12 (1): 212-219 Aziz Z, Cyriac S, Beena V & Philomina PT. 2012.Comparison of cholesterol content in chicken, duck and quail eggs. Journal Veterinary Animal Science. 43: 64-66 Bragagnolo N & Rodriguez-Amaya DB. 2003. Comparison of the cholesterol content of Brazilian chicken and quail eggs. Journal of food Composition and Analysis. 16(2): 147-153 Chimote MJ, Barmase BS, Raut AS, Dhok AP & Kuralkar SV.2009. Effect of supplementation of probiotic and enzymes on performance of Japanese quails. Veterinary World. 2 (6): 219-220 Damongilala LJ. 2008. Kandungan asam lemak tak jenuh minyak hati ikan cucut botol (Cenctrophorus sp) yang diekstraksi dengan cara pemanasan. Jurnal Ilmiah Sains. 8(2): 249-253 Grigorova S, Nikolova M, Penkov D & Gerzilov V. 2014. Egg yolk lipid change in Japanese given Tribulus terrestris extract. Bulgarian Journal of Agricultural Science. 20 (6) : 1472-1476 Guclu BK, Uyanik F & Iscan KM. 2008. Effect of dietary oil sources on egg quality, fatty acid composition of eggs and blood lipids in laying quail. South American Journal of Animal Science. 38 (2): 91-100 Hartoyo B, Irawan I & Iriyanti N. 2005. Pengaruh asam lemak dan kadar serat kasar yang berbeda dalam ransum broiler terhadap kandungan kolesterol, HDL dan LDL serum darah. Animal Production. 7(1):27-33. Hemid, AEA, El-Gawad AAH, El-Wardany I, El-Daly EF & El-Azeem NAA. 2010. Alleviating effect of some environmental stress factors on productive performance in Japanese quail 2.Laying performance. World Journal of Agricultural Science. 6(5): 517-524 Hilmi M, Sumiati & Astuti DA.2015. Egg production and physical quality in Coturnix coturnix japonica fed diet containing piperine as phytogenic feed additive. Media Peternakan. 38(3): 150-155 Kamely M, Torshizi MAK & Khosravinia H. 2016. Omega 3 enrichment of quail eggs: age, fish oil, and savory essensial oil. Journal of Agricultural Science and Technology. 18 (2): 347-359 Khairani, Sumiati & Wiryawan KG. 2016. Egg production and quality of quails fed diets with varying levels of methionine and choline chloride. Media Peternakan. 39 (1): 34-39 Kurniawan M, Izzati M & Nurchayati Y. 2010. Kandungan klorofil, karotenoid, dan vitamin C pada beberapa spesies tumbuhan akuatik. Buletin Anatomi dan Fisiologi. 18(1):28-40 Leeson S & Summers JD. 2005. Commercial Poultry Nutrition. Third Edition. Canada (CA): Nottingham University Pr. LiYX, Wang YQ, Pang YZ, Li JX, Xie XH, Guo TJ & Li WQ. 2011. The effect of crude protein level in diets on laying performance, nutrien digestibility of yellow quails. International Journal of Poultry Science. 10(2): 110-112 Malik AA, Aremu A, Ayanwale BA & Ijaiya. AT 2016. A Nutritional evaluation of water hyacinth (Eichhornia crassipes. Martius Solms-laubach) meal diets supplemented with Maxigrain* Enzyme for growing pulllets. Journal of Raw Material Research Nigeria. 10(2): 18-44 Mahmood M, Sial AR, Saima, Akram M, Pasha TN & Jabbar MA. 2014. Effect of dietary energy levels on growth performance and feed cost analysis in Japanese quail. Pakistan Journal of Zoology. 45(5): 1357-1362 Mangisah I, Tristiarti, Murningsih W, Nasoetion MH, Jayanti ES & Astuti Y. 2006. Kecernaan nutrien eceng gondok yang difermentasi dengan Aspergillus niger pada ayam broiler. Journal of Indonesian Tropical Animal Agricultural. 31 (2): 124-128 Maulana IT, Sukraso & Damayanti S. 2014 .Kandungan asam lemak dalam minyak ikan Indonesia. Jurnal Ilmu dan Teknologi Kelautan Tropis. 6(1): 121-130 Metwally AA, El-Gellal AM & El-Sawaisi SM. 2009). Effect of silymarin on lipid metabolism in rat. World Applied Sciences Journal. 6 (12): 1634-1637 Mona MH, Morsy AS & Hasan AM. 2013. Egg yolk cholesterol and productive performance of laying hens influenced by dietary crude fiber levels under drinking natural salin water. Journal of Animal and Poultry Production. 4(3): 161-176 Muhammad M, Peter S, James G & Wosilat A. 2015. Growth performance of growing quails (Coturnix japonica) fed graded levels of Neem. International Journal of Applied Research. 1(2): 04-07 NRC.1994. Nutrient Requirement of Poultry. 9th Edition. Wahington D.C (US): National Academy Odo BI & Nnadi AE. 2014. Growth response of quails (Coturnix coturnix japonica) to varying levels of cassava (Manihot esculenta) tuber meal as a replacement for maize (Zea mays). American Journal of Experimental Agricultural. 4(12): 1898-1903 Riswandi. 2014. Kualitas silase eceng gondok (Eichhornia crassipes) dengan penambahan dedak halus dan ubi kayu. Jurnal Peternakan Sriwijaya. 3(1): 1-6 Rusmana,D. 2007. Pengaruh substitusi minyak sawit oleh minyak ikan lemuru dan suplementasi vitamin E dalam ransum ayam broiler terhadap performans. Jurnal Ilmu Ternak. 7(2): 101-106 Saha S. & Ray AK. 2011. Evaluation of nutritive value of water hyacinth (Eichhornia crassipes) leaf meal in compound diets for rohu Labeo rohita (Hamilton, 1822) fingerlings after fermentation with two bacterial strains isolated from fish gut. Turkish Journal of Fisheries and Aquatic Science. 11: 199-207 Sastrodihardjo S, Suci DM & Cahyanto MN. 1998. Penggunaan Minyak Ikan Lemuru dan Minyak Kelapa Sawit dalam ransum terhadap Kandungan Asam lemak Omega 3 dan Omega 6 dalam Kuning Telur Ayam. Bogor (ID): Seminar Nasional Peternakan dan Veteriner. Penelitian dan Pengembangan Pertanian Savory CJ & Gentle MJ. 1976. Changes in food intake and gut size in Japanese quail in response to manipulation of dietary fibre content. British Poultry Science. 17(6): 571-580 Sotolu AO & Sule SO. 2011. Digestibility and performance of water hyacinth meal in the diets of African catfish (Clarias gariepinus BURCHELL, 1822). Tropical and Subtropical Agroecosystem. 14: 245-250 Sim JS, Kitts WD & Bragg DB. 1984. Effect of dietary saponin on egg cholesterol level and laying hen performance. Canadian Journal of Animal Science. 64: 97-98 Tyagi T & Agarwal M. 2017. Antioxidant properties and phenolic compound in methanolic extracts of Eichornia crassipes. Reserarch journal of Phytochemistry. 11(2): 85-89. Tolik D, Polawska E, Charuta A, Nowaczewski S & Cooper R. 2014.Characteristics of egg parts, chemical composition and nutritive value of Japanese quail eggs-a review. Folia Biological (Krakow). 62 (4): 287-292 Tunsaringkarn T, Tungjaroenchai W & Siriwong W. 2013. Nutrient benefits of quail (Coturnix coturnix japonica) eggs. International Journal of Scientific and Research Publications. 3(5): 1-8

The aim of the study was to evaluated the effect of giving water hyacinth and fish oil in quail diet on the performance, egg cholesterol and egg fatty acid profile. This study used 200 unsex day old quail divided into 5 treatments and 4 replications that were reared 5 weeks and then selected male or female. The results of sexing quail at week 5 were 95 females and 86 males. Growth period diets (0-5 weeks) contains 24% crude protein and metabolic energy of 2900 kcal kg-1 and production period diets (5-12 weeks) contains 22% crude protein and 2900 kcal kg-1. The experimental design used a completely randomized design with the treatment of using water hyacinth that was 0%,1%, 2%, 3 % and 4% with fish oil which was 0%, 4%, 5%, 6% and 7% in quail diet. The variables measured were quail performance (0-5 week age and 5-12 week age), egg cholesterol, and egg fatty acid profile. The results showed that using of water hyacinth meal 1% -4% and fish oil 4%-5% in the diet of the growth period resulted in higher feed consumption and body weight gain than diet without water hyacinth and fish oil but feed conversion rasio were same. Quail performance of the production period was not affected by all treatments. Unsaturated fatty acids tend to increased in quail eggs. The lowest cholesterol level of quail eggs was by giving 2% of water hyacinth meal and 5% of fish oil in the diet. It was concluded that water hyacinth can be used as local feed ingredients in quail diet until 4%. Key words: Coturnix coturnix japonica, egg cholesterol, egg fatty acid profile, performance, production DAFTAR PUSTAKA Aboul-Enein AM, Al-Abd A, Shalaby EA, Abul-Ela F, Nasr-Allah AA & Mahmoud AM. 2011. Eichornia crassipes (MarT) solm. Plant Signal Behaviour. 6(6): 834-836 Afrose S, Hossain MS & Tsuji H. 2010. Effect of dietary karaya saponin on serum and egg yolk cholesterol in laying hens. British Poultry Science. 51 (6) : 797-804 Adeyemi OA, Adekoya JA & Abayomi R. 2012. Performance of broiler chickens fed diets containing cassave leaf: blood meal mix as replacement for soybean meal. Revista Cientifica UDO Agricola. 12 (1): 212-219 Aziz Z, Cyriac S, Beena V & Philomina PT. 2012.Comparison of cholesterol content in chicken, duck and quail eggs. Journal Veterinary Animal Science. 43: 64-66 Bragagnolo N & Rodriguez-Amaya DB. 2003. Comparison of the cholesterol content of Brazilian chicken and quail eggs. Journal of food Composition and Analysis. 16(2): 147-153 Chimote MJ, Barmase BS, Raut AS, Dhok AP & Kuralkar SV.2009. Effect of supplementation of probiotic and enzymes on performance of Japanese quails. Veterinary World. 2 (6): 219-220 Damongilala LJ. 2008. Kandungan asam lemak tak jenuh minyak hati ikan cucut botol (Cenctrophorus sp) yang diekstraksi dengan cara pemanasan. Jurnal Ilmiah Sains. 8(2): 249-253 Grigorova S, Nikolova M, Penkov D & Gerzilov V. 2014. Egg yolk lipid change in Japanese given Tribulus terrestris extract. Bulgarian Journal of Agricultural Science. 20 (6) : 1472-1476 Guclu BK, Uyanik F & Iscan KM. 2008. Effect of dietary oil sources on egg quality, fatty acid composition of eggs and blood lipids in laying quail. South American Journal of Animal Science. 38 (2): 91-100 Hartoyo B, Irawan I & Iriyanti N. 2005. Pengaruh asam lemak dan kadar serat kasar yang berbeda dalam ransum broiler terhadap kandungan kolesterol, HDL dan LDL serum darah. Animal Production. 7(1):27-33. Hemid, AEA, El-Gawad AAH, El-Wardany I, El-Daly EF & El-Azeem NAA. 2010. Alleviating effect of some environmental stress factors on productive performance in Japanese quail 2.Laying performance. World Journal of Agricultural Science. 6(5): 517-524 Hilmi M, Sumiati & Astuti DA.2015. Egg production and physical quality in Coturnix coturnix japonica fed diet containing piperine as phytogenic feed additive. Media Peternakan. 38(3): 150-155 Kamely M, Torshizi MAK & Khosravinia H. 2016. Omega 3 enrichment of quail eggs: age, fish oil, and savory essensial oil. Journal of Agricultural Science and Technology. 18 (2): 347-359 Khairani, Sumiati & Wiryawan KG. 2016. Egg production and quality of quails fed diets with varying levels of methionine and choline chloride. Media Peternakan. 39 (1): 34-39 Kurniawan M, Izzati M & Nurchayati Y. 2010. Kandungan klorofil, karotenoid, dan vitamin C pada beberapa spesies tumbuhan akuatik. Buletin Anatomi dan Fisiologi. 18(1):28-40 Leeson S & Summers JD. 2005. Commercial Poultry Nutrition. Third Edition. Canada (CA): Nottingham University Pr. LiYX, Wang YQ, Pang YZ, Li JX, Xie XH, Guo TJ & Li WQ. 2011. The effect of crude protein level in diets on laying performance, nutrien digestibility of yellow quails. International Journal of Poultry Science. 10(2): 110-112 Malik AA, Aremu A, Ayanwale BA & Ijaiya. AT 2016. A Nutritional evaluation of water hyacinth (Eichhornia crassipes. Martius Solms-laubach) meal diets supplemented with Maxigrain* Enzyme for growing pulllets. Journal of Raw Material Research Nigeria. 10(2): 18-44 Mahmood M, Sial AR, Saima, Akram M, Pasha TN & Jabbar MA. 2014. Effect of dietary energy levels on growth performance and feed cost analysis in Japanese quail. Pakistan Journal of Zoology. 45(5): 1357-1362 Mangisah I, Tristiarti, Murningsih W, Nasoetion MH, Jayanti ES & Astuti Y. 2006. Kecernaan nutrien eceng gondok yang difermentasi dengan Aspergillus niger pada ayam broiler. Journal of Indonesian Tropical Animal Agricultural. 31 (2): 124-128 Maulana IT, Sukraso & Damayanti S. 2014 .Kandungan asam lemak dalam minyak ikan Indonesia. Jurnal Ilmu dan Teknologi Kelautan Tropis. 6(1): 121-130 Metwally AA, El-Gellal AM & El-Sawaisi SM. 2009). Effect of silymarin on lipid metabolism in rat. World Applied Sciences Journal. 6 (12): 1634-1637 Mona MH, Morsy AS & Hasan AM. 2013. Egg yolk cholesterol and productive performance of laying hens influenced by dietary crude fiber levels under drinking natural salin water. Journal of Animal and Poultry Production. 4(3): 161-176 Muhammad M, Peter S, James G & Wosilat A. 2015. Growth performance of growing quails (Coturnix japonica) fed graded levels of Neem. International Journal of Applied Research. 1(2): 04-07 NRC.1994. Nutrient Requirement of Poultry. 9th Edition. Wahington D.C (US): National Academy Odo BI & Nnadi AE. 2014. Growth response of quails (Coturnix coturnix japonica) to varying levels of cassava (Manihot esculenta) tuber meal as a replacement for maize (Zea mays). American Journal of Experimental Agricultural. 4(12): 1898-1903 Riswandi. 2014. Kualitas silase eceng gondok (Eichhornia crassipes) dengan penambahan dedak halus dan ubi kayu. Jurnal Peternakan Sriwijaya. 3(1): 1-6 Rusmana,D. 2007. Pengaruh substitusi minyak sawit oleh minyak ikan lemuru dan suplementasi vitamin E dalam ransum ayam broiler terhadap performans. Jurnal Ilmu Ternak. 7(2): 101-106 Saha S. & Ray AK. 2011. Evaluation of nutritive value of water hyacinth (Eichhornia crassipes) leaf meal in compound diets for rohu Labeo rohita (Hamilton, 1822) fingerlings after fermentation with two bacterial strains isolated from fish gut. Turkish Journal of Fisheries and Aquatic Science. 11: 199-207 Sastrodihardjo S, Suci DM & Cahyanto MN. 1998. Penggunaan Minyak Ikan Lemuru dan Minyak Kelapa Sawit dalam ransum terhadap Kandungan Asam lemak Omega 3 dan Omega 6 dalam Kuning Telur Ayam. Bogor (ID): Seminar Nasional Peternakan dan Veteriner. Penelitian dan Pengembangan Pertanian Savory CJ & Gentle MJ. 1976. Changes in food intake and gut size in Japanese quail in response to manipulation of dietary fibre content. British Poultry Science. 17(6): 571-580 Sotolu AO & Sule SO. 2011. Digestibility and performance of water hyacinth meal in the diets of African catfish (Clarias gariepinus BURCHELL, 1822). Tropical and Subtropical Agroecosystem. 14: 245-250 Sim JS, Kitts WD & Bragg DB. 1984. Effect of dietary saponin on egg cholesterol level and laying hen performance. Canadian Journal of Animal Science. 64: 97-98 Tyagi T & Agarwal M. 2017. Antioxidant properties and phenolic compound in methanolic extracts of Eichornia crassipes. Reserarch journal of Phytochemistry. 11(2): 85-89. Tolik D, Polawska E, Charuta A, Nowaczewski S & Cooper R. 2014.Characteristics of egg parts, chemical composition and nutritive value of Japanese quail eggs-a review. Folia Biological (Krakow). 62 (4): 287-292 Tunsaringkarn T, Tungjaroenchai W & Siriwong W. 2013. Nutrient benefits of quail (Coturnix coturnix japonica) eggs. International Journal of Scientific and Research Publications. 3(5): 1-8

PRIKAZI – REVIEWS Geoadria, vol. 8/1, 161-166, 2003. IZVJEŠĆA SA ZNANSTVENIH SKUPOVA - CONFERENCE REPORTS 3rd International Conference CLIMATE CHANGES: THE KARST RECORDS III, 11.-15. svibnja 2003., Montpellier, Francuska Od 11. do 15. svibnja 2003. u Montpellieru (Francuska) održana je treća međunarodna konferencija Climate Changes: The Karst Records III. Prvi ovakav skup održan je 1996. u Bergenu (Norveška), sljedeći 2000. u Krakowu (Poljska), nakon čega je zbog pojačanog interesa za ovu tematiku, a time i veće znanstvene produkcije, dogovoreno da se konferencija održava svaku treću godinu. Nakon Franuske (2003.), za domaćina konferencije 2006. godine predložena je Rumunjska. Ovaj skup okupio je znanstvenike iz 27 država sa 6 kontinenata koji su kroz 62 usmena izlaganja i 37 postera prezentirali svoja recentna znanstvena dostignuća iz područja paleoklimatologije temeljena na istraživanju krša, točnije speleoloških objekata i njihovih akumulacijskih oblika – siga. Sige, prepoznate kao medij koji zbog zaštićenosti i stabilnih mikroklimatskih uvjeta vrlo dobro "pamti" klimatska stanja šireg okoliša za vrijeme taloženja (a osim toga su i puno dostupnije od jezgri dubokomorskih bušotina i polarnih ledenih pokrova), zadnjih su desetljeća u središtu znanstvenog interesa različitih znanstvenih disciplina. Stoga su i teme radova bile doista raznolike; najveći je dio radova obuhvaćao paleoklimatske varijacije utvrđene na temelju omjera stabilnih izotopa siga iz gotovo svih klimatskih područja, te njihovo datiranje različitim metodama. Sige kao objekt istraživanja bile su obrađene i vezano uz petrografska svojstva, fluidne inkluzije, luminiscenciju, sezonske varijacije intenziteta taloženja itd., dok se kod speleoloških objekata proučavao stupanj okršavanja, utjecaj tektonike, špiljski sedimenti kao i paleontološki i arheološki nalazi. Dio radova obuhvaćao je rezultate monitoringa trenutnog stanja špilja, hidrologije, geokemije, atmosferskih uvjeta itd., a bilo je riječi i o promjenama morske razine kao posljedici klimatskih fluktuacija tijekom geološke prošlosti.Osim već tiskane knjige izvadaka u pripremi je i zbornik, dok se u međuvremenu kvalitetniji radovi recenzirani tiskaju u respektabilnom časopisu Francuskoga geološkog društva Bulletin de la Société Géologique de France.A gdje je Hrvatska, zemlja "klasičnog krša", u svemu tome? Država s 46% nacionalnog teritorija prekrivenog kršem (26000 km2) i još mnogo više pod morem, bila je zastupljena samo s jednim (1) radom – zapaženim, ali gotovo "pionirskim" u odnosu na radove sofisticiranih laboratorija i instituta zapadnih zemalja. Rad Isotope records in submarine speleothems from the Adriatic Coast, Croatia, autora Maše Surić, Nade Horvatinčić, Axela Suckowa, Mladena Juračića i Jadranke Barešić, analizira paleoklimatske promjene na istočnoj obali Jadrana koje su kroz omjere stabilnih izotopa kisika i ugljika ostale zabilježene u danas potopljenim sigama. Terenski dio konferencije obuhvatio je posjet mjestu Saint-Guilhem-le-Désert (tradicionalnoj postaji hodočasnika na putu prema svetištu Santiago de Compostella), te špiljskom sustavu Grotte de Clamouse, ukupne dužine oko 4 km od čega je 1965. gotovo 1 km uređen za turističke posjete. Osim impozantnih primjeraka špiljskog nakita, čija je raznolikost posljedica izmjena kalcitnih, aragonitnih i dolomitnih karakteristika nadsloja, ovaj objekt može biti i primjer kako se prekrasan špiljski prostor može upropastiti prilagođivanjem turističkim posjetima brojnim metalnim, staklenim i električnim instalacijama. Na trenutke posjetitelj može dobiti dojam da se kreće kroz muzej ili zbirku, a ne kroz više od stotinu metara dubok speleološki objekt. Dojam dodatno pojačava i ambiciozno zamišljen, ali kičasto izveden sound & light show. Obične turiste može fascinirati, ali istinske prirodnjake, zaljubljenike u krš – jedino ogorčiti. U svakom slučaju, terenski dio skupa i ovaj put bio je iskorišten za stvaranje novih i obnavljanje starih poznanstava koja će rezultirati međunarodnom znanstvenom suradnjom, posebno kad su u kombinaciji oprema i financije bogatijih zemalja i neistražena područja "onih drugih" zemalja. Ostaje nada da će takvim oblikom suradnje, na sljedećoj konferenciji Climate Changes: The Karst Records IV, Hrvatska biti malo bolje predstavljena svojim prirodnim i ljudskim potencijalima. Maša Surić 161 PRIKAZI - REVIEWS Geoadria, vol. 8/1, 161-166, 2003. PRIKAZI Atlas svijeta za 21. stoljeća, urednik: M. Lapaine i suradnici, Naklada Fran, Zagreb, 2003., 751 str. Nakladnik Fran iz Zagreba objavio je hrvatsko izdanje atlasa The 21 st Century World Atlas, koji je izvorno publicirao izdavač Trident Press International. Hrvatsko izdanje uredio je M. Lapaine sa suradnicima. Atlas nije tek hrvatski prijevod izvornika jer su pojedini stručnjaci dopunili i izmijenili neke sadržaje, a osim toga, S. Frangeš preveo je velik broj toponima na hrvatski jezik. Prijevodi su ispisani uz gornji rub karte kako se ne bi mijenjao izvorni jezik karata (engleski). Atlas je podijeljen u deset glavnih cjelina: Geopolitički okvir, Klimatologija, geologija i biogeografija, Demografija i socijalni pokazatelji , Osnovne ekonomske djelatnosti, Industrija, trgovina i promet, Afrika, Amerika, Azija, Europa i Oceanija. Na kraju je dodan rječnik osnovnih geografskih pojmova s odgovarajućim prijevodima (npr. perz. Kavir = solna pustinja) i kazalo s preko 60 000 geografskih imena. U općegeografskom dijelu atlasa na brojnim tematskim kartama zorno je prikazana prostorna raspodjela različitih prirodnih i socio-ekonomskih pojava i procesa. Iscrpnost kartografskih prikaza može se uočiti na primjeru poglavlja Socijalni i ekonomski pokazatelji, u kojemu su objavljene sljedeć i tematski zemljovidi: Potrošnja kalorija, Donacije hrane, Proizvodnja hrane, Smrtnost dojenčadi, Zdravstvena zaštita, Bolnička infrastruktura, Telefoni, Potrošnja energije, Pismenost, Izdavanje knjiga, Tiskanje novina, Broj upisa u školu, Omjer đaka i nastavnika u osnovnim školama, Znanstvenici i tehničari, Ekonomski aktivno stanovništvo, Dječja radna snaga, Struktura ekonomski aktivnog stanovništva, Ekonomska aktivnost, Ekonomska aktivnost žena, Ekonomska aktivnost muškaraca, Nezaposlenost, Bruto nacionalni dohodak, Bruto nacionalni dohodak po osobi, Struktura bruto nacionalnog dohotka, Inflacija, Ekonomski rast, Inozemni dug, Sredstva potrošena na obrazovanje, Sredstva potrošena na zdravstvenu zaštitu, Vojni izdaci, Izvoz i uvoz oružja, Trgovinska razmjena oružja i Logistika nuklearnog oružja. Kartogrami i kartodijagrami su jasni, pregledni i informativni.Kartografsko -geografski pregled po kontinentima ima jedinstvenu shemu. Ponajprije se nižu satelitske snimke, a potom digitalni modeli reljefa kopna i podmorja, geografske karte i kratki, ali sadržajni prikazi pojedinih zemalja. Na geografskim kartama kontinenata sitnim su slovima ispisani brojni toponimi. Njihova je čitljivost, na žalost, mala na prikazima planinskih predjela, koji su označeni nijansama sme đe i plavo-ljubičaste boje. Korisnik može doznati osnovne geografske informacije o svakoj državi putem kratkog geografskog uvodnika, zemljovida i različitih dijagrama.U hrvatskom izdanju atlasa svijeta mogao bi se očekivati iscrpniji prikaz Hrvatske. Priređivači nisu htjeli odstupati od izvornika, ali u reprintu zemljovida mogla se obratiti pozornost na pogrešno ispisane toponime (npr. naselje Sali na Dugom otoku ucrtano je u uvali Telašćica, Golfo di Venezia neobično se proteže duž zapadne obale Istre, naveden je stari naziv Požege – Slavonska Požega i sl.) . Međutim, navedene pogrješke ne umanjuju vrijednost atlasa, koji doista čini izvrstan kompendij najnovijih znanstvenih spoznaja o državama svijeta i Zemlji u cjelini, pa ga zbog toga rado preporučujem. Josip Faričić Nikola STRAŽIČIĆ: Svi hrvatski otoci, Descriptio Croatiae, Hrvatska revija, časopis Matice hrvatske, godište 1/2001., broj 3-4, Zagreb, 77-103. Hrvatska obala je najrazvedenija na Jadranskom moru, jer obuhvaća 97,2% jadranskog arhipelaga. S ponosom se ističe da je Hrvatska "zemlja tisuću otoka". Stvarni broj je i ve ći. Na pitanje koliko ih je unutar granica suvremene Hrvatske najmjerodavniji odgovor dao je prof. dr. sc. Nikola Stražičić. 162 PRIKAZI - REVIEWS Geoadria, vol. 8/1, 161-166, 2003. U uvodu se razmatraju podatci o ukupnom broju hrvatskih otoka kritički prema pojedinim autorima. U nastavku izložene su teškoće oko kategorizacije osnovnih pojmova "otok" - "otočić" - "greben" i "hrid". Posebno je zanimljiv dio članka u kojem su opisani i predočeni "zaboravljeni" - "novi" i nekadašnji otoci. U timskom radu autora iz Hidrografskog instituta Republike Hrvatske u Splitu (2000.) navodi se, na temelju topografskih karata u razmjeru 1:25000, da unutar granica Hrvatske postoje 79 otoka, 526 otočića i 641 grebena i hridi; ukupno 1246 otoka.Prof. Stražičić upozorio je kritič ki i dokumentirano na manjkavost dosadašnjih rezultata i naglasio da je ukupan broj hrvatskih otoka i dalje otvoren. U zaklju čnim razmišljanjima dao je niz svrhovitih prijedloga. Ponajprije predlaže, uz potporu državnih službi, imenovanje interdisciplinarne ekipe (od geografa, hidrogeologa, oceanografa, kartografa, lingvista i drugih specijalnosti) koja bi odredila kriterije za kategorizaciju pojedinih otoka, prema veličini i nazivu, te za određivanje kategorija naseljenosti. Nadalje, kako nazvati najmanji oblik stalno nad razinom mora "greben" ili "hrid", o tome posavjetovati se s lingvistima, ali i sa stanovništvom dotičnog otoka. Problem se javlja i kod napučenosti otoka, primjerice "stalno naseljen", da li prema domaćem (autohtonom) ili doseljenom stanovništvu, kako razlikovati pojmove "sezonski naseljen" i "povremeno naseljen"...Na kraju, uz pomoć lučkih kapetanija njihovim plovilima potrebno je obići i snimiti sve otoke unutar granica Hrvatske, istodobno provjeriti stanje na topografskim i posebice pomorskim kartama i planovima. Prof. Stražičić je otočanin, rođen na Mljetu, a čitav radni vijek proveo je u Rijeci. Najveći dio svoga života posvetio je istraživanju mora u najširem smislu, posebice Jadrana i nadasve naših hrvatskih otoka. Godine 1968. izradio je magistarsku tezu Otok Mljet – primjer izoliranog otoka. Deset godina kasnije (1978.) obranio je disertaciju Otok Cres – prilog poznavanju geografije naših otoka. Za sveukupan životni opus godine 1998. Senat Sveuč ilišta u Rijeci dodijelio mu je počasno zvanje "profesor emeritus". prof. Stražičić prvi je geograf u Hrvatskoj koji je dobio to visoko priznanje. U reprezentativnoj Hrvatskoj reviji s novim glavnim urednikom, ambicioznim magistrom Mladenom Klemenčić em, izašao mu je i najnoviji rad Svi hrvatski otoci ilustriran s 27 jedinstvenih panoramskih snimaka u boji. Članak Svi hrvatski otoci sinteza je dugogodišnjih minucioznih istraživanja u kojima je prof. Stražičić, na sebi svojstven na čin, prenio jezgrovito, veliko i bogato iskustvo, istodobno i poruka, kako bi trebalo nastaviti s interdisciplinarnim istraživanjima tih dragulja na pročelju Hrvatske i u trećem mileniju.Josip Riđanović Tihomir KOVAČEVIĆ Tihi: Baraćeve špilje, Turistička zajednica općine Rakovica, Rakovica, 2003., 48 str. Baraćevim špiljama pripada počasno mjesto u povijesti istraživanja hrvatskog krša i speleologiji. Davne godine 1892. u Rakovici je osnovan "Odbor za istraživanje i uređenje Baraćevih špilja", prva takva udruga na tlu Hrvatske i u ovom dijelu svijeta. Od prvih podataka objavljenih u literaturi 1874. do danas špilje su više puta bile predmetom speleoloških, hidrogeoloških, paleonotoloških, arheoloških i biospeleoloških istraživanja. Na temelju njihovih rezultata i rezultata najnovijih istraživanja nastala je i ova knjiga u kojoj nam autor otkriva njezine ljepote i tajne.Knjigu čini 8 poglavlja. Zanimljiv tekst bogato je ilustriran sa 65 fotografija, crteža i nacrta špilja. Opisan je položaj špilja, osnovni podatci o geološkim značajkama terena, nazivlje i podatci o dimenzijama različitih istraživača. Slijedi poglavlje o povijesti istraživanja s nizom zanimljivih podataka – od prvih opisa do suvremenih istraživanja. Opći dio zaokružen je poglavljem o paleontološkim i arheološkim istraživanjima. Dosad su nađeni ostatci pleistocenske faune i tragovi boravka ljudi iz srednjeg vijeka i razdoblja turskih ratova. 163 PRIKAZI - REVIEWS Geoadria, vol. 8/1, 161-166, 2003. U drugom dijelu knjige detaljno su opisane značajke Donje, Gornje i Nove Baraćeve špilje. Opisan im je položaj, a u iznošenju značajki autor se poslužio citatima Dragutina Hirca i Ivana Krajača s početka 20. stoljeć a. Navedeni su i najnoviji rezultati istraživanja prema kojima je Donja Baraćeva špilja dugačka 565 metara, Gornja 520 metara, a Nova 94,5 metara. Poglavlje o biospeleologiji napisao je dipl. ing. Roman Ozimec. Objavio je dosad poznate podatke o povijesti biospeleoloških istraživanja, podatke o ekološkim uvjetima, pregled i analizu špiljske faune te istaknuo važnost nastavka istraživanja i zaštite. Poglavlje je opremljeno odličnim fotografijama te tablicama s kronologijom biospeleoloških istraživanja, preliminarnim taksonomskim popisom kavernikolnih vrsta i biospeleološkom bibliografijom špilja. Završno poglavlje posvećeno je rezultatima Međunarodne speleološke ekspedicije "Rakovica 2002.". Na samom početku ekspedicije otvoren je Prvi speleološki dom Republike Hrvatske u Novoj Kršlji. Tijekom ekspedicije istraživani su sustav Panjkov ponor - Varićakova špilja, vrelo Sinjac i Kusa i dr. Na kraju knjige objavljena je speleološka bibliografija koja dodatno pridonosi vrijednosti ove knjige. Nenad Buzjak Milenko M. PASINOVIĆ: Područ je Kotora na listi svjetske i prirodne baštine UNESCO. "Cicero" – Cetinje, kompjutorska priprema "Tricen", Kotor, 2001., 110 str. Autor je rođeni Bokelj, redoviti sveučilišni profesor na Fakultetu za turizam i hoteljerstvo u Kotoru. Knjižica je praktičnog formata (23x15 cm), otisnuta je na kvalitetnom papiru. Opremljena je s 14 reprezentativnih fotosa u boji i 7 crno-bijelih slika i crteža. Upotrijebljeno je 20 bibliografskih jedinica literature i 4 izvora podataka uključujući i vlastita istraživanja. Kratak izvadak dat je na engleskom, talijanskom, francuskom i njemačkom jeziku.Poslije predgovora slijede u tekstu: Boka kotorska (prikaz granica, prostorni pojam i pregled glavnih dijelova, Morfogenetske i morfološke karakteristike, Kotorsko-Risanski zaliv – embrion Boke kotorske, Područje Kotora na listi svjetske prirodne baštine UNESCO, Simbioza prirode i čovjeka stara pet milenijuma i Dvije decenije nakon zemljotresa.Bokokotorski zaljevi duboko su oko 30 km (29,6) uvučeni na sjeveru između Orjena (1893 m), najviše obalne planine u istočnoj regiji Jadrana, Katunskog krša (1308 m, 1228 m i 1212 m) na istoku i Lovćenu (Štirovnik, 1749 m) na jugu. Impozantan okvir krševitih planina s izrazitim strmcima zatvara plitko more (površine 87,3 km2 i dubine do 60 m), u stvarnosti čudesan i jedinstven sklop Bokokotorskih zaljeva. Boka kotorska je horizontalno najrazvedeniji kraj (105,7 km duljina obale) i vertikalno najraščlanjeniji dio u najvišoj reljefnoj strukturi Jadranskog primorja. Geografski položaj Boke je specifičan. Na njezinu prostoru dodiruje se prirodno visoki i najljući krš izravno s najdubljim dijelom morske pučine Jadrana. Društveno, povijesno i gospodarski u Boki se isprepliću utjecaji milenijskog stvaralaštva Mediterana, posebice u gradskoj arhitekturi, s tradicionalnim i suvremenim kulturama Istoka. Boka kotorska je izraziti primjer jedinstva suprotnosti. Pri određ ivanju prostornog pojma Boke logič ki je kriterij "slijevno područ je" tj. prostor odakle voda teče prema zaljevima odnosno prema moru. "Slijevno područje" odre đuje se razvodnicom. U vododrživim stijenama to je površinska ili topografska razvodnica, koja se povlači najvišim vrhovima na terenu. U karbonatnim stijenama na kojima je razvijen krški reljef, što se pretežno odnosi na prostor Boke kotorske, mjerodavna je dubinska ili hidrogeološka razvodnica. Preuzeti brojčani podatci o veličini slijevnog područja na osnovi površinske (topografske) razvodnice za Boku kotorsku ne odgovaraju stvarnosti. O postanku Boke kotorske Pasinović iznosi kritički i potanko gledanja ranijih autora. Znakovito, me đutim, ističe sadašnji izgled zaljeva, koji je relativno mlad i posljedica je izdizanja razine mora u holocensko doba. Navodi činjenice da je prije 25 tisuća godina razina Jadrana bila niža za 96,4 m od sadašnjeg. Boka je tada bila kopno. Na Orjenu i Lovčenu snježna granica spuštala 164 PRIKAZI - REVIEWS Geoadria, vol. 8/1, 161-166, 2003. se do visine 600 m odnosno 900 m. Dno Boke kotorske u to vrijeme karakterizirala su izolirana udubljenja prekrivena rastresitim materijalom. Dokazano je da je prije 10 tisuća godina razina Jadranskog mora bila niža za 31 m od današnjega. Tada se već počeo nazirati složeni izgled današnjih zaljeva Boke kotorske. Batimetrijska istraživanja u najnovijem razdoblju potvrđuju postojanje izdvojenih krških udubljenja na morskom dnu, posebice na lokalitetu Verige, gdje je maksimalna dubina od 45 m veća za 4 m i u kumburskom suženju od 50 m veća, najveća dubina 5 m od okolnog dna mora.U najvećem dijelu zaljeva žalo je ograničeno na uski pojas ili ga uopć e nema (Risan – Perast i Orahovac). Na tom potezu obalni strmci spuštaju se izravno ispod mora do njegova dna. Prosje čna dubina mora u Boki je 27,6 m. Srednje dubine u pojedinim zaljevima iznose u Kotorskom 27 m, Risanskom 25,7 m, Tivatskom 25,5 m i Toplanskom 31 m. Opća značajka batometrije svih zaljeva Boke kotorske je da su male dubine. Posebna je zanimljivost horizontalne razvedenosti Boke kotorske 7 otoka. To su u Kotorskom zaljevu ispred Perasta Sveti Đorđe (Juraj) i umjetni otok Gospa od Škrpjela. U Tivatskom zaljevu: Stradioti (Sveti Marko), otok Gospe od Milosrđa i Prevlaka (otok cvijeća). U Toplanskom zaljevu su otok Lastvica (Mamula) i otok Mala Gospa (Gospa od Žanjice).Boka sa svojim zaleđem prima najveć e količ ine padalina u Europi. Crkvice, mjerna stanica u Malovom dolu na 1050 m nadmorske visine u Krivošijama na Orjenu, zabilježila je količinu od 5317 mm i to tijekom mokrog dijela godine! Boka je najvećim dijelom u stijenama karbonatnog sastava, koje dosežu dubinu i do 5 km! Na toj podlozi razvijen je najizrazitiji krški reljef, kako na površini, tako još više u podzemlju, odnosno u podmorju. Tu je najveće izvorište vode istodobno i najsušniji kraj u istočnoj regiji Jadrana. Prema podatcima skupa stručnjaka za opskrbu vodom 1986. godine u Risnu s navedenog prostora u sušnim mjesecima godine svake sekunde dotječe u more oko 1000 litara vode od koje se tek 220 litara (22%) iskoristi za pitku vodu! Zaključeno je, da Boka spada u "najžednije" krajeve u Europi! Hidrografske karakteristike Boke kotorske u skladu su s prevladavajućim litološkim značajkama karbonatnih stijena, geološkom građom i hidrogeološkom funkcijom terena. Od hidro-pojava najviše su rašireni izvori, vrulje, povremene tekućice i jedna katavotra (Gurdić). Katavotra je specifični izvor, zapravo otvor kroz koji poslije dugotrajnih kiša izbija na površinu slatka voda, a u doba hidrološkog minimuma tim istim otvorom voda ponire u dublje dijelove podmorja. Ukratko su opisani i predočeni izvori Ljute u Dobroti, Sopota i Spile kod Risna, Morinjske rijeke, koja odvodnjava zapadne i jugozapadne strane Orjena, te Gurdić i Škurda kod Kotora. Škurda je svojevrsna hidrografska specifičnost Boke kotorske. To je krška rječica. Izvori su joj na Lovćenu, a odvodnjava Njeguško polje. Škurda je usjekla korito kanjonskog tipa u masivnim i dobro uslojenim vapnencima lovćenskog strmca. Vodostaj Škurde ovisan je od količine i duljine trajanja kiše. Bez obzira na godišnje doba, poslije izdašnijih kiša teče Škurda čitavom duljinom toka kao bujica. Na ušću je nataložila obilje šljunčanih nanosa u obliku manje delte zvane Benovo. U blizini mora Škurda se račva u dva rukava. Jednim rukavom otječe sjevernom stranom gradskih zidina. To je kotorska Škurda, obično stalan tok, jer ga napajaju izvori iz vlastitog korita. Drugim rukavom teče dobrotska Škurda jedino poslije dužih kiša. S izvora Škurde opskrbljuje se ponajprije i ponajviše gradski vodovod u Kotoru. Poslije potresa 1979. pokušalo se ugradnjom betonske zavjese izolirati utjecaj mora. U ljetnim mjesecima ponovno je zaslanila voda. Škurda je tipična krška tekućica podložna naglim i znatnim promjenama. U zadnje vrijeme znalo se dogoditi da na njezinom izvorištu potpuno nestane vode čak u trajanju jednoga dana! Boka kotorska svojim smještajem je u geotektonski vrlo labilnom kraju, štoviše, u pojasu razornih potresa. Značajniji potresi u južnom Jadranu jezgrovito su opisani. O katastrofalnom potresu 15. travnja 1979. dat je iscrpan prikaz. U općini Kotor na spomenicima kulture procijenjena je golema šteta u visini od 18.658,930 USA dolara!Područje Kotora na listi prirodne i kulturne baštine UNESCO najopsežniji i najzanimljiviji je dio sveukupnog teksta. Autor nas potanko i dokumentirano upoznaje s brojnim postupcima koji su prethodili upisu Kotora na listu svjetske prirodne i kulturne baštine UNESCO. 165 PRIKAZI - REVIEWS Geoadria, vol. 8/1, 161-166, 2003. Odluka je usvojena na Skupštini op ćine Kotor, 14. lipnja 1979. i glasi: "Ovom odlukom kao prirodno, kulturno i istorijsko dobro od posebnog zna čenja, proglašava se Kotor s područjem: Dobrote, Orahovca, Perasta, Risna, Morinja, Kostanjice, Stoliva, Prčanja, Mula, Škaljara i morskog bazena ovog područja, koje obuhvaća 12000 ha kopna i 2600 ha mora." Katastrofalni potres 15. travnja 1979. pospješio je prijam Kotora za upis u svjetsku prirodnu i kulturnu baštinu UNESCO, štoviše i za kulturnu baštinu u opasnosti. Prijedlog je prihvaćen na sjednici Međunarodnog komiteta od 22. do 26. listopada 1979. u Kairu i Luksoru. Također, u Berlinu 10. ožujka 1997. Boka kotorska uvrštena je među 28 najljepših zaljeva na svijetu. Prema podatcima Regionalnog zavoda za zaštitu spomenika kulture u općini Kotor izvršena je kategorizacija od prvog do trećeg stupnja za 104 spomenika kulture. Zanimljivo je da je 12 spomenika uvršteno u prvu, najvišu kategoriju spomeničkog blaga. Simbioza prirode i čovjeka u Boki kotorskoj stara je pet milenija. Prvi tragovi ljudskog postojanja, oko 3000 godina prije Krista, iz mlađeg kamenog doba, otkriveni su na lokalitetu Spila, 300 m nad morem, sjeveroistočno od Perasta.Na obali Risanskog zaljeva, točnije u mjestu Lipci, pronađeni su na svodu otisci između kojih se posebno ističe brod na jedra. To potvrđuje rani početak pomorstva u Boki kotorskoj. Najstariji ostatci likovnog izražavanja tadašnjih stanovnika datirani su u rano brončano doba.Prof. Pasinović je geograf društveno-gospodarskog usmjerenja s posebnim interesom za pomorstvo i turizam. Poslije obranjene disertacije "Pomorstvo i turizam s posebnim osvrtom na crnogorsko primorje" (1977.) i nakon objavljivanja reprezentativnog vodiča: Kotor – vjekovi sačuvani za budućnost" (1988.) poklonio je javnosti i najnovije djelo "Područje Kotora na listi svjetske prirodne i kulturne baštine UNESCO". Prof. Pasinović je jedan od osnivača Fakulteta za turizam i hotelijerstvo u Kotoru i najzaslužniji je što je ta visokoškolska, sveučilišna institucija ostala u Kotoru. Svojim je radom i organizacijskim sposobnostima znač ajno pridonio da se Kotor upiše u listu svjetske prirodne i kulturne baštine UNESCO. Sada se zalaže da se to priznanje mjerodavnih stručnjaka zapamti i blago sačuva za mlađi naraštaj. Čestitamo profesoru Pasinoviću i želimo mu puno daljnjih uspjeha. Josip Riđanović 166

Abstract Introduction: Osteoporosis is a major public health problem, increasing in incidence with the growth of the aging population. It affects over 200 million women worldwide and is associated with fragility fractures leading to increased morbidity, mortality and poor quality of life (1). Bisphosphonates are among the most widely used first line forms of treatment for management of osteoporosis. They have a structure like pyrophosphate and inhibit bone resorption by attaching to hydroxyapatite binding sites on the bone in areas with active resorption. While initiating treatment with bisphosphonates, endocrinologists generally discuss side effects including gastrointestinal symptoms related to gastroesophageal reflux disease and gastritis, acute phase reactions related to infusion of the bisphosphonates, musculoskeletal pain, hypocalcemia, osteonecrosis of the jaw, and atypical femur fractures. There are rare but severe side effects causing ocular inflammation related to bisphosphonate use - Bisphosphonate Related Ocular Inflammation (BROI). While these are rare based on few case reports, they are significant side effects, which if patients are not aware of or not addressed in timely manner can result in vision loss. We report a clinical scenario of a patient who experienced bisphosphonate-related ocular inflammation. Clinical History: 62-year-old female with cerebral palsy presented to the emergency room with 1 day of marked left eye redness and swelling. When the symptoms began, she felt that her eye was itchy. She had mild left eye discomfort. She did not perceive any decreased visual acuity. Patient had her first infusion of bisphosphonate, 4 days prior to the emergency room visit. On Exam: She was alert, no apparent distress, left eyelids were swollen, almost completely shut with minimal discoloration, there was underlying severe chemosis and conjunctival redness, pupils equal and round, visual acuity 20/100 OD and 20/100 OS. She was diagnosed with allergic conjunctivitis, and advised to apply Tobradex drops and Diphenhydramine, and to follow-up in eye clinic. Scleritis related to bisphosphonates was also considered as a possible cause of her symptoms. The patient called the endocrinologist about the eye symptoms the following day. The endocrinologist also raised the possibility bisphosphonate related ocular inflammation and advised to be seen in ophthalmology clinic urgently. The endocrinologist also communicated with the ophthalmologist indicating that her eye symptoms could be due to inflammatory response related to bisphosphonates and to consider starting systemic steroids. The patient was seen in ophthalmology clinic the following day: The ophthalmology exam revealed severe orbital inflammation with conjunctival chemosis OS: Table 1.She was started on Prednisone 80mg a day with tapering by 10mg daily over the next 2 weeks. She was also advised to apply Durezol eye drops twice a day. She was referred to Oculoplastics for further evaluation. Table 1: Oculoplastics evaluation next day Table 2: Revealed orbital inflammation with good initial response to steroids and advised to continue prednisone taper. Table 2: On the 2 weeks follow up: Table 3: Resolved orbital inflammation and was advised to stop prednisone Table 3: Clinical Discussion: Bisphosphonates are widely prescribed and effective forms of treatment for osteoporosis in preventing fractures. Ocular side effects are rare but reported over the past 2 decades (2). First time users of bisphosphonates are at a higher risk compared with nonusers (3).There is also an association of bisphosphonate-related ocular inflammation (BROI) with coexisting inflammatory conditions that associated with ocular inflammation, such as rheumatoid arthritis, ankylosing spondylitis, psoriasis, inflammatory bowel disease, systemic lupus erythematosus or sarcoidosis (4,8).Symptoms related to BROI typically occur within 24 to 72 hours of the bisphosphonate exposure but can range between few hours to 3 years. Those who receive systemic bisphosphonates present earlier compared to orally administered bisphosphonates (5,6,7). In prior case reports, patients presented with flu like symptoms, lasting for lasting for 24 to 72h prior to onset of orbital disease (5). The range of ocular inflammation is variable, and can include conjunctivitis, uveitis, scleritis, episcleritis and keratitis. The symptoms can be unilateral or bilateral. Discontinuation of bisphosphonates is necessary for resolution of ocular inflammation (7).The postulated cellular mechanism causing BROI is as follows: Bisphosphonates are secreted into the lacrimal system, and induce an inflammatory response resulting in release of cytokines that results in ocular inflammation: Fig 1: (9). Fig 1: It is unclear as to why BROI is a rare side effect, though related to release of inflammatory reactants, which are also responsible for the more common flu like side effect. The risk of BROI is increased in those with associated inflammatory condition (arthritis or inflammatory bowel disease). It is possible that in individuals susceptible to inflammatory disorders, there is pre-existing infiltration of the lacrimal gland with mononuclear cells which causes a robust local inflammatory response to bisphosphonate treatment in the eye. Our patient with cerebral palsy and learning disability, was taken to the emergency room within few hours of onset symptoms and signs of ocular inflammation. Though she was diagnosed with severe orbital inflammation, she did not express eye pain, which is commonly seen in scleritis. Through multidisciplinary teamwork between the emergency physician, endocrinologist, ophthalmologist and oculoplastic specialists, she was promptly started on systemic steroids and her symptoms resolved completely with no vision loss. While considering bisphosphonates as an option for osteoporosis treatment, the endocrinologist should discuss the rare but serious complications of BROI. With use of bisphosphonates in the aging population to treat osteoporosis, specific attention should be given to underlying eye disease, inflammatory conditions, and cognition. References: 1. IOF statistics: (https://www.iofbonehealth.org/epidemiology). 2. Clark EM, Durup D. Inflammatory eye reactions with bisphosphonates and other osteoporosis medications: what are the risks?. Ther Adv Musculoskelet Dis. 2015;7(1):11–16. doi:10.1177/1759720X145664243. Etminan M, Forooghian F, Maberley D. Inflammatory ocular adverse events with the use of oral bisphosphonates: a retrospective cohort study. CMAJ. 2012;184(8):E431–E434. doi:10.1503/cmaj.1117524.French DD1, Margo CE. Postmarketing surveillance rates of uveitis and scleritis with bisphosphonates among a national veteran cohort. Retina. 2008 Jun;28(6):889-93. doi: 10.1097/IAE.0b013e31816576ef. 5.Herrera I, Kam Y, Whittaker TJ, Champion M, Ajlan RS. Bisphosphonate-induced orbital inflammation in a patient on chronic immunosuppressive therapy. BMC Ophthalmol. 2019;19(1):51. Published 2019 Feb 14. doi:10.1186/s12886-019-1063-8 6. Ehsan Rahimy, Simon K. Law. Orbital inflammation after zoledronate infusion: an emerging complication.https://doi.org/10.1016/j.jcjo.2012.09.011 7. Frederick W. Fraunfelder, M.D Bisphosphonates and Ocular Inflammation. NEngJ Med 2003; 348:1187-1188. DOI: 10.1056/NEJM200303203481225 8.Pazianas M1, Clark EM, Eiken PA, Brixen K, Abrahamsen B. Inflammatory eye reactions in patients treated with bisphosphonates and other osteoporosis medications: cohort analysis using a national prescription database. J Bone Miner Res. 2013 Mar;28(3):455-63. doi: 10.1002/jbmr.1783.9.Keith Thompson and Michael J. Rogers. New Insights into Old Drugs. BoneKEy-Osteovision. 2006 August;3(8):5-13

Abstract: Establishing a process of interpreting the high-resolution seismic profile according to a sedimentary geological point of view is a very urgent task. The explanation process can be divided into the following steps: (1) Boundary demarcation of sequences based on unconformable surfaces showing signs of erosion of the river bed; (2) Analysis of lithofacies and lithofacies association according to time and to space in relation to global sea level change; (3) Demarcation of systems tract: low stand systems tract (LST), Transgressive systems tract (TST) and Highstand systems tract (HST). On that basis, Tran Nghi (2012) established an integrated general formula between lithofacies and systems tract: (1) Li LST = arLST + amrLST; (2) LiTST = atTST + amtTST + mtTST; (3) LiHST = ahHST + amhTST Where, Li - Lithofacies; ar - Alluvial facies of lowstand systems tract; at - Alluvial facies of transgressive systems tract; ah - Deltaic facies of lowstand systems tract; amr - Deltaic facies of highstand systems tract; amt- Coastal facies of transgressive systems tract; mt - Shallow sea facies of maximum transgressive systems tract; The results have determined the exact location of the ancient river channels and their’s change history in the shallow coastal area of ​​the Red River Delta. Before 1787, the ancient Red River channel had the largest scale flowing to the sea through Ha Lan mouth (T22-1), while the river channel flowing into Ba Lat mouth was only a tributary of the Red River (T12). The seismic section of line T22-1 (Ha Lan mouth) allows the determination of the ancient Red River channel and line T12 (Ba Lat mouth) has identified the tributary channel of the Red River. The boundary between lithofacies complexes in vertical seismic section (bottom up) is determined as follows: arLSTQ13b à atTSTQ21 à amt1TSTQ21-2 à amt2TSTQ21-2 à mtTSTQ22 à amhHSTQ23. Keywords: Lithofacies, lithfacies association, seismic wave field, systems tract, transgressive alluvial lithofacies (atTST). References: [1] Trần Nghi, Ngô Quang Toàn, Đặc điểm các chu kỳ trầm tích và lịch sử tiến hóa địa chất Đệ tứ đồng bằng Sông Hồng, Tạp chí địa chất số 206-207, (1991) 65-69. http://www.idm.gov.vn/ nguon_luc /Xuat_ban/1991/a2069.htm[2] Trần Nghi, Trầm tích học (tái bản), Nhà xuất bản Đại học Quốc gia Hà Nội, Hà Nội, 2012.[3] Trần Nghi, Trần Thị Thanh Nhàn, Trần Ngọc Diễn, Đinh Xuân Thành, Trần Thị Dung, Nguyễn Thị Phương Thảo, Trần Xuân Trường, Đỗ Mạnh Tuân, Diễn biến bồi tụ - xói lở bờ biển Thái Bình-Nam Định từ Holocen muộn đến nay trong mối quan hệ với tiến hóa các thùy châu thổ và lịch sử sông Sò, Tạp chí Khoa học, ĐHQGHN (2018). https://doi.org/10.25073/2588-1094/vnuees.4346[4] Trần Nghi, Nguyễn Thị Tuyến, Đinh Xuân Thành, Nguyễn Đình Nguyên, Trần Thị Thanh Nhàn, Nguyễn Đình Thái, Nguyễn Thị Huyền Trang, Lê Viết Chuẩn, Nguyễn Hoàng Long, Đặc điểm tướng đá – cổ địa lý Pleistocen muộn – Holocen khu vực cửa sông Ba Lạt, Tạp chí Khoa học và Công nghệ Biển; Tập 17, Số 1 (2017) 23-34. DOI: 10.15625/ 1859-3097/17/1/8476[5] Trần Nghi, Nguyễn Thị Tuyến, Đinh Xuân Thành, Nguyễn Đình Nguyên, Trần Thị Thanh Nhàn, Nguyễn Đình Thái, Nguyễn Thị Huyền Trang. Đường bờ cổ và ranh giới chéo các miền hệ thống trầm tích Pleistocen muộn - Holocen khu vực Bắc bộ và Bắc trung bộ. Tạp chí Địa chất, loạt A, số 358, 9-10 (2016) 1-13.[6] Vũ Cao Minh, Nguyễn Khắc Nghĩa, Nguyễn Huy Thịnh, Biến động cửa Ba Lạt, cửa Hà Lạn trong thời kỳ cận đại và ảnh hưởng của chúng tới diễn biến bồi tụ xói lở khu vực Hải Hậu - Nam Định. Tạp chí KH&CN Thủy lợi Viện KHTLVN (2006) 32 - 41.[7] Doãn Đình Lâm, Tiến hóa trầm tích Holocen châu thổ Sông Hồng, Luận án tiến sĩ địa chất, ĐHQGHN, 2003.[8] Tran Nghi, Mai Trong Nhuan, Chu Van Ngoi, Nguyen Van Dai, Dinh Dinh Xuan Thanh, Nguyen Dinh Nguyen, Nguyen Thanh Lan, Dam Quang Minh and Ngo Quang Toan, GIS and image analysis to study the process of late Holocene sedimentary evolution in Balat River Mouth, Vietnam, Geoinformatics, vol. 14, no. 1 (2003) 43-48. https://www.jstage.jst.go.jp/article/geoinformatics /14/1/14_1_43/_pdf[9] Tran Nghi, Mai Trong Nhuan, Chu Van Ngoi, P. Hoekstra, Utrecht, TJ. Van Weering, J.H. Van Denbergh, Dinh Xuan Thanh, Nguyen Dinh Nguyen, Vu Van Phai, Holocene sedimentary evolution, geodynamic and anthropogenic control of the Balat river mouth formation (Red River-delta, northern Vietnam), Z. geol. Wiss., Berlin 30, 3 (2002.) 157 -172.[10] Vũ Quang Lân, Các mặt cắt địa chất chủ yếu của hệ tầng Hải Hưng vùng đồng bằng Sông Hồng. Tạp chí địa chất, số 251 (1999) 9-13.[11] Nguyễn Quang Miên, Lê Khánh Phồn, Some results of C14 dating in investigation on Quaternary geology and geomorphology in Nam Định - Ninh Bình area, Việt Nam. Tạp chí địa chất B/15 (2000) 106-109.[12] Vũ Nhật Thắng, Phạm Đình Xin, Địa chất và Khoáng sản vùng Thái Bình – Nam Định (giới thiệu kết quả đo vẽ BDĐC và TNKS tỉ lệ 1/50.000 nhóm tờ Thái Bình – Nam Định, 1997.[13] Trần Đức Thạnh, Nguyễn Hữu Cử, Nguyễn Đức Cự, và nnk, Tình trạng và nguyên nhân xói lở, bồi tụ ven bờ châu thổ sông Hồng, Tuyển tập Tài nguyên và Môi trường biển. Tập III, Nhà xuất bản khoa học và kỹ thuật.[14] Trần Đức Thạnh, Đinh Văn Huy, Trần Đình Lân, Đặc điểm phát triển của vùng đất bồi ngập triều ven bờ châu thổ Sông Hồng. Tạp chí các Khoa học về Trái đất, số 18-1 (1996) 50-60.[15] Ngô Quang Toàn, Đặc điểm trầm tích và lịch sử phát triển các thành tạo Đệ tứ ở phần đông bắc đồng bằng Sông Hồng, Luận án TS Khoa học Địa lí – Địa chất; Đại học Tổng hợp Hà Nội, 1995.[16] Trần Nghi, Đinh Xuân Thành và nnk, Quá trình tích tụ trầm tích Đệ tứ của đáy Sông Hồng trong mối quan hệ với hoạt động nhân sinh. Tuyển tập báo cáo hội thảo khoa học đánh giá tác động của quá trình xói mòn tại lưu vực Sông Hồng (2000) 124-151.

O objetivo do presente artigo foi relatar uma forma de confecção de prótese total utilizando a clonagem da prótese provisória com a finalidade de reduzir as etapas do tratamento. Paciente desdentada total superior e classe I de Kennedy inferior compareceu ao consultório apresentando inflamação severa do tecido periodontal, mobilidade grau III de todos os dentes e supuração à sondagem. Optou-se por realizar prótese total superior convencional e realização das exodontias dos dentes remanescentes, seguida de prótese total provisória e como tratamento definitivo mandibular uma prótese total convencional. Na primeira sessão foi realizada a reavaliação dos tecidos bucais, moldagem da prótese total superior para obter o modelo antagonista, seleção da cor do dente, registro para montagem no articulador semi-ajustável e a clonagem da prótese total inferior provisória. 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