Predicting Composite Component Behavior Using Element Level Crashworthiness Tests, Finite Element Analysis and Automated Parametric Identification.

Fibre reinforced plastics have tailorable and superior mechanical characteristics compared to metals and can be used to construct relevant components such as primary crash structures for automobiles. However, the absence of standardized methodologies to predict component level damage has led to their underutilization as compared to their metallic counterparts, which are used extensively to manufacture primary crash structures. This paper presents a methodology that uses crashworthiness results from in-plane impact tests, conducted on carbon-fibre reinforced epoxy flat plates, to tune the related material card in Radioss using two different parametric identification techniques: global and adaptive response search methods. The resulting virtual material model was then successfully validated by comparing the crushing behavior with results obtained from experiments that were conducted by impacting a Formula SAE (Society of Automotive Engineers) crash box. Use of automated identification techniques significantly reduces the development time of composite crash structures, whilst the predictive capability reduces the need for component level tests, thereby making the development process more efficient, automated and economical, thereby reducing the cost of development using composite materials. This in turn promotes the development of vehicles that meet safety standards with lower mass and noxious gas emissions.

Ophthalmic manifestations of leukemia.

PURPOSE OF REVIEW: This article aims to describe the ocular manifestations of leukemia, resulting both from direct infiltration of neoplastic cells and from the more common secondary effects of leukemia and its treatment. The prevalence of these findings is also discussed, along with their clinical significance, association with hematologic markers and the ophthalmologist's role caring for these patients. RECENT FINDINGS: Recent studies have included a large case series examining the prevalence of ocular manifestations in newly diagnosed leukemic patients as well as case reports of ocular manifestations of leukemia. SUMMARY: Patients with leukemia often have ocular manifestations. These occur either from direct infiltration of neoplastic cells or from indirect or secondary causes, including hematologic abnormalities, central nervous system involvement, opportunistic infections, or from treatment. Although nearly all ocular structures can be affected, leukemic retinopathy is often the most clinically apparent manifestation. Awareness of the ophthalmic manifestations of leukemia is important as they may precede systemic diagnosis or may be a sign of leukemia recurrence.

The prognostic difference of monoallelic versus biallelic deletion of 13q in chronic lymphocytic leukemia.

BACKGROUND: Fluorescence in situ hybridization can detect genomic abnormalities in up to 80% of cases and provides prognostic information on patients with chronic lymphocytic leukemia (CLL). Although 13q deletion as the sole abnormality has been found to confer a favorable prognosis, there are little data as to whether there is a difference in prognostic value between monoallelic versus biallelic deletion of 13q. METHODS: The authors reviewed the electronic database for patients with CLL who carried the 13q deletion as the sole abnormality and presented to The University of Texas MD Anderson Cancer Center (MDACC). Untreated patients were separated into 2 groups: those having monoallelic versus those with biallelic deletion of 13q. Using Mann-Whitney, chi-square, and Kaplan-Meier analysis, the baseline quantitative and qualitative variables for each group, along with the time from presentation to MDACC to treatment, were compared. RESULTS: A total of 176 patients were identified; 143 patients had a monoallelic deletion of 13q, whereas 33 patients had a biallelic deletion. The only significantly different values between the groups were albumin (4.5 g/dL vs 4.4 g/dL; P = .01) and zeta-chain-associated protein kinase 70 (ZAP70) expression (1.7% vs 4.8%; P = .010). The median time from fluorescence in situ hybridization analysis to treatment in both the monoallelic and biallelic groups had not been reached (P = not significant). CONCLUSIONS: Except for inconsequential differences in albumin and ZAP70 expression, there was no difference in the baseline characteristics between patients with CLL who had monoallelic or biallelic deletion of 13q. In addition, there was no significant difference in endpoints, including time to treatment.

Experimental therapeutics for patients with myeloproliferative neoplasias.

Philadelphia chromosome (Ph)-negative myeloproliferative neoplasms (MPNs) are characterized by stem cell-derived, unrestrained clonal myeloproliferation. The World Health Organization classification system, proposed in 2008, identifies 7 distinct categories of Ph-negative MPNs including essential thrombocythemia (ET); polycythemia vera (PV); primary myelofibrosis (PMF); mastocytosis; chronic eosinophilic leukemia; chronic neutrophilic leukemia; and MPN, unclassifiable. For many years, the treatment of ET, PV, and PMF, the most frequently diagnosed Ph-negative MPNs, has been largely supportive. In recent years, that paradigm has been challenged because of the discovery of a recurrent point mutation in the Janus kinase 2 (JAK2) gene (JAK2(V617F)). This mutation can be detected in the vast majority of patients with PV and approximately half of patients with ET or PMF and serves as both a diagnostic marker as well as representing a putative molecular target for drug development. Several putative targeted agents with significant in vitro JAK2 inhibitory activity and various degrees of JAK2 specificity are currently undergoing clinical evaluation. Furthermore, other investigational non-tyrosine kinase inhibitor approaches such as immunomodulatory agents and pegylated interferon- have also shown promising results in MPNs.

Chronic myeloid leukemia in the tyrosine kinase inhibitor era: what is the "best" therapy?

The introduction of imatinib mesylate, a Bcr-Abl1 tyrosine kinase inhibitor (TKI), has revolutionized the treatment of chronic myeloid leukemia (CML). By directly targeting the Bcr-Abl kinase, imatinib leads to durable cytogenetic remissions and in turn improved survival. However, many patients with CML develop resistance, fail to respond, or become intolerant to imatinib due to side effects. This has spurred interest in developing second-generation TKIs to overcome the mechanisms of resistance that lead to treatment failure, specifically Bcr-Abl1 kinase domain mutations. Two second-generation TKIs, nilotinib and dasatinib, are approved for the treatment of CML after imatinib failure or intolerance. Unfortunately, many patients fail subsequent treatment with these agents, as they can develop highly resistant mutations such as T315I. Various other strategies are now in use to optimize the treatment of CML, including dose optimization of imatinib, combination therapy, upfront use of second-generation TKIs, and use of maintenance therapy with interferon-alpha and vaccines. This review highlights progress made in the treatment of CML in the past year.

Tyrosine kinase inhibitors: the first decade.

The treatment of chronic myeloid leukemia (CML) drastically changed with the introduction of imatinib mesylate, a Bcr-Abl1 tyrosine kinase inhibitor (TKI), in 1998. By directly targeting this leukemogenic protein kinase, imatinib affords patients with CML sustained chromosomal remissions, which translate into prolonged survival. However, there has been concern over the emergence of resistance to imatinib, and some patients fail to respond or are intolerant of imatinib therapy because of untoward toxicity. This has spurred interest in developing novel TKIs to overcome the mechanisms of resistance that lead to treatment failure-most importantly, Bcr-Abl1 kinase domain mutations. Two of these second-generation TKIs, nilotinib and dasatinib, are approved worldwide for the treatment of CML after imatinib failure or intolerance. Although these agents are active, they fail in many patients because of the development of highly resistant mutations such as the T315I, against which several novel agents are currently being tested in clinical trials. This review provides an account of the progress made in the field of TKI therapy for CML over the past decade.

The use of nilotinib or dasatinib after failure to 2 prior tyrosine kinase inhibitors: long-term follow-up.

Responses can be achieved with dasatinib or nilotinib after failure of 2 prior tyrosine kinase inhibitors (TKIs). We report on 48 chronic myeloid leukemia patients sequentially treated with 3 TKIs: 34 with dasatinib after imatinib/nilotinib failure and 14 with nilotinib after imatinib/dasatinib failure. Before the third TKI, 25 patients were in chronic phase (CP), 10 in accelerated phase (AP), and 13 in blast phase (BP). Best response to third TKI in CP was 5 major molecular responses (MMR), 3 complete cytogenetic (CCyR), 2 partial cytogenetic (PCyR), 3 minor cytogenetic (mCyR), 6 complete hematologic responses (CHR), and 6 with no response (NR). In AP, 1 patient achieved MMR, 1 CCyR, 2 PCyR, 1 mCyR, 4 CHR, and 1 NR. In BP, 1 achieved MMR, 2 CCyR, 1 PCyR, 1 mCyR, 2 returned to CP, and 6 NR. Median CCyR duration was 16.3 months; 3 CP patients achieving CCyR had a response more than 12 months. Median failure-free survival was 20 months for patients in CP, 5 months in AP, and 3 months in BP. Use of second-generation TKI after failure to 2 TKIs may induce responses, but these are usually not durable except in some CP patients. New treatment options are needed.

Adults with acute lymphoblastic leukemia and translocation (1;19) abnormality have a favorable outcome with hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and high-dose cytarabine chemotherapy.

BACKGROUND: Among the well described cytogenetic abnormalities in adults with acute lymphoblastic leukemia (ALL), a translocation involving chromosomes 1 and 19 (t[1;19] [q23;p13]) occurs in a small subset but has been associated variously with an intermediate prognosis or a bad prognosis in different studies. METHODS: Adults with ALL and t(1;19) who were treated at The University of Texas M. D. Anderson Cancer Center were reviewed. Their clinical features and outcomes were compared with those of patients who had other cytogenetic abnormalities. The study endpoints included the complete remission (CR) rate, the complete response duration (CRD), and overall survival (OS). RESULTS: Of 411 adults with pre-B-cell ALL, 12 patients had t(1;19). Ten of 12 patients with t(1;19) received hyperfractionated cyclophosphamide, vincristine, doxorubicin (Adriamycin), and dexamethasone alternating with methotrexate and high-dose cytarabine (hyper-CVAD) chemotherapy; and the other 2 patients received combined vincristine, doxorubicin, and dexamethasone (VAD). All 12 patients achieved CR, and the 3-year survival rate was 73%. Patients with t(1;19) had significantly better CRD and OS compared with all other patients combined and compared individually with patients who had Philadelphia chromosome-positive, t(4;11), and lymphoma-like abnormalities (deletion 6q, addition q14q, t[11;14], and t[14;18]). CONCLUSIONS: Adults with ALL and t(1;19) had an excellent prognosis when the received the hyper-CVAD regimen.