TONs of copper fun: There is considerable interest in developing catalysts to harness the abundant natural supply of methane for various industrial applications. Two tricopper complexes capable of ...mediating efficient oxidation of methane to methanol under ambient conditions were tested: a biomimetic tricopper complex (see figure) and a tricopper‐peptide species derived from the particulate methane monooxygenase (pMMO) protein.
Activation of Akt is a marker of decreased event-free or overall survival in neuroblastoma patients. MK-2206, a novel allosteric Akt inhibitor, is now tested in clinical trials in adult cancers. In ...this study, effect of MK-2206 on tumor growth and murine survival, alone or in combination, with etoposide or rapamycin was evaluated.
The anticell proliferation effect of MK-2206 was tested in eight neuroblastoma cell lines by MTS assay. Caspase-3/7 activity, cell-cycle analysis, and reactive oxygen species (ROS) production were determined. Effect of MK-2206 combined with etoposide or rapamycin was evaluated in vitro and in vivo. Akt phosphorylation was measured by Western blotting in neuroblastoma cells and tumors.
In vitro, MK-2206 treatment inhibited neuroblastoma cell proliferation, which was accompanied by a cell line selective G(1) arrest of cell cycle or production of ROS. A synergistic effect between MK-2206 and etoposide was detected in four tested neuroblastoma cell lines via caspase-dependent apoptosis, whereas increased inhibition of cell growth induced by combination of MK-2206 and rapamycin was mediated by ROS production. In vivo, MK-2206 alone decreased tumor growth and increased murine survival at dose that inhibited Akt phosphorylation in tumors. MK-2206, in combination with etoposide or rapamycin, caused a significant decrease in tumor growth and increase of murine survival compared with MK-2206 alone.
Akt inhibition by MK-2206 increased the efficacy of etoposide or rapamycin. Our study supports future clinical evaluation of MK-2206 in combination with conventional cytotoxic therapy or with rapamycin in high-risk neuroblastoma patients.
Abstract
Objective
To determine the efficacy of a program to limit the use of the intravenous (IV) push route for opioids on the experience of pain by inpatients and on associated safety events.
...Design
Retrospective cohort study.
Setting
Two inpatient general medicine floor units at an urban tertiary care academic medical center.
Subjects
4,752 inpatient opioid recipients.
Methods
Patients in one unit were exposed to a multidisciplinary intervention to limit the prescription of opioids via the IV push route, with the other unit used as a control unit. The primary study outcome was the mean numeric pain score per patient during the hospital stay. Secondary measures included the hospital length of stay and postdischarge patient satisfaction. Fidelity measures included the percentage of the patient population exposed to each opioid administration route and the amount of opioid administered per route. Safety measures included patient disposition, transfer to intensive care, and incidence of naloxone administration.
Results
The intervention was successful in decreasing both the percentage of patients exposed to IV push opioids and the amount of opioid administered via the IV push route, but no associated changes in other study outcomes were identified.
Conclusions
For the treatment of acute pain in medical inpatients, no evidence of benefit or harm was identified in relation to an increase or decrease in the use of the IV push opioid route.
Zwei Trikupfer‐Komplexe wurden entwickelt, die die effiziente Oxidation von Methan zu Methanol unter Umgebungsbedingungen vermitteln: ein biomimetischer Trikupfer‐Komplex (siehe Bild) und eine von ...der Methan‐Monooxygenase (pMMO) abgeleitete Trikupferpeptid‐Spezies.
Abstract
Background: Activated Akt in tumor tissue of NB patients is a marker of decreased event-free as well as overall survival. Our studies indicate activated Akt induces chemoresistance in NB ...cells and chemoresistance is a major problem in the treatment of Neuroblastoma (NB). The allosteric Akt inhibitor, MK-2206 inhibits the activation of the 3 Akt isoforms with IC50-Akt1 = 5.3nM, -Akt2 = 12nM and -Akt3 = 65nM. In this study we tested the effects of MK-2206 in vitro and in vivo pre-clinical models of NB.
Methods: NB cell lines (NGP, SY5Y, KCNR, BE2, SKNFI, and AS) were treated with increasing concentrations of MK-2206 for 48 hours. MK-2206-induced cell death was evaluated by MTS assay. Phosphorylated Akt and its downstream target S6 were determined by Western Blot analysis. The effect of MK-2206 (100 or 200mg/kg/3 days/wk) on NB tumor growth was evaluated in a xenograft nude mouse model.
Results: NB cell lines express all 3 Akt isoforms to varying levels. In in vitro studies, MK-2206 inhibited cell growth in all NB cell lines although with different sensitivities. The growth of NGP, SY5Y, KCNR and BE2 cells were more sensitive to MK-2206, with IC50<4μM; while the growth of AS and SKNFI were less sensitive, with IC50>11μM. MK-2206 treatment decreased phosphorylated-Akt and its target phosphorylated-S6 in NB cells to a comparable level in all tested cell lines regardless of biologic sensitivity to MK-2206. In in vivo studies, mice bearing the sensitive BE2 NB tumors were treated with MK-2206 (100 or 200mg/kg) while mice bearing the less sensitive AS tumors received MK-2206 (200mg/kg). There was an approx. 30% inhibition of tumor growth in each tumor model only in mice treated with 200mg/kg MK-2206 (P<0.01). MK-2206 (200mg/kg) treatment led to a comparable increase in survival in both models (P<0.01).
Conclusion: This study indicates that despite differences in in vitro growth sensitivities, the Akt inhibitor, MK-2206 has a comparable anti-tumor cell growth inhibiting activity in vivo. This study supports the future evaluation of the combination of MK-2206 with chemotherapeutic drugs to improve the treatment efficacy in NB.
Citation Format: {Authors}. {Abstract title} abstract. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4342. doi:10.1158/1538-7445.AM2011-4342
Background:
Lympho-proliferative disorders are among the most common neoplasms affecting the ocular adnexa. OALD represents 1% of all lymphomas and 10-15% of extra nodal presentations. The outcomes ...of local radiation therapy (RT) in MALT vs. non-MALT histology are not known. Herein we present outcomes of local therapy in MALT vs. non-MALT OALD treated at a specialized lymphoma program.
Methods:
The analysis included 112 consecutive patients (pts) with OALD diagnosed at our institution between 1975- 2014. Patient characteristics, treatment modality and the response to treatment were retrospectively collected. Histology was reviewed by an expert hematopathologist. The primary objective of the study was to assess the failure free survival (FFS) in pts with marginal zone lymphoma of mucosa associated lymphoid tissue (MALT) of ocular adnexa (OA) and non-MALT OA lymphomas treated with local radiation therapy. Complete remission was defined as absence of any disease by imaging. Local failure was defined as any failure within the OA; extra-orbital failure was either regional (within the radiation field) or distant (for cases with limited stage disease at presentation). FFS was defined as time from treatment to any failure (local, regional and distant) and overall survival (OS) as time from treatment to last follow up or death from any cause. FFS and OS were estimated using the Kaplan-Meier methods.
Results:
Baseline characteristics are shown in Table 1. Of 112, 71(57.7%) of the pts had ocular MALT, and 41(33.3%) had non-MALT (23 follicular, 8 diffuse large cell B cell lymphomas, 3 mantle cell, 6 small lymphocytic lymphoma and 1 T cell lymphoma). Unilateral eye involvement (83.9%) with mass/swelling (55.3%) was the most common presentation. Staging was performed with CT scan and bone marrow biopsy in select cases (n=63, 51%). PET scan was utilized in 33 (29.4%) pts. but was able to upstage in only 5 cases.
For ocular MALT, 62(87.3%) received involved field radiation therapy (IFRT), 9(12.6%) chemotherapy. For non-MALT, 34(82.9%) had IFRT, 7(17%) chemotherapy. Among those who received IFRT, 55(75%) in MALT and 21(52%) in non-MALT had limited stage disease (I/II).
Among OALD pts treated with only IFRT, 91.7% in ocular MALT and 90.9% in non-MALT achieved complete remission. Resolution of symptoms occurred in 83.3% and 93.3% of ocular MALT and non-MALT respectively. Failure rates of IFRT in ocular MALT vs. non-MALT were as follows: local (7% vs. 12.1%), regional (9.8% vs. 7.3%), and distant (5.6% vs 2.4%). Median follow-up was 3(1-22) years in each group. Median time to failure was 14 years for ocular MALT and 9 years for non-MALT. 3 year and 5 year failure-free survival was 88% and 81% for ocular MALT and 78% and 71% for non-MALT respectively (log rank p=0.26 for FFS) (Fig 1).
Conclusions:
Both the MALT and non-MALT OALD pts achieved excellent disease control with IFRT with no significant difference in local, regional and distant failure rates. 3 year and 5-year failure free survival were comparable between the two groups. PET scan resulted in upstaging in 5% of pts but did not alter treatment selection, indicating that PET had minimal utility in initial staging of OALD.
Table 1Baseline characteristicsTOTAL, N=112MALT71(63.3%)NON-MALT41(36.6%)Age (median),years64 (22-84)66(25-87)Sex, M25 (35.2%)16(39%)Race, Caucasian63 (88%)34(83%)Symptoms at presentation - Mass/Swelling - Visual changes - Other35 (49.2%) 11 (15.4%) 2 (2.8%)27(66%) 11(27%) 1(2.4%)Site of origin - Orbital - Conjunctival - Lacrimal gland - Eyelid - Other31 (43.6%) 26 (36.6%) 10 (14%) 1 (1.4%) 4 (5.6%)14(34.1%) 14(34.1%) 10(24.3%) 3(7.3%) 0Unilateral Involvement60 (86%)34(83%)Stage at presentation - I - II - III - IV - Unknown60 (85%) 0 1 (1.4%) 8 (11.2%) 2(2.8%)24(59%) 4(9.7%) 2(4.8%) 7(17%) 4(9.7%)
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Hari:BMS: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Takeda: Consultancy; Sanofi: Consultancy; Spectrum: Consultancy. Fenske:Millennium/Takeda: Research Funding; Seattle Genetics: Honoraria; Pharmacyclics: Honoraria; Celgene: Honoraria.
Abstract We present a single-center, large cohort, retrospective study of the efficacy of involved field radiation therapy (IFRT) in ocular adnexal lymphoproliferative disorders (OALDs). Failure free ...survival (FFS), complete remission (CR), and local, regional and distant failure were determined for 112 patients with marginal zone lymphoma of mucosa associated lymphoid tissue (MALT) OALDs (n=71) and non-MALT OALDs (n=41) cohorts. Fifty-six patients with MALT OALD and 26 patients with non-MALT OALD received IFRT only (without any planned concurrent or sequential systemic chemo- or chemo-immunotherapies). Among these OALD cohorts treated with only IFRT, CR was achieved in 49 (87.5%) patients in the MALT cohort and 23 (88.4%) in the non-MALT cohort (p=0.99). Clinically, resolution of symptoms occurred in 83.3% and 93.3% of MALT and non-MALT cohorts respectively. Local failure occurred in 4 (7.1%) patients in the MALT cohort, compared to 4 (15.3%) patients in the non-MALT cohort (p= 0.24). Regional failure (or extra-orbital failure) occurred in 5 (8.9%) patients in the MALT cohort and in 3 (11.5%) of non-MALT patients in the non-MALT cohort (p= 0.71). Distant failure was reported in 1 (1.7%) and 2 patients (7.6%) in MALT and non-MALT cohorts respectively (p= 0.18). The median follow-up of survivors was 5.1 (0.1-22.5) in MALT and 3.9 (0.1-22.9) years in the non-MALT cohort. The 5 year and 10-year failure-free survival was 95% (95% CI 88-100) and 83% (95% CI 70-98) for ocular MALT and 67% (95% CI 48-94) and 56% (95% CI 34-91) for non-MALT cohorts respectively (log rank for p=0.025). On multivariate analyses, age (HR 1.06, 95% CI 1.10-1.12, p=0.03), presence of non-MALT histology (HR 13.9, 95% CI 2.05-94.4, p=0.007) and radiation dose <30.6 Gy (HR 5.27, 95% CI 1.14-24.3, p=0.03) were associated with worse FFS. The 5-year and 10-year OS was 92% (95% CI 83-100) and 80% (95% CI 66-96) for MALT and 78% (95% CI 61-100) and 62% (95% CI 38-100) for non-MALT cohorts respectively (p=0.80). Our results reveal that IFRT provided excellent disease control with superior FFS in MALT cohort when compared to non-MALT histologies.
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