Osimertinib in poor performance status patients with T790M-positive advanced non-small-cell lung cancer after progression of first- and second-generation EGFR-TKI treatments (NEJ032B)

Background

Osimertinib is effective in patients with T790M mutation-positive advanced non-small-cell lung cancer (NSCLC) resistant to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). However, its effectiveness and safety in patients with poor performance status (PS) are unknown.

Methods

Enrolled patients showed disease progression after treatment with gefitinib, erlotinib, or afatinib; T790M mutation; stage IIIB, IV, or recurrent disease; and PS of 2–4. Osimertinib was orally administered at a dose of 80 mg/day. The primary endpoint of this phase II study (registration, jRCTs061180018) was response rate and the secondary endpoints were progression-free survival (PFS), overall survival (OS), disease control rate, and safety.

Results

Thirty-three patients were enrolled, of which 69.7% and 24.2% had PS of 2 and 3, respectively. One patient was excluded due to protocol violation; in the remaining 32 patients, the response rate was 53.1%; disease control rate was 75.0%; PFS was 5.1 months; and OS was 10.0 months. The most frequent adverse event of grade 3 or higher severity was lymphopenia (12.1%). Interstitial lung disease (ILD) was observed at all grades and at grades 3–5 in 15.2% (5/33) and 6.1% (2/33) of patients, respectively. Treatment-related death due to ILD occurred in one patient. Patients negative for activating EGFR mutations after osimertinib administration had longer median PFS than those positive for these mutations.

Conclusion

Osimertinib was sufficiently effective in EGFR-TKI-resistant, poor PS patients with T790M mutation-positive advanced NSCLC. Plasma EGFR mutation clearance after TKI treatment could predict the response to EGFR-TKIs.

     

Pharmacokinetic study of the oral fluorouracil antitumor agent S‐1 in patients with impaired renal function

Although dose reduction of S‐1 is recommended for patients with impaired renal function, dose modification for such patients has not been prospectively evaluated. The aim of the present study was to investigate the pharmacokinetic parameters of 5‐fluorouracil, 5‐chloro‐2,4 dihydroxypyridine and oteracil potassium, and to review the recommended dose modification of S‐1 in patients with renal impairment. We classified patients receiving S‐1 into 4 groups according to their renal function, as measured using the Japanese estimated glomerular filtration rate (eGFR) equation. The daily S‐1 dose was adjusted based on the patient's eGFR and body surface area. Blood samples were collected for pharmacokinetic analysis. A total of 33 patients were enrolled and classified into 4 groups as follows: 10 patients in cohort 1 (eGFR ≥ 80 mL/min/1.73 m²), 10 patients in cohort 2 (eGFR = 50‐79 mL/min/1.73 m²), 10 patients in cohort 3 (eGFR = 30‐49 mL/min/1.73 m²), and 3 patients in cohort 4 (eGFR < 30 mL/min/1.73 m²). Those in cohorts 3 and 4 treated with an adjusted dose of S‐1 showed a similar area under the curve for 5‐fluorouracil (941.9 ± 275.6 and 1043.5 ± 224.8 ng/mL, respectively) compared with cohort 2 (1034.9 ± 414.3 ng/mL). Notably, while there was a statistically significant difference between cohort 1 (689.6 ± 208.8 ng/mL) and 2 (P = 0.0474) treated with an equal dose of S‐1, there was no significant difference observed in the toxicity profiles of the cohorts. In conclusion, dose adjustment of S‐1 in patients with impaired renal function using eGFR is appropriate and safe.     

Porphyromonas gingivalis promotes murine abdominal aortic aneurysms via matrix metalloproteinase-2 induction

Aoyama N, Suzuki J, Wang D, Ogawa M, Kobayashi N, Hanatani T, Takeuchi Y, Izumi Y, Isobe M. Porphyromonas gingivalis promotes murine abdominal aortic aneurysms via matrix metalloproteinase‐2 induction. J Periodont Res 2011; 46: 176–183. © 2010 John Wiley & Sons A/S Background and Objective: Abdominal aortic aneurysm (AAA) is a common and lethal disorder, and MMPs are highly expressed in AAA lesions. Large numbers of periodontopathic bacteria have been reported to be present in specimens obtained from the aortic walls of patients with an AAA. The purpose of this study was to analyze the influence of periodontopathic bacteria on AAA dilatation. Material and Methods: AAAs were produced in mice by the periaortic application of 0.25 m CaCl₂, and NaCl was used as a control. The mice were inoculated once weekly with live Porphyromonas gingivalis, live Aggregatibacter actinomycetemcomitans or vehicle. Results: Four weeks after the periaortic application of either CaCl₂ or NaCl, a significant increase was observed in the aortic diameter of P. gingivalis‐challenged mice compared with the vehicle control mice (p < 0.05), whereas there was no statistically significant increase in the aortic diameter of the A. actinomycetemcomitans‐challenged mice. Immunohistochemical analysis found significantly higher numbers of CD8‐positive and MOMA2‐positive cells and significantly higher levels of MMP‐2 in the aneurysmal samples of P. gingivalis‐challenged mice compared with control mice. Live P. gingivalis promoted a significant proliferation of splenocytes in comparison with P. gingivalis‐lipopolysaccharide and live A. actinomycetemcomitans (p < 0.05). Conclusion: These findings demonstrate that challenge with P. gingivalis, but not with A. actinomycetemcomitans, can accelerate, or even initiate, the progression of experimental AAA through the increased expression of MMPs.     

Solid-state structures of peapod bearings composed of finite single-wall carbon nanotube and fullerene molecules

A supramolecular combination of carbon nanotube and fullerene, so-called a peapod, has attracted much interest, not solely because of its physical properties but also for its unique assembled structures of carbonaceous entities. However, the detailed structural information available was not sufficient for in-depth understanding of its structural chemistry or for exploratory research inspired by novel physical phenomena, mainly because of the severely inhomogeneous nature of currently available carbon nanotubes. We herein report solid-state structures of a molecular peapod. This structure, solved with a belt-persistent finite carbon nanotube molecule at the atomic level by synchrotron X-ray diffraction, revealed the presence of a smooth, inflection-free Hirshfeld surface inside the tube, and the smoothness permitted dynamic motion of the C₆₀ guest molecule even in the solid state. This precise structural information may inspire the molecular design of carbonaceous machines assembled purely through van der Waals contacts between two neutral molecules.A carbonaceous supramolecular system called a peapod, i.e., a host–guest composite of a single-wall carbon nanotube (SWNT) and fullerene, is attracting considerable interest in various fields due to its unique electronic and molecular structures (1). Although interesting physical phenomena of peapods are being discovered, especially in solid-state physics (2–5), little fundamental and in-depth understanding of peapods has been accumulated at the molecular or atomic levels until quite recently. The first reports of structural chemistry related to peapods appeared through the studies of [10]cycloparaphenylene ([10]CPP) (6): Yamago and coworkers (7) first reported a moderate level of association (association constant K_a ∼ 10³ M in o-dichlorobenzene) with C₆₀ in the solution phase, and solid-state crystal structures were reported with C₆₀ and C₇₀ by Jasti and coworkers (8) and Yamago and coworkers (9). Although this moderate level of association in [10]CPP raised a question regarding the stability of peapods in general (5, 10), we recently showed that the association of belt-persistent tubular molecules, [4]cyclo-2,8-chrysenylenes ([4]CC_2,8) (11–13), with C₆₀ was much higher and recorded a 10⁶- and 10⁹-fold higher association constant in the same medium (K_a ∼ 10⁹ M) and in benzene (K_a ∼ 10¹² M), respectively (Fig. 1A) (14, 15). The level of association in this molecular peapod was comparable to the one expected from theoretical studies with infinite SWNT peapods (10) and, to the best of our knowledge, was highest among host–guest complexes in organic media to date. The uniqueness of molecular recognition in the curved π-systems was further accentuated by the fact that this tight association does not hamper dynamic rolling motions of the guest, providing an intriguing possibility as a molecular bearing (16). To deepen the understanding of tightest host–guest complex composed of two apolar and neutral components and also to accelerate the development of carbonaceous molecular machines (17), the structural information of this molecular peapod, especially at the atomic level, is indispensable. We herein report the solid-state structures of the peapod bearing. We show that, even in the solid state, the belt-persistent tubular molecule allows the dynamic motion of the encapsulated C₆₀ molecule. An inflection-free, smooth surface inside the tube was revealed by a combination of diffraction analysis using a high-flux X-ray beam (18) and graphical inspection using the Hirshfeld surface of the encapsulated C₆₀ probe (19). The atomic-level structural information at the tube–sphere interface should be valuable and useful for the in-depth understanding of curved π-systems, for the discussion of peapods in the solid state, and for the design of peapod molecular machines in the future.Open in a separate windowFig. 1.Solid-state NMR analysis of peapod bearing. (A) Chemical structure of (M)-(12,8)-[4]CC_2,8⊃C₆₀. (B) Spectra of C₆₀, (M)-(12,8)-[4]CC_2,8⊃C₆₀ and a mixture of C₆₀ and (M)-(12,8)-[4]CC_2,8⊃C₆₀ at 25 °C under MAS conditions. See SI Appendix, Fig. S1, for the whole region. (C) VT NMR spectra of (M)-(12,8)-[4]CC_2,8⊃C₆₀ under static conditions without MAS. See SI Appendix, Fig. S3, for all of the data.     

Discovery of Novel SPAK Inhibitors That Block WNK Kinase Signaling to Cation Chloride Transporters

Upon activation by with-no-lysine kinases, STE20/SPS1-related proline–alanine-rich protein kinase (SPAK) phosphorylates and activates SLC12A transporters such as the Na⁺-Cl⁻ cotransporter (NCC) and Na⁺-K⁺-2Cl⁻ cotransporter type 1 (NKCC1) and type 2 (NKCC2); these transporters have important roles in regulating BP through NaCl reabsorption and vasoconstriction. SPAK knockout mice are viable and display hypotension with decreased activity (phosphorylation) of NCC and NKCC1 in the kidneys and aorta, respectively. Therefore, agents that inhibit SPAK activity could be a new class of antihypertensive drugs with dual actions (i.e., NaCl diuresis and vasodilation). In this study, we developed a new ELISA-based screening system to find novel SPAK inhibitors and screened >20,000 small-molecule compounds. Furthermore, we used a drug repositioning strategy to identify existing drugs that inhibit SPAK activity. As a result, we discovered one small-molecule compound (Stock 1S-14279) and an antiparasitic agent (Closantel) that inhibited SPAK-regulated phosphorylation and activation of NCC and NKCC1 in vitro and in mice. Notably, these compounds had structural similarity and inhibited SPAK in an ATP-insensitive manner. We propose that the two compounds found in this study may have great potential as novel antihypertensive drugs.     

Platelet Transfusion Refractoriness in Single-Unit Cord Blood Transplantation for Adults: Risk Factors and Clinical Outcomes

Platelet transfusion refractoriness (PTR) is frequently observed after allogeneic hematopoietic cell transplantation (HCT). However, the incidence of and risk factors for PTR, and impact of PTR on transplant outcomes after cord blood transplantation (CBT) have not been fully investigated. We retrospectively analyzed 185 adult patients who received single-unit CBT in our institute. The mean 16-hour corrected count increment (CCI) for the 5840 platelet transfusions was 3.68?×?10⁹/L. Among them, 3196 transfusions (54.7%) were associated with a PTR with 16-hour-CCI <4.5?×?10⁹/L. Results of multivariate analysis indicated that the following factors were significantly associated with decreased platelet transfusion responses: female sex with pregnancy history, male sex, the presence of HLA class I antibody, lower cord blood total nucleated cell dose, lower cord blood CD34⁺?cell dose, 3 locus HLA disparities, body temperature ≥38°C, C-reactive protein ≥10?mg/dL, cytomegalovirus reactivation, use of foscarnet, and use of liposomal amphotericin B. By contrast, graft-versus-host disease prophylaxis including methotrexate, ABO minor mismatch, use of ganciclovir, and use of linezolid were significantly associated with better platelet transfusion responses. PTR had a significant effect on poor neutrophil and platelet recovery, and overall mortality after CBT. These data suggest that early phase PTR may be predictive of engraftment and mortality after single-unit CBT for adults.     

Adverse Effects of High Temperature On Mammary Alveolar Development In Vitro

Journal of Mammary Gland Biology and Neoplasia - In the mammary glands during pregnancy, the alveolar buds are first branched from the mammary ducts after which they form the alveolar luminal...