The clinical utility of comprehensive measurement of autoimmune disease-related antibodies in patients with advanced solid tumors receiving immune checkpoint inhibitors: a retrospective study.

BACKGROUND: The comprehensive measurement of autoimmune disease-related antibodies (Abs) before immune checkpoint inhibitor (ICI) treatment may be useful for predicting the development of immune-related adverse events (irAEs); however, the clinical utility is not well known. MATERIALS AND METHODS: We retrospectively analyzed patients with advanced solid tumors treated with ICI monotherapy or doublet combination therapy between July 2014 and December 2020 at single institute. Anti-nuclear antibody (ANA), anti-thyroglobulin (Tg) Ab, anti-thyroid peroxidase (TPO) Ab, anti-glutamic acid decarboxylase (GAD) Ab, anti-acetylcholine esterase receptor (AchR) Ab, and platelet-associated immunoglobulin G (PA-IgG) Ab were comprehensively measured for the screening before ICI therapy. RESULTS: Of 275 registered patients (median age, 70 years; male, 64.4%; Eastern Cooperative Oncology Group performance status of 0 or 1, 88.7%; and prior regimen of 0-1/≥2, 88.7%/11.3%), 128 non-small-cell lung cancer, 35 gastric cancer, 33 head and neck cancer, 24 melanoma, 19 renal cell carcinoma, 13 urothelial carcinoma, 12 esophageal cancer, 5 malignant mesothelioma of pleura, 2 endometrial cancer, and 4 other cancer were included. The number of patients with positive ANA, Tg, TPO, PA-IgG, GAD, and AchR Abs was 52 (24.9%), 38 (14.5%), 11 (10.1%), 6 (3.5%), 5 (2.0%), and 1 (0.5%), respectively. There was no association between the development of any irAEs and Abs positivity, while thyroid dysfunction developed more frequently among patients with than without Tg Ab or TPO Ab (39.5% versus 12.5%, P < 0.01; 45.5% versus 14.3%, P = 0.02). CONCLUSIONS: The clinical utility of comprehensive measurement of autoimmune disease-related Abs before introduction of ICI therapy was limited for predicting irAE. However, Tg and TPO Abs were risk factors as regards the development of ICI-induced thyroid dysfunction.

Petahertz non-linear current in a centrosymmetric organic superconductor.

Charge acceleration during an intense light field application to solids attracts much attention as elementary processes in high-harmonic generation and photoelectron emission. For manipulating such attosecond dynamics of charge, carrier-envelope-phase (CEP: relative phase between carrier oscillation of light field and its envelope function) control has been employed in insulators, nanometal and graphene. In superconducting materials, collective control of charge motion is expected because of its strongly coherent nature of quasi-particles. Here we report that, in a layered organic superconductor, a non-linear petahertz current driven by a single-cycle 6 femtosecond near infrared field shows up as second harmonic generation (SHG), which is in contrast to the common belief that even harmonics are forbidden in the centrosymmetric system. The SHG represents a CEP sensitive nature and an enhancement near the superconducting temperature. The result and its quantum many-body analysis indicate that a polarized current is induced by non-linear acceleration of charge, which is amplified by superconducting fluctuations. This will lead to petahertz functions of superconductors and of strongly correlated systems.

Nanofocusing of X-ray free-electron laser using wavefront-corrected multilayer focusing mirrors.

A method of fabricating multilayer focusing mirrors that can focus X-rays down to 10 nm or less was established in this study. The wavefront aberration induced by multilayer Kirkpatrick-Baez mirror optics was measured using a single grating interferometer at a photon energy of 9.1 keV at SPring-8 Angstrom Compact Free Electron Laser (SACLA), and the mirror shape was then directly corrected by employing a differential deposition method. The accuracies of these processes were carefully investigated, considering the accuracy required for diffraction-limited focusing. The wavefront produced by the corrected multilayer focusing mirrors was characterized again in the same manner, revealing that the root mean square of the wavefront aberration was improved from 2.7 (3.3) rad to 0.52 (0.82) rad in the vertical (horizontal) direction. A wave-optical simulator indicated that these wavefront-corrected multilayer focusing mirrors are capable of achieving sub-10-nm X-ray focusing.

Element Selectivity in Second-Harmonic Generation of GaFeO_{3} by a Soft-X-Ray Free-Electron Laser.

Nonlinear optical frequency conversion has been challenged to move down to the extreme ultraviolet and x-ray region. However, the extremely low signals have allowed researchers to only perform transmission experiments of the gas phase or ultrathin films. Here, we report second harmonic generation (SHG) of the reflected beam of a soft x-ray free-electron laser from a solid, which is enhanced by the resonant effect. The observation revealed that the double resonance condition can be met by absorption edges for transition metal oxides in the soft x-ray range, and this suggests that the resonant SHG technique can be applicable to a wide range of materials. We discuss the possibility of element-selective SHG spectroscopy measurements in the soft x-ray range.

Integration of humoral and cellular HLA-specific immune responses in cord blood allograft rejection.

In allo-stem cell transplantation (SCT), it is unclear whether donor-specific anti-HLA Abs (DSAs) can actually mediate graft rejection or if they are simply surrogate markers for the cellular immunity that causes graft rejection. Here, we first analyzed a case of cord blood allograft rejection in which DSA and cytotoxic T lymphocyte (CTL) specific for donor HLA-B*54:01 were detected at the time of graft rejection. Both the DSA and CTL inhibited colony formation by unrelated bone marrow mononuclear cells sharing HLA-B*54:01, suggesting that the humoral and cellular immune responses were involved in the graft rejection. Interestingly, the DSA and CTL were also detected in cryopreserved pre-transplant patient blood, raising a hypothesis that the presence of anti-HLA Abs could be an indicator for corresponding HLA-specific T cells. We then evaluated the existence of HLA-specific CD8(+) T cells in other patient blood specimens having anti-HLA class I Abs. Interferon-γ enzyme-linked immunospot assays clearly confirmed the existence of corresponding HLA-specific T-cell precursors in three of seven patients with anti-HLA Abs. In conclusion, our data demonstrate that integrated humoral and cellular immunity recognizing the same alloantigen of the donor can mediate graft rejection in DSA-positive patients undergoing HLA-mismatched allo-SCT. Further studies generalizing our observation are warranted.

Acute type A aortic dissection repair with mild-to-moderate hypothermic circulatory arrest and selective cerebral perfusion.

AIM: The purpose of this study was to evaluate surgical results of aortic repair with antegrade selective cerebral perfusion (ASCP) and mild-to-moderate hypothermia (MH) from 28 to 31°C comparing with previous series with hypothermia from 20°C to 27 °C. METHODS: Between 2000 and 2011, 109 consecutive patients underwent surgical repair for acute type A aortic dissection with circulatory arrest and ASCP and MH in our institution. Mean patient age was 67±11 years old. Total arch replacement was performed in 85 patients (78%). Thirty (27%) patients had shock status preoperatively. The patients were divided into two different subsets, which is group A (circulatory arrest at less than 27.9 °C, N.=70), and group B (at more than 28 °C, N.=39). RESULTS: The mean extra-corporeal circulation time was 185±47 minutes in group A and 155±38 minutes in group B (P<0.001). The hospital mortality was 11.4% in group A and 10.3% in group B (P>0.05). Permanent neurological deficit occurred in 10 patients (14.3%) in group A, and in 5 (12.8%) in group B (P>0.05). Two (2.8%) paraplegia occurred in group A, and none in group B (P>0.05). The incidence of renal failure requiring hemodialysis was 17.1% in group A and 7.7% in group B, (P>0.05). Respiratory failure after surgery occurred in 27.1% of patients in group A, and 5.1% in group B (P=0.005). CONCLUSION: Circulatory arrest at more than 28 °C offered sufficient cerebral and distal organ protection for acute type A aortic dissection.

Temperature Dependence of Magnetically Active Charge Excitations in Magnetite across the Verwey Transition.

We study the electronic structure of bulk single crystals and epitaxial films of Fe_{3}O_{4}. Fe 2p core level spectra show clear differences between hard x-ray (HAX) and soft x-ray photoemission spectroscopy (PES). The bulk-sensitive spectra exhibit temperature (T) dependence across the Verwey transition, which is missing in the surface-sensitive spectra. By using an extended impurity Anderson full-multiplet model-and in contrast to an earlier peak assignment-we show that the two distinct Fe species (A and B site) and the charge modulation at the B site are responsible for the newly found double peaks in the main peak above T_{V} and its T-dependent evolution. The Fe 2p HAXPES spectra show a clear magnetic circular dichroism (MCD) in the metallic phase of magnetized 100-nm-thick films. The model calculations also reproduce the MCD and identify the contributions from magnetically distinct A and B sites. Valence band HAXPES shows a finite density of states at E_{F} for the polaronic half metal with a remnant order above T_{V} and a clear gap formation below T_{V}. The results indicate that the Verwey transition is driven by changes in the strongly correlated and magnetically active B-site electronic states, consistent with resistivity and optical spectra.

Endovascular treatment of ruptured intracranial aneurysms in patients 70 years of age and older.

BACKGROUND: An increasing number of elderly patients present with intracranial aneurysms. In addition to female gender, an older age is associated with a higher risk of developing a subarachnoid hemorrhage (SAH), and these patients often fare poorly in terms of long-term outcome. It is often thought that elderly patients would especially benefit from endovascular aneurysm treatment. We assessed the clinical outcomes in elderly patients with ruptured intracranial aneurysms (RIAs) who were treated by endovascular procedures. METHODS: We performed a retrospective review of a prospective database of elderly patients treated with coil embolization for RIAs. The clinical outcomes were assessed using the modified Glasgow Outcome Scale. The rates of procedural complications and adverse events were also recorded. RESULTS: During a period of 5 years, 162 patients with 183 intracranial aneurysms were treated in our hospital by means of an endovascular approach. Among them, 51 patients (31.5%) with a ruptured aneurysm were aged 70 years or older. These patients aged 70-91 years (mean age, 74 years) were treated by coil embolization for RIAs. Among them, seven had a Hunt and Hess (HH) grade of I or II, 42 had an HH grade of III or IV, and 2 had an HH grade of V. Endovascular treatment resulted in 32 complete occlusions (62.7%), 15 neck remnants (22%), and 4 body fillings (7.9%). Procedural complications occurred in five patients (9.8%). The outcomes were good or excellent in 17 patients (33.3%). Three patients (5.8%) who died had an HH grade of IV or V. Rebleeding occurred during follow-up in one patient (1.9%). CONCLUSIONS: Coil embolization of intracranial aneurysms is safe and effective in the elderly. However, the morbidity and mortality rates are higher in patients with high HH grades. This finding suggests that the timing of treatment should be based on the patient's initial clinical status.

Electronic excitations of a magnetic impurity state in the diluted magnetic semiconductor (Ga,Mn)As.

The electronic structure of doped Mn in (Ga,Mn)As is studied by resonant inelastic x-ray scattering. From configuration-interaction cluster-model calculations, the line shapes of the Mn L3 resonant inelastic x-ray scattering spectra can be explained by d-d excitations from the Mn ground state dominated by charge-transferred states, in which hole carriers are bound to the Mn impurities, rather than a pure acceptor Mn2+ ground state. Unlike archetypical d-d excitation, the peak widths are broader than the experimental energy resolution. We attribute the broadening to a finite lifetime of the d-d excitations, which decay rapidly to electron-hole pairs in the host valence and conduction bands through the hybridization of the Mn 3d orbital with the ligand band.

Coffin-Siris syndrome is a SWI/SNF complex disorder.

Coffin-Siris syndrome (CSS) is a congenital disorder characterized by intellectual disability, growth deficiency, microcephaly, coarse facial features, and hypoplastic or absent fifth fingernails and/or toenails. We previously reported that five genes are mutated in CSS, all of which encode subunits of the switch/sucrose non-fermenting (SWI/SNF) ATP-dependent chromatin-remodeling complex: SMARCB1, SMARCA4, SMARCE1, ARID1A, and ARID1B. In this study, we examined 49 newly recruited CSS-suspected patients, and re-examined three patients who did not show any mutations (using high-resolution melting analysis) in the previous study, by whole-exome sequencing or targeted resequencing. We found that SMARCB1, SMARCA4, or ARID1B were mutated in 20 patients. By examining available parental samples, we ascertained that 17 occurred de novo. All mutations in SMARCB1 and SMARCA4 were non-truncating (missense or in-frame deletion) whereas those in ARID1B were all truncating (nonsense or frameshift deletion/insertion) in this study as in our previous study. Our data further support that CSS is a SWI/SNF complex disorder.

RISING beamline (BL28XU) for rechargeable battery analysis.

The newly installed BL28XU beamline at SPring-8 is dedicated to in situ structural and electronic analysis of rechargeable batteries. It supports the time range (1 ms to 100 s) and spatial range (1 µm to 1 mm) needed for battery analysis. Electrochemical apparatus for battery charging and discharging are available in experimental hutches and in a preparation room. Battery analysis can be carried out efficiently and effectively using X-ray diffraction, X-ray absorption fine-structure analysis and hard X-ray photoelectron spectroscopy. Here, the design and performance of the beamline are described, and preliminary results are presented.

Successful treatment of monomorphic primary central nervous system post-transplantation lymphoproliferative disorder 5 years after kidney transplantation.

A 31-year-old man underwent living-related kidney transplantation in 2004 as a consequence of primary focal segmental glomerulosclerosis (FSGS). Four years after the transplantation, we confirmed nephrotic syndrome caused by recurrent FSGS. We performed plasmapheresis and low-density lipoprotein adsorption. We also combined steroid therapy with a reduction in the dose of tacrolimus and an increased dose of mycophenolate mofetil. The nephrotic syndrome improved dramatically with this combined therapeutic approach. However, 10 months after these treatments, he revisited our hospital because of altered consciousness. We detected multiple tumor masses in his brain that were ring enhanced on contrast magnetic resonance imaging. Consequently, we suspected primary central nervous system post-transplantation lymphoproliferative disorder (CNS-PTLD). We performed a craniotomy to biopsy the brain tumors. The biopsy specimen showed Epstein-Barr virus-associated diffuse large B-cell lymphoma. There is no definitive treatment for CNS-PTLD. Therefore, we treated the primary CNS-PTLD successfully with whole-brain radiation and discontinuation of immunosuppression therapy.

Scanning photoelectron microscope for nanoscale three-dimensional spatial-resolved electron spectroscopy for chemical analysis.

In order to achieve nondestructive observation of the three-dimensional spatially resolved electronic structure of solids, we have developed a scanning photoelectron microscope system with the capability of depth profiling in electron spectroscopy for chemical analysis (ESCA). We call this system 3D nano-ESCA. For focusing the x-ray, a Fresnel zone plate with a diameter of 200 µm and an outermost zone width of 35 nm is used. In order to obtain the angular dependence of the photoelectron spectra for the depth-profile analysis without rotating the sample, we adopted a modified VG Scienta R3000 analyzer with an acceptance angle of 60° as a high-resolution angle-resolved electron spectrometer. The system has been installed at the University-of-Tokyo Materials Science Outstation beamline, BL07LSU, at SPring-8. From the results of the line-scan profiles of the poly-Si/high-k gate patterns, we achieved a total spatial resolution better than 70 nm. The capability of our system for pinpoint depth-profile analysis and high-resolution chemical state analysis is demonstrated.

Activity of pegylated liposomal doxorubicin for extragenital mullerian adenosarcoma with sarcomatous overgrowth: a case report and a review of the literature.

A 47-year-old woman was diagnosed with extragenital mullerian adenosarcoma with sarcomatous overgrowth. One month after her initial surgery, the patient developed pelvic recurrence, which was completely excised by surgery. However, one month later, the patient developed further recurrences in her pelvis and upper abdomen. A clinical complete response was achieved with three cycles of liposomal doxorubicin and is currently clinically free of disease. So far, including the present case, 23 cases of extragenital mulleian adenosarcoma have been reported in the English literature. Because of the rarity of the reported cases, there are no treatment guidelines based on a good level of evidence. In the current report, through a literature review, we provide information on the activity of pegylated liposomal doxorubicin for extragenital mullerian adenosarcoma with sarcomatous overgrowth.

Second-order autocorrelation of XUV FEL pulses via time resolved two-photon single ionization of He.

Second-order autocorrelation spectra of XUV free-electron laser pulses from the Spring-8 Compact SASE Source (SCSS) have been recorded by time and momentum resolved detection of two-photon single ionization of He at 20.45 eV using a split-mirror delay-stage in combination with high-resolution recoil-ion momentum spectroscopy (COLTRIMS). From the autocorrelation trace we extract a coherence time of 8 ± 2 fs and a mean pulse duration of 28 ± 5 fs, much shorter than estimations based on electron bunch-length measurements. Simulations within the partial coherence model [Opt. Lett. 35, 3441 (2010)] are in agreement with experiment if a pulse-front tilt across the FEL beam diameter is taken into account that leads to a temporal shift of about 6 fs between both pulse replicas.

Wavefront analysis of nonlinear self-amplified spontaneous-emission free-electron laser harmonics in the single-shot regime.

The single-shot spatial characteristics of the vacuum ultraviolet self-amplified spontaneous emission of a free electron laser (FEL) is measured at different stages of amplification up to saturation with a Hartmann wavefront sensor. We show that the fundamental radiation at 61.5 nm tends towards a single-mode behavior as getting closer to saturation. The measurements are found in good agreement with simulations and theory. A near diffraction limited wavefront was measured. The analysis of Fresnel diffraction through the Hartmann wavefront sensor hole array also provides some further insight for the evaluation of the FEL transverse coherence, of high importance for various applications.

Role of Ti 3d carriers in mediating the ferromagnetism of Co∶TiO2 anatase thin films.

We study the surface and bulk electronic structure of the room-temperature ferromagnet Co∶TiO(2) anatase films using soft- and hard-x-ray photoemission spectroscopy with probe sensitivities of ∼1 and ∼10 nm, respectively. We obtain direct evidence of metallic Ti(3+) states in the bulk, which get suppressed to give a surface semiconductor, thus indicating the difference in electronic structure between surface and bulk. X-ray absorption and resonant photoemission spectroscopy reveal Ti(3+) electrons at the Fermi level (E(F)) and high-spin Co(2+) electrons occurring away from E(F). The results show the importance of the charge neutrality condition: Co(2+)+V(O)(2-)+2Ti(4+)↔Co(2+)+2Ti(3+) (V(O) is oxygen vacancy), which gives rise to the elusive Ti 3d carriers mediating ferromagnetism via the Co 3d-O 2p-Ti 3d exchange interaction pathway of the occupied orbitals.

A prospective dose-finding trial using a modified continual reassessment method for optimization of fludarabine plus melphalan conditioning for marrow transplantation from unrelated donors in patients with hematopoietic malignancies.

BACKGROUND: Because of the less graft-facilitating effect by bone marrow (BM), we need to assess a dosage of conditioning more accurately particularly in combination with reduced-intensity conditioning. Thus we examined that modified continual reassessment method (mCRM) is applicable for deciding appropriate conditioning of allogeneic BM transplantation. PATIENTS AND METHODS: The conditioning regimen consisted of i.v. fludarabine (125 mg/m2) plus an examination dose of i.v. melphalan. The primary endpoint was a donor-type T-cell chimerism at day 28 with successful engraftment defined as >90% donor cells. Five patients per dose level were planned to be accrued and chimerism data were used to determine the next dose. RESULTS: Seventeen patients were enrolled at doses between 130 and 160 mg/m2. The dose was changed from 160 to 130 mg/m(2) (second level) after five full-donor chimerisms. With one patient of 0% chimera in the second level, the dose was increased to 135 mg/m2 (third level). Following five full-donor chimerisms in the third level, the study was complete as projected. CONCLUSIONS: mCRM was shown to be a relevant method for dose-finding of conditioning regimen. The melphalan dose of 135 mg/m2 was determined as the recommended phase II dose to induce initial full-donor chimerism.