PS02.244: PEDICLED FLAPS IN ESOPHAGEAL SURGERY: WHERE THORACIC-, PLASTIC- AND ENT- SURGEONS MEET

2018 ◽  
Vol 31 (Supplement_1) ◽  
pp. 191-191
Author(s):  
Elisabeth Gschwandtner ◽  
Jörg Lindenmann ◽  
Nicole Fink-Neuböck ◽  
Melanie Fediuk ◽  
Christian Porubsky ◽  
...  
Keyword(s):  
De Novo ◽  
Conflicts Of Interest ◽  
Anastomotic Stricture ◽  
Multiorgan Failure ◽  
External Irradiation ◽  
Muscle Flaps ◽  
Myocutaneous Flaps ◽  
Pedicled Flaps ◽  
Surgical Closure ◽  
Life Saving

Abstract Background Esophageal, esophago-hypopharyngeal and esophago-tracheobronchial fistulae or strictures arising either de novo or following therapeutic interventions constitute serious therapeutic challenges. If conservative measures fail, pedicled muscular or myocutaneous flaps are life-saving assets. Methods During the last 10 years we treated 13 patients (11 males, 2 females; mean age: 59; range: 44–82y) with complex esophageal/hypopharyngeal problems by using pedicled muscle flaps. Results All had but one case of lye ingestion had underlying malignant disease, all but two of the latter had had chemo- and or radiotherapy. At the time of the intervention eight patients were in a critical, septic condition. There were 5 esophago-tracheal, 2 esophago-bifurcational, one esophago-colo-bronchial, and one hypopharyngo-tracheal fistula, as well as one pharyngo-cutaneous fistula all following resection/reconstruction and/or attempts of surgical closure. One patient had stricture following external irradiation, another one anastomotic stricture. We applied a total of 17 pedicled flaps: 10 pectoralis major flaps (7 of them myocutaneous, three split flaps), 5 deltoideo-pectoral myocutaneous flaps and 2 sternocleidomastoideus flaps. In 11 patients additional intermittent stenting was used. In 6 patients the respective condition healed, 4 patients could be discharged but had minor recurrent fistulae that could be handled conservatively, in three cases persisting sepsis and multiorgan failure could not be overcome. Conclusion Muscle flaps can be life-saving in large fistulae of the esophagus and the hypopharynx and are useful for refractory cervical stenosis. In presence of multiorgan dysfunction, however, healing of flaps however initially vital, is often impaired. Disclosure All authors have declared no conflicts of interest.

scholarly journals De Novo Design of Granulopoietic Proteins

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 34-35
Author(s):  
Julia Skokowa ◽  
Mohammad Elgamacy ◽  
Patrick Müller
Keyword(s):  
Protein Design ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Specific Activity ◽  
Structural Information ◽  
Coiled Coil ◽  
Design Strategies ◽  
Nmr Structure Determination ◽  
Binding Epitope

Protein therapeutics are clinically developed and used as minorly engineered forms of their natural templates. This direct adoption of natural proteins in therapeutic contexts very frequently faces major challenges, including instability, poor solubility, and aggregation, which may result in undesired clinical outcomes. In contrast to classical protein engineering techniques, de novo protein design enables the introduction of radical sequence and structure manipulations, which can be used to address these challenges. In this work, we test the utility of two different design strategies to design novel granulopoietic proteins, using structural information from human granulocyte-colony stimulating factor (hG-CSF) as a template. The two strategies are: (1) An epitope rescaffolding where we migrate a tertiary structural epitope to simpler, idealised, proteins scaffolds (Fig. 1A-C), and (2) a topological refactoring strategy, where we change the protein fold by rearranging connections across the secondary structures and optimised the designed sequence of the new fold (Fig. 1A,D,E). Testing only eight designs, we obtained novel granulopoietic proteins that bind to the G-CSF receptor, have nanomolar activity in cell-based assays, and were highly thermostable and protease-resistant. NMR structure determination showed three designs to match their designed coordinates within less than 2.5 Å. While the designs possessed starkly different sequence and structure from the native G-CSF, they showed very specific activity in differentiating primary human haematopoietic stem cells into fully mature granulocytes. Morever, one design shows significant and specific activity in vivo in zebrafish and mice. These results are prospectively directing us to investigate the role of dimerisation geometry of G-GCSF receptor on activation magnitude and downstream signalling pathways. More broadly, the results also motivate our ongoing work on to design other heamatopoietic agents. In conclusion, our findings highlight the utility of computational protein design as a highly effective and guided means for discovering nover receptor modulators, and to obtain new mechanistic information about the target molecule. Figure 1. Two different strategies to generate superfolding G-CSF designs. (A) X-ray structure of G-CSF (orange) bound to its cognate receptor (red) through its binding epitope (blue). According to the epitope rescaffolding strategy, (B) the critical binding epitope residues were disembodied and used as a geometric search query against the entire Protein Data Bank (PDB) to retrieve structurally compatible scaffolds. The top six compatible scaffolds structures are shown in cartoon representation. (C) The top two templates chosen for sequence design, were a de novo designed coiled-coil and a four-helix bundle with unknown function. The binding epitopes were grafted, and the scaffolds were optimised to rigidly host the guest epitope. (D-E) According to the topological refactoring strategy (D) the topology of the native G-CSF was rewired from around the fixed binding epitope, and then was further mutated to idealise the core residues (blue volume (E)) and residues distal from the binding epitope (orange crust (E)). Both strategies aimed at simplifying the topology, reducing the size, and rigidifying the bound epitope conformation through alternate means. Figure 1 Disclosures No relevant conflicts of interest to declare.

scholarly journals Hemagglutinin-Dependent Tropism of H5N1 Avian Influenza Virus for Human Endothelial Cells

2009 ◽  
Vol 83 (24) ◽  
pp. 12947-12955 ◽  
Author(s):  
Manuela Ocaña-Macchi ◽  
Michael Bel ◽  
Laurence Guzylack-Piriou ◽  
Nicolas Ruggli ◽  
Matthias Liniger ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Avian Influenza ◽  
Cell Activation ◽  
De Novo ◽  
Binding Capacity ◽  
Multiorgan Failure ◽  
Influenza Viruses ◽  
Human Influenza ◽  
Receptor Specificity ◽  
Activation Markers

ABSTRACT Although current H5N1 highly pathogenic avian influenza viruses (HPAIV) are inefficiently transmitted to humans, infected individuals can suffer from severe disease, often progressing rapidly to acute respiratory distress syndrome and multiorgan failure. This is in contrast with the situation with human influenza viruses, which in immunocompetent individuals usually cause only a respiratory disease which is less aggressive than that observed with avian H5N1 viruses. While the biological basis of inefficient transmission is well documented, the mechanisms by which the H5N1 viruses cause fatal disease remain unclear. In the present study, we demonstrate that human pulmonary microvascular endothelial cells (hPMEC) had a clearly higher susceptibility to infection by H5N1 HPAIV than to infection by human influenza viruses. This was measurable by de novo intracellular nucleoprotein production and virus replication. It was also related to a relatively higher binding capacity to cellular receptors. After infection of hPMEC, cell activation markers E-selectin and P-selectin were upregulated, and the proinflammatory cytokines interleukin-6 and beta interferon were secreted. H5N1 virus infection was also associated with an elevated rate of cell death. Reverse genetics analyses demonstrated a major role for the viral hemagglutinin in this cell tropism. Overall, avian H5N1 viruses have a particular receptor specificity targeting endothelial cells that is different from human influenza viruses, and this H5N1 receptor specificity could contribute to disease pathogenesis.

scholarly journals Distal major pedicle of sartorius muscle flap: Anatomical study and its clinical implications

2018 ◽  
Vol 51 (01) ◽  
pp. 040-045
Author(s):  
K. N. Manjunath ◽  
M. S. Venkatesh ◽  
Ashwini Shivaprasad
Keyword(s):  
Gastrocnemius Muscle ◽  
Muscle Flap ◽  
Sartorius Muscle ◽  
Lateral Aspect ◽  
Muscle Flaps ◽  
Suitable Alternative ◽  
Myocutaneous Flaps ◽  
Mean Diameter ◽  
The Mean ◽  
Clinical Cases

ABSTRACT Background: Reconstruction of the popliteal region has limited option in terms of muscle flaps or myocutaneous flaps. Gastrocnemius muscle or the myocutaneous flaps are the option for majority of cases. However, reach of Gastrocnemius is limited if the wound is on the distal one-third thigh or the lateral aspect of knee region. Similarly, if the wound injures the muscle, then coverage becomes all the more difficult. Although inferiorly based fasciocutaneous flaps can cover the wound in case of bony injuries, muscle flaps are beneficial as they help in fracture healing. However, in cases with direct gastrocnemius muscle injury or if the wound on the distal one-third thigh or the lateral aspect then the options of muscle flaps is limited. An inferiorly based sartorius muscle can be one suitable alternative to cover this region. Aims and Objective: The aim is to devise an inferiorly based sartorius muscle flap for coverage of lower thigh, popliteal and upper one-third leg region. Objectives: (1) To identify the location of distal major (largest diameter) pedicle in cadavers and its clinical application. (2) To determine the arc of rotation with distal major pedicle as pivot point. Methods: Ten Cadavers and 20 sartorius muscle dissected out. Prior silicone injection onto the femoral vessels was done to identify the location of the perforators for the sartorius muscle. The distance of perforators from anterior superior iliac spine (ASIS) measured and the diameter of each perforator by transverse cut measured using callipers. In clinical cases, the arc of rotation was measured by keeping the distal perforator intact as pedicle (detaching the muscle from the ASIS without detaching from the insertion and then rotating it). Results: Out of the 10 cadavers analysed, 6 were male and 4 were female. The mean location of the distal major pedicle was at 35.25 cm from ASIS and range was between 30.4 cm to 38.3 cm. There was no significant variation between right and left limbs in individual cadaver (range 0.2 cm–1.6 cm). The mean diameter of the arterial component of distal major pedicle was 1.54 mm. In three clinical cases where this flap was harvested the arc of rotation were 95°, 110°, 125°. In one of the cases where flap was used to cover the tibial plateau (arc of rotation 155°), distal end of the muscle necrosed. Conclusion: This cadaver study supported by various other studies show that it has sizeable distal pedicle based on which whole muscle can be harvested as flap. In our study, the usual location of this pedicle is at 35 cm from ASIS. The mean diameter of the widest pedicle in distal one-third was 1.54 mm which along with other small diameter pedicle can support the entire muscle. This flap reached up to the infrapatellar region without any vascular compromise.

Brief Report: A Case of Tramadol Overdose: Extracorporeal Life Support and Hemoperfusion as Life-Saving Treatment

2020 ◽  
Vol 49 (4) ◽  
pp. 509-512 ◽  
Author(s):  
Fiorenza Ferrari ◽  
Alessandro Carletti ◽  
Nicola Peroni ◽  
Silvia Mongodi ◽  
Pasquale Esposito ◽  
...  
Keyword(s):  
Medical Service ◽  
Life Support ◽  
Extracorporeal Life Support ◽  
Multiorgan Failure ◽  
Rebound Effect ◽  
Metabolic Encephalopathy ◽  
Life Saving ◽  
Before And After ◽  
Organ Failures ◽  
Severe Shock

We describe the case of a 49-year-old woman with a Tramadol intoxication associated with multiorgan failure. Veno-arterial femoro-femoral extracorporeal life support (VA-ECLS) and hemoperfusion (HP) were used as rescue treatments. The emergency medical service found a woman at home unconscious. Once in the hospital, she was intubated and catecholamines support was immediately started for a severe shock. Brain CT was normal, whereas EEG revealed a metabolic encephalopathy pattern. Toxic levels of Tramadol and Quetiapine were detected. VA-ECLS was implanted due to persistent multiorgan failure, and HP with a charcoal cartridge was set to increase the Tramadol clearance. To quantify the charcoal cartridge’s removal efficiency of Tramadol, Tramadol concentration was measured before and after the cartridge and before and after the treatment in the patient’s blood. The charcoal cartridge showed good extraction ratio during the treatment and no significant rebound effect. VA-ECLS and HP allowed the patient to be weaned from vasoconstrictors and the resolution of the organ failures. These treatments might be lifesaving in the Tramadol intoxication.

PS01.155: ANALYSIS ON THE INCIDENCE AND RISK FACTOR OF READMISSION AFTER ESOPHAGECTOMY FOR ESOPHAGEAL CANCER FOR ESOPHAGEAL CANCER

2018 ◽  
Vol 31 (Supplement_1) ◽  
pp. 93-93
Author(s):  
Seong Yong Park ◽  
Dae Joon Kim ◽  
Jee Won Suh ◽  
Go Eun Byun
Keyword(s):  
Esophageal Cancer ◽  
Anastomotic Leakage ◽  
Conflicts Of Interest ◽  
Anastomotic Stricture ◽  
Oral Intake ◽  
Vocal Cord Palsy ◽  
Jejunostomy Tube ◽  
The Mean ◽  
Secondary Hospital ◽  
Wound Problem

Abstract Background Esophageal complications consensus group (ECCG) recommended that readmissions to primary or secondary hospital within 30 days of discharge after esophagectomy can be an important quality outcome indicator for esophagectomy. This retrospective study was performed to investigate the frequencies and risk factors for readmission after esophagectomy. Methods We retrospectively reviewed 291 patients who received the esophagectomy and mediastinal lymphadenectomy for curative aim from January 2006 to June 2017. Results The mean age was 63.02 ± 8.02 years and male patients were 264 (90.7%). Thirty-nine (13.4%) patients readmit within 30 days after discharge. The mean readmission day after discharge was 14.76 ± 8.84. The common causes of readmission were anastomotic stricture requiring the ballooning (12, 30.7%), wound problem (7, 17.9%), pneumonia (6, 15.4%), and poor oral intake (4, 10.2%). Other causes of readmission were delayed gastric emptying (3), jejunostomy tube problem (2), ileus (2), pain (1), pneumothorax (1) and pleural effusion (1). On multivariate analysis, anastomotic leakage (odd ratio = 2.872, P = 0.022) were related to readmission, whereas age, pathologic stage, vocal cord palsy and neoadjuvant therapy were not related to readmission. In 30 patients with postoperative anastomotic leakage, the frequency of readmission due to wound problem (13.3% vs. 1.1%, P = 0.003) and anastomotic stricture (13.3% vs. 3.4%, P = 0.034) were significantly higher. Conclusion The incidence of readmission within 30 days after discharge was 13.4% and postoperative anastomotic leakage was related to the readmission, and it might be related to the wound problem and anastomotic stricture. Disclosure All authors have declared no conflicts of interest.

Improving Outcomes in Patients with Renal Failure Secondary to Multiple Myeloma: Results From ChAR2M2.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1875-1875
Author(s):  
Colin Hutchison ◽  
Parisa Airia ◽  
Mark Cook ◽  
Daniel Grima
Keyword(s):  
Multiple Myeloma ◽  
Renal Failure ◽  
Side Effects ◽  
Light Chain ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Treatment Patterns ◽  
Free Light Chain ◽  
High Rate ◽  
Sustained Reduction

Abstract Abstract 1875 Poster Board I-900 Study purpose: To explore how free light chain (FLC) removal by high cut-off haemodialysis (HCO-HD) has been adopted into clinical practice for the management of renal failure secondary to multiple myeloma. Describing treatment patterns and the laboratory and clinical outcomes associated with its use. Methods: A chart audit of patients treated with FLC removal by HCO-HD, using the Gambro HCO 1100 dialyser, was performed in 16 dialysis centers across 9 countries. Patient demographics, treatment patterns and dialysis side-effects were recorded. In addition, the following outcomes were measured: dialysis independence and reductions in serum FLCs concentrations at 12 and 21 days. Results: Data for 66 patients was entered. Patients had an average age of 65.1 (SD×10.1); 42 of them (63.64%) were male and 24 (36.36%) were female. Sixteen (24%) presented with relapsing myeloma and 50 (76%) had de novo disease. On average, each patient received 13 HCO-HD sessions (SD×8). Forty-one patients became dialysis independent (62.12%), after an average of 12 sessions. Dialysis related side-effects were reported in 6% of all patients. Forty patients (60.61%) were reported to have a sustained reduction in serum FLC concentrations by day 12. By day 21 this had increased to forty-one (62.12%). Among the patients who achieved a sustained reduction in serum FLC concentrations, 28 (70%) had a decline in FLC levels of more than 50% by day 12 and 34 (82.93%) by day 21. Among patients who achieved sustained reduction of more than 50% in serum FLC concentrations by day 12, 75% became dialysis independent. In comparison only 53% of those with a reduction of less than 50% became dialysis independent (p×0.007). Furthermore, among patients who achieved sustained FLC reduction of greater than 75%, 81% became dialysis independent. The rate of dialysis independence was also significantly higher in patients with de novo disease compared with those with relapsing myeloma (64% versus 56%, p×0.04). Conclusion: Free light chain removal by HCO-HD was well tolerated and associated with a very high rate of dialysis independence in patients with renal failure secondary to multiple myeloma. Rates of renal recovery were greater in patients with de novo myeloma and those who achieved an early reduction in serum FLC concentrations. Disclosures: No relevant conflicts of interest to declare.

The Rho GTPase Rac1 Is Not Required for Definitive Hematopoietic Specification in ES-Derived Hematopoiesis.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1494-1494
Author(s):  
Michael D. Milsom ◽  
Akiko Yabuuchi ◽  
George Q. Daley ◽  
David A. Williams
Keyword(s):  
Rho Gtpase ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Embryoid Body ◽  
Es Cells ◽  
Yolk Sac ◽  
Embryoid Bodies ◽  
Hematopoietic Progenitors ◽  
The Impact

Abstract Abstract 1494 Poster Board I-517 Rac1 is a Rho GTPase involved in integrating signaling pathways that regulate numerous cellular processes including adhesion, migration, proliferation and HSC engraftment. Homozygous deletion of Rac1 is lethal in the murine embryo prior to E9.5 and Rac1−/− embryos demonstrate defective gastrulation associated with reduced epiblast adhesion and motility. We have recently demonstrated using lineage-specific conditional deletion that Rac1 insufficiency results in severely impaired hematopoiesis in the embryonic sites of hematopoiesis (AGM, aortic clusters and fetal liver) in the setting of normal hematopoietic development in the yolk sac (YS) and reduced HSC and progenitors in the fetal circulation. This data appears to support the controversial hypothesis that YS derived HSC seed embryonic sites, but an alternative explanation is that Rac1 is essential for some aspect of the induction of intraembryonic hematopoiesis in situ. Another possibility is that Vav1-Cre-mediated excision of Rac1 occurs prior to the onset of hematopoiesis in the embryo proper but not early enough to affect yolk sac hematopoiesis. To test whether Rac1 insufficiency perturbs the normal early differentiation of hematopoietic cells in vitro, we used a lentivirus expressing a Rac1-specific shRNA to knock down expression in an ES line previously characterized to have good hemogenic potential. We observed that the de novo knockdown of Rac1 expression appeared to have no impact upon derivation of hematopoietic progenitors. To demonstrate that this was not the result of inefficient knockdown of Rac1, we derived Rac1−/− ES lines from blastomeres resulting from the mating of Rac1+/− mice. Rac1−/− ES lines were produced in normal Mendelian ratios (4 Rac1+/+: 9 Rac1+/−: 3 Rac1−/−) and did not demonstrate any evidence of abnormal expansion on murine embryonic fibroblasts. In order to assess the impact of Rac1 deficiency on the hemogenic potential of ES cells, standard in vitro differentiation via embryoid body formation was utilized. Neither Rac1 haploinsufficiency nor complete absence of Rac1 had any impact on the production of CD41+/c-Kit+ hematopoietic progenitors within embryoid bodies (Table 1). Furthermore, colony forming assays demonstrated that Rac1 insufficiency did not alter the relative frequency of hematopoietic progenitor compartments (Table 2). We conclude that in the absence of a requirement for vascular migration of HSC, Rac1 is not required for the specification of definitive hematopoiesis. These data, together with our previously published in vivo data continue to support the hypothesis that HSC migration from the YS to the embryo may be required for development of hematopoiesis in the embryo proper. Disclosures: No relevant conflicts of interest to declare.

Count Recovery in AML Patients Achieving a Complete Response.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2062-2062 ◽  
Author(s):  
Steven Lawrence Rosinski ◽  
Farhad Ravandi ◽  
Stefan Faderl ◽  
Guillermo Garcia-Manero ◽  
Sherry Pierce ◽  
...  
Keyword(s):  
Recovery Time ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Complete Response ◽  
Platelet Recovery ◽  
Neutrophil Recovery ◽  
Secondary Aml ◽  
Recovery Times ◽  
Md Anderson ◽  
Count Recovery

Abstract Abstract 2062 Poster Board II-39 AML is typically defined as “de novo” or “secondary”, the latter referring to patients diagnosed only after persistent blood count abnormalities (AHD) or after prior “chemotherapy” (PCT) for other illnesses. Patients with secondary AML may have a different bone marrow microenvironment leading to prolonged neutrophil and platelet recovery times following induction chemotherapy. Accordingly, we compared time from start of chemotherapy to neutrophil recovery (>1,000/μl) and platelet recovery (>100,000/μl) in 424 patients who achieved a complete response (CR) following treatment with ara-C-containing induction therapy at MD Anderson Hospital from 1995 to 2008. We divided the 424 patients as follows: (1) no AHD, no PCT (236 patients); (2) AHD, no PCT (131 patients); (3) PCT, no AHD (28 patients); and (4) AHD and PCT (29 patients). Because time to recovery may also be influenced by cytogenetics and age we subdivided patients in each of the four groups according to age (< vs. ≥ 60) and cytogenetics (normal vs. complex or -5/-7). Despite very differing CR rates, time to neutrophil recovery in patients achieving CR while statistically longer in PCT patients (p=0.05) was from a medical standpoint essentially uninfluenced by AHD and PCT status (table, median delays 2 days with PCT). Platelet recovery was affected by such status (p<0.001) being delayed by a median of 6-8 days in patients who had received PCT. Age had no effect on time to neutrophil (p=0.42) or platelet (p=0.23) recovery, while complex or -5/-7 cytogenetics had a statistically significant (p=0.002 neutrophils, 0.009 platelets) but medically insignificant (median delays of 2 days) effect on recovery time. There was no interaction between age or cytogenetics and AHD or PCT status. A similar analysis in patients who do not achieve CR would be of interest, but might be confounded by the difficulty in distinguishing between the effects of chemotherapy and those of residual AML on count recovery. Our data suggest that older patients, patients with complex or -5/-7 cytogenetics, and patients with secondary AML should not be excluded from clinical trials because of concern about prolonged time to count recovery. Group CRs CR Rate Median Days to > 1000 Neut Median Days to > 100,000 Plt No AHD no PCT 236 68% 27 28 AHD no PCT 131 50% 27 30 PCT no AHD 28 44% 29 34 AHD + PCT 29 35% 30 36 Age < 60 255 64% 28 29 Age ≥ 60 169 48% 26 30 Normal cyto 281 69% 27 29 Complex cyto or -5/-7 143 41% 29 31 Disclosures: No relevant conflicts of interest to declare.

Evaluation of Patients with Myelodysplastic Syndromes (MDS) Obtaining Stable Disease with the Use of Decitabine.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2790-2790
Author(s):  
Henry G. Kaplan ◽  
Michael Milder
Keyword(s):  
Stable Disease ◽  
Dna Methyltransferase ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Clinical Importance ◽  
Hematologic Malignancies ◽  
Median Number ◽  
Outpatient Setting ◽  
Entire Cohort ◽  
Increased Risk

Abstract Abstract 2790 Poster Board II-766 BACKGROUND: MDS is a group of hematologic malignancies associated with reduced quality of life related to progressive cytopenias and increased risk of infections and bleeding. Successful treatment in MDS is typically defined in terms of complete remission (CR). Treatment with decitabine, a DNA methyltransferase inhibitor, has led to CR in 9 to 39% of MDS patients. Many patients have responses that do not meet criteria for CR or partial remission, but may be of clinical importance, especially for older MDS patients. Since patients who achieve stable disease may receive benefits from treatment, it was of interest to evaluate patient characteristics and treatment response results of those who achieved stable disease with decitabine. METHODS: 99 patients with de novo (n=88) or secondary (n=11) MDS were treated with decitabine, 20 mg/m2 daily for 5 days every 4 weeks in an outpatient setting (Steensma et al. J Clin Oncol 2009). No dose reductions were allowed but dose delays were permissible. Any FAB, including CMML, were eligible if ECOG 0-2 and normal hepatic and renal function. Supportive care, including blood products, were permitted. G-CSF was permitted for serious infection or sepsis. Twenty-three patients (18 de novo and 5 secondary MDS) achieved stable disease as the best response by IWG 2006 criteria. RESULTS: At baseline, stable disease patients had a median age of 75 years (70% >70 years) and were mainly men (70%). Ten patients had RA, 7 had RAEB, 4 had RAEB-t, and one each had RARS or CMML. The IPSS scores for these patients were Low (n = 1; 4%), INT-1 (n = 8; 35%), INT-2 (n = 5; 22%), and High (n = 9; 39%). Cytogenetics were good 10 (43%), 1 (4%) intermediate, 10 (43%) poor, or unknown 2 (9%). At baseline 19 (83%) were RBC transfusion dependent, 3 (13%) platelet transfusion dependent. 22 patients were ECOG 0-1. Five patients had received prior cytotoxic chemotherapy, none with azacitidine or decitabine. The median number of cycles initiated was 5.0 (range 2 – 19). At the time of the analysis, 12 of the 23 patients had died with a median survival of 19.2 months (95% CI: 9.4, not estimable). This is consistent with the survival response (19.4 months (95% CI: 15, not estimable) for the entire cohort, which included the stable disease patients, 50% who achieved a hematologic improvement or better, and 10% with progressive disease with decitabine (15% not assessable). Median time to AML or death was 16.1 months (95% CI: 7.2, not estimable). Three of 19 RBC-dependent patients at baseline became transfusion independent for at least 8 weeks with treatment. Conversely, 3 of 4 baseline RBC-independent patients became transfusion dependent. One of 3 platelet-dependent patients became transfusion independent. Three of 20 platelet-independent patients at baseline became transfusion dependent. Of ten patients evaluable for cytogenetic responses, 2 patients had partial cytogenetic responses. Eleven out of 23 patients had at least one related SAE. Myelosuppression-related adverse events were common (≥10%) in these 23 patients with grade 3 or higher adverse experiences of anemia (26%), febrile neutropenia (17%), neutropenia (39%), and thrombocytopenia (30%). CONCLUSIONS: In an outpatient setting, approximately one-quarter of MDS patients maintained stable disease with decitabine treatment, with acceptable and manageable toxicity. Overall survival in this subset of patients appeared to be similar to that observed with the entire cohort, which included 50% of patients with an objective clinical benefit. Larger analyses are needed to fully understand the characteristics of and treatment-related benefits for patients who achieve stable disease with decitabine treatment. Disclosures: No relevant conflicts of interest to declare.

Bortezomib Has No. Ex Vivo Activity in Chronic Myeloid Leukemia: Individual Tumor Response Testing Comparative Study in Pediatric and Adult Acute and Chronic Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4257-4257
Author(s):  
Krzysztof Czyzewski ◽  
Lidia Gil ◽  
Beata Kolodziej ◽  
Beata Rafinska ◽  
Krzysztof Lewandowski ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Kinase Inhibitors ◽  
De Novo ◽  
Advanced Disease ◽  
Conflicts Of Interest ◽  
Ex Vivo ◽  
Chemotherapy Resistance ◽  
Kinase Domain ◽  
Pediatric Leukemia ◽  
Pediatric Aml

Abstract Abstract 4257 Background Resistance to imatinib is one of the most important issues in treatment of CML. Proteasome inhibitor, bortezomib, is known to be effective in therapy of various neoplasms. Preclinical studies demonstrate the ability of bortezomib in chemosensitization and overcoming of chemotherapy resistance. Objective Analysis of ex vivo drug resistance to bortezomib and another 23 drugs including tyrosine kinase inhibitors (TKI) in CML, in comparison to acute adult and pediatric leukemia. Material and methods A total number of 241 patients entered the study, including: 106 Ph(-)ALL and 53 AML children (age 0.1-18, median 7 years) and 46 AML and 36 CML adults (age 18-69, median 41 years). All children were diagnosed as de novo leukemia, AML adults as de novo (n=20) or relapsed/refractory (n=26). Due to similar drug sensitivity, all adult AML patients were pooled into one group (Gil et al, Anticancer Res, 2007;27:4021). Among CML patients 19 had advanced disease; 16 were resistant to imatinib and 6 had ABL-kinase domain mutations (M244V, E255K, Y253H, M351T and 2 with F317L). Ex vivo drug resistance profile was studied by the MTT assay with the use of following drugs: prednisolone, vincristine, idarubicin, daunorubicin, doxorubicin, mitoxantrone, etoposide, L-asparaginase, melphalan, cytarabine, fludarabine, cladribine, thiotepa, treosulfan, 4-HOO-cyclophosphamide, thioguanine, bortezomib, topotecan, clofarabine and busulfan. CML patients were also tested for sensitivity to TKI: imatinib, dasatinib and nilotinib. Results CML cells were more resistant than AML blasts to following drugs: prednisolone (1.5-fold; p=0.037), vincristine (2.3-fold; p=0.004), doxorubicin (>6.9-fold; p<0.001), etoposide (7.4-fold; p<0.001), melphalan (5.9-fold; p=0.001), cytarabine (12.5-fold; p=0.005), fludarabine (2.6-fold; p=0.008), thiotepa (5.4-fold: p=0.001), 4-HOO-cyclophosphamide (2.3-fold; p=0.015), thioguanine (>4-fold; p<0.001), bortezomib (6.2-fold; p<0.001), topotecan (20-fold; p<0.001), and clofarabine (50-fold; p<0.001). No differences in sensitivity were found for idarubicin, daunorubicin, mitoxantrone, L-asparaginase, cladribine, and treosulfan, while CML cells were 2-fold more sensitive to busulfan (p=0.035). Adult and pediatric AML samples did not differ significantly in ex vivo drug resistance to all tested drugs. Pediatric AML samples were more resistant than pediatric ALL samples to most of tested drugs, however they had comparable sensitivity to cytarabine, thioguanine, bortezomib, and clofarabine. CML patients with mutation had higher ex vivo resistance to: vincristine (3.3-fold; p=0.044), idarubicin (7.9-fold; p=0.031), thiotepa (13.7-fold; p=0.044), and busulfan (21.6-fold; p=0.024). No significant differences were observed with respect to other drugs, including all 3 TKI's. CML patients resistant to imatinib had higher ex vivo resistance to: vincristine (2.5-fold; p=0.016), daunorubicin (3.1-fold; p=0.011), etoposide (2.2-fold; p=0.031), and busulfan (4.5-fold; p=0.032). No significant differences were observed in respect to other drugs, including all 3 TKI's. No significant differences were observed between CML patients with non-advanced and advanced disease to all tested drugs, including TKI's. Conclusions CML cells are ex vivo more resistant to most drugs than acute leukemia blasts. Bortezomib alone has no ex vivo activity in CML patients. No differences between CML subgroups in sensitivity to 3 various TKI was detected. These findings require further investigations. Acknowledgments This study was supported by grants: EC 2008/2009 ZPORR SPS.IV-3040-UE/217/2009; EFS 9/9/POKL/4.4.1/2008; UMK 09/2009 and MNiSW N407 078 32/2964. Disclosures: No relevant conflicts of interest to declare.

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