Anaplastic lymphoma kinase (ALK) fusions need to be accurately and efficiently detected for ALK inhibitor therapy. Fluorescence in situ hybridization (FISH) remains the reference test. Although ...increasing data are supporting that ALK immunohistochemistry (IHC) is highly concordant with FISH, IHC screening needed to be clinically and prospectively validated.
In the AF-001JP trial for alectinib, 436 patients were screened for ALK fusions through IHC (n = 384) confirmed with FISH (n = 181), multiplex RT-PCR (n = 68), or both (n = 16). IHC results were scored with iScore.
ALK fusion was positive in 137 patients and negative in 250 patients. Since the presence of cancer cells in the samples for RT-PCR was not confirmed, ALK fusion negativity could not be ascertained in 49 patients. IHC interpreted with iScore showed a 99.4% (173/174) concordance with FISH. All 41 patients who had iScore 3 and were enrolled in phase II showed at least 30% tumor reduction with 92.7% overall response rate. Two IHC-positive patients with an atypical FISH pattern responded to ALK inhibitor therapy. The reduction rate was not correlated with IHC staining intensity.
Our study showed (i) that when sufficiently sensitive and appropriately interpreted, IHC can be a stand-alone diagnostic for ALK inhibitor therapies; (ii) that when atypical FISH patterns are accompanied by IHC positivity, the patients should be considered as candidates for ALK inhibitor therapies, and (iii) that the expression level of ALK fusion is not related to the level of response to ALK inhibitors and is thus not required for patient selection.
JapicCTI-101264 (This study is registered with the Japan Pharmaceutical Information Center).
The effect of Arsenic substitution on the properties of Bi-2212 superconductors was studied. Solid-state reaction technique was used for the synthesis of Bi
2−x
As
x
Sr
2
Ca
1.1
Cu
2.1
O
8
samples, x ...= 0, 0.1, 0.2 and 0.4. The X-ray diffraction confirmed the formation of the tetragonal phase of Bi-2212 superconductors. The decrement in the c parameter confirmed that As insertions were introduced into the Bi sites of the system. The grain morphology of the surface was analysed by scanning electron microscopy, where the amount of arsenic increases with As substitution. The superconducting transition temperature (T
c
) was determined from the DC-electrical resistivity by the standard four-probe technique. T
c
was enhanced up to x = 0.1 above which it was suppressed. For magnetism, half magnetic-hysteresis loops were obtained by SQUID magnetometer at different temperatures (5 and 30 K). The hysteresis loops sizes increased with increasing As-concentrations. The critical current density (J
c
) and the flux pinning mechanisms were investigated via different models.
Polycrystalline samples of novel oxypnictides, Sr2ScCo1−xFexPO3, with Fe-doped Co1−xFexP layer were synthesized, and their resistivities and Seebeck coefficients were measured. These materials, ...Sr2ScCo1−xFexPO3, crystallize in a layered structure which represent an alternative stack of ThCr2Si2 type Co1−xFex layers and K2NiF4 type Sr2ScO3 layers. The resistivities (ρ) decrease with decreasing temperature like a metal. The Seebeck coefficients (S) show negative values at room temperature, while the S show positive values for x = 0.04-0.7 at low temperature.
We report that nonmagnetic heavy-fermion (HF) iron oxypnictide CeFePO with two-dimensional XY-type anisotropy shows a metamagnetic behavior at the metamagnetic field H(M)≃4 T perpendicular to the c ...axis and that a critical behavior is observed around H(M). Although the magnetic character is entirely different from that in other Ce-based HF metamagnets, H(M) in these metamagnets is linearly proportional to the inverse of the effective mass, or to the temperature where the susceptibility shows a peak. This finding suggests that H(M) is a magnetic field breaking the local Kondo singlet, and the critical behavior around H(M) is driven by the Kondo breakdown accompanied by the Fermi-surface instability.
Aberrant reactivation of hedgehog (Hh) signaling has been described in a wide variety of human cancers including cancer stem cells. However, involvement of the Hh-signaling system in the bone marrow ...(BM) microenvironment during the development of myeloid neoplasms is unknown. In this study, we assessed the expression of Hh-related genes in primary human CD34(+) cells, CD34(+) blastic cells and BM stromal cells. Both Indian Hh (Ihh) and its signal transducer, smoothened (SMO), were expressed in CD34(+) acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS)-derived cells. However, Ihh expression was relatively low in BM stromal cells. Remarkably, expression of the intrinsic Hh-signaling inhibitor, human Hh-interacting protein (HHIP) in AML/MDS-derived stromal cells was markedly lower than in healthy donor-derived stromal cells. Moreover, HHIP expression levels in BM stromal cells highly correlated with their supporting activity for SMO(+) leukemic cells. Knockdown of HHIP gene in stromal cells increased their supporting activity although control cells marginally supported SMO(+) leukemic cell proliferation. The demethylating agent, 5-aza-2'-deoxycytidine rescued HHIP expression via demethylation of HHIP gene and reduced the leukemic cell-supporting activity of AML/MDS-derived stromal cells. This indicates that suppression of stromal HHIP could be associated with the proliferation of AML/MDS cells.
We report the results of 31P-nuclear magnetic resonance (NMR) measurements on the layered cobalt oxyphosphide Sr2Sc(Co1−xFex)PO3 in order to investigate the magnetic properties at low temperatures ...from a microscopic view point. The 31P-Knight shifts measured at the resonance peak maximum of Sr2Sc(Co1−xFex)PO3 have positive values and are T-independent in an entire temperature range, and the absolute value decreases with increasing Fe content. Also, the nuclear spin-lattice relaxation rate 1/T1 is almost proportional to the temperature at low temperatures. The magnitude of 1/T1T decreases with increasing the Fe content, which suggests the decrease of the density of states around the Fermi level.
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