Female and preserved platelet count subgroups of myelodysplastic syndrome patients benefit from standard-dose azacitidine.

BACKGROUND: Hypomethylating agents, including azacytidine (AZA), are standard therapeutics for patients with high-risk myelodysplastic syndromes (MDS), a group of myeloid neoplasms. However, treatment schedules are not unified in real-world practice; in addition to the standard 7-day (standard-dose) schedule, shortened (reduced-dose) schedules are also used. AIMS: The aim of this study was to discover the patient group(s) which show differential efficacy between standard-and reduced-dose AZA to MDS. METHODS AND RESULTS: The outcome of different AZA doses in a cohort of 151 MDS patients were retrospectively analyzed. Overall survival (OS) was not significantly different between standard- and reduced-dose AZA groups by multivariate analysis. However, an interaction was found between either the sex (female vs. male), the platelet counts (< 40 × 103 /µl vs. ≥ 40 × 103 /µl), or the karyotype risk (< poor vs. ≥ poor) and standard-dose AZA for longer OS. Subgroup analyses revealed better OS with standard- over reduced-dose AZA in female patients (HR, 0.27 [95% CI, 0.090-0.79]; p = 0.011), and those with platelet counts ≥ 40 × 103 /µl (HR, 0.51 [95% CI, 0.26-0.99]; p = 0.041). The union of female and preserved platelet count subgroups also benefited from standard-dose AZA. With this as a test cohort, we next analyzed patients registered in the JALSG MDS212 study, for whom 7-day and 5-day AZA treatment strategies were prospectively compared, as a validation cohort (N = 172). That cohort showed the same tendency as the retrospective results. CONCLUSION: We identified the union of female and preserved platelet count subgroups which benefited from standard-dose AZA, imparting crucial information to physicians planning treatment regimens in MDS patients.

Survey of malignant pleural mesothelioma treatment in Japan: Patterns of practice and clinical outcomes in tomotherapy facilities.

We conducted a nationwide survey of tomotherapy for malignant pleural mesothelioma (MPM) in Japan. Fifty-six facilities were surveyed and data on 31 patients treated curatively between 2008 and 2017 were collected from 14 facilities. Twenty patients received hemithorax irradiation after extrapleural pneumonectomy (EPP) (first group). Five patients received irradiation without EPP (second group), while six received salvage radiotherapy for local recurrence (salvage group). Among the seven patients not undergoing EPP, five (four in the second group and one in the salvage group) were treated with lung sparing pleural irradiation (LSPI) and two with irradiation to visible tumors. Two-year overall survival (OS) rates in the first and second groups were 33% and 60%, respectively (median, 13 vs 30 months, P = 0.82). In the first and second groups, 2-year local control (LC) rates were 53 and 67%, respectively (P = 0.54) and 2-year progression-free survival (PFS) rates were 16% and 60%, respectively (P = 0.07). Distant metastases occurred in 15 patients in the first group and three in the second group. In the salvage group, the median OS was 18 months. Recurrence was observed in the irradiated volume in four patients. The contralateral lung dose was higher in LSPI than in hemithorax irradiation plans (mean, 11.0 ± 2.2 vs 6.1 ± 3.1 Gy, P = 0.002). Grade 3 or 5 lung toxicity was observed in two patients receiving EPP and hemithorax irradiation, but not in those undergoing LSPI. In conclusion, outcomes of EPP and hemithorax irradiation were not satisfactory, whereas LSPI appeared promising and encouraging.

Distribution of Deep Gray Matter Lesions on Magnetic Resonance Imaging in Lymphomatosis Cerebri.

We herein report the distribution of gray matter lesions on magnetic resonance imaging (MRI) in two patients with lymphomatosis cerebri (LC). In our patients, the fluid-attenuated inversion recovery sequence of brain MRI demonstrated a bilateral and diffuse high signal intensity, not only in the white matter but also in the thalamus, globus pallidus, putamen, and hippocampus. Among the deep gray matter, the caudate head and putamen (striatum) were relatively spared when compared with the globus pallidus, thalamus, and hippocampus. Interestingly, we found seven previous reports of similar MRI findings, with relative sparing of the striatum, in patients with LC. This finding may be characteristic of LC and help facilitate its diagnosis. Further investigations of a larger number of LC patients are necessary to confirm these findings.

Human metaphase chromosome consists of randomly arranged chromatin fibres with up to 30-nm diameter.

During cell division, mitotic chromosomes assemble and are equally distributed into two new daughter cells. The chromosome organisation of the two chromatids is essential for even distribution of genetic materials. Although the 11-nm fibre or nucleosome structure is well-understood as a fundamental fibrous structure of chromosomes, the reports on organisation of 30-nm basic chromatin fibres have been controversial, with debates on the contribution of 30-nm or thicker fibres to the higher order inner structure of chromosomes. Here, we used focused ion beam/scanning electron microscopy (FIB/SEM) to show that both 11-nm and 30-nm fibres are present in the human metaphase chromosome, although the higher-order periodical structure could not be detected under the conditions employed. We directly dissected the chromosome every 10-nm and observed 224 cross-section SEM images. We demonstrated that the chromosome consisted of chromatin fibres of an average diameter of 16.9-nm. The majority of the chromatin fibres had diameters between 5 and 25-nm, while those with 30-nm were in the minority. The reduced packaging ratio of the chromatin fibres was detected at axial regions of each chromatid. Our results provide a strong basis for further discussions on the chromosome higher-order structure.

Conductance Tunable Suspended Graphene Nanomesh by Helium Ion Beam Milling.

This paper demonstrates that the electrical properties of suspended graphene nanomesh (GNM) can be tuned by systematically changing the porosity with helium ion beam milling (HIBM). The porosity of the GNM is well-controlled by defining the pitch of the periodic nanopores. The defective region surrounding the individual nanopores after HIBM, which limits the minimum pitch achievable between nanopores for a certain dose, is investigated and reported. The exponential relationship between the thermal activation energy (EA) and the porosity is found in the GNM devices. Good EA tuneability observed from the GNMs provides a new approach to the transport gap engineering beyond the conventional nanoribbon method.

Dielectric-Screening Reduction-Induced Large Transport Gap in Suspended Sub-10 nm Graphene Nanoribbon Functional Devices.

The predicted quasiparticle energy gap of more than 1 eV in sub-6 nm graphene nanoribbons (GNRs) is elusive, as it is strongly suppressed by the substrate dielectric screening. The number of techniques that can produce suspended high-quality and electrically contacted GNRs is small. The helium ion beam milling technique is capable of achieving sub-5 nm patterning; however, the functional device fabrication and the electrical characteristics are not yet reported. Here, the electrical transport measurement of suspended ≈6 nm wide mono- and bilayer GNR functional devices is reported, which are obtained through sub-nanometer resolution helium ion beam milling with controlled total helium ion budget. The transport gap opening of 0.16-0.8 eV is observed at room temperature. The measured transport gap of the different edge orientated GNRs is in good agreement with first-principles simulation results. The enhanced electron-electron interaction and reduced dielectric screening in the suspended quasi-1D GNRs and anti-ferromagnetic coupling between opposite edges in the zigzag GNRs substantiate the observed large transport gap.

Intensity-modulated radiation therapy for elderly patients (aged ≥75 years) with localized prostate cancer: Comparison with younger patients (aged <75 years).

The aim of the present study was to evaluate the efficacy and safety of intensity-modulated radiation therapy (IMRT) for elderly patients with prostate cancer (age ≥75 years) compared with younger patients (<75 years). The numbers of patients enrolled into the elderly and younger groups were 238 and 853, respectively. More than half of the patients in the elderly group were high-risk, and the total risk of the elderly group was higher than that of younger group. The median follow-up periods for the elderly and younger groups were 42 (range, 2-108) and 49 (range, 2-120) months, respectively. All patients were treated with IMRT at a dose of 74-78 Gy with or without androgen-deprivation therapy. The biochemical failure-free rates (BFFRs) at 3-year follow-up for the elderly and younger groups were 93.3 and 95.7%, respectively; there was no significant difference between the 2 groups in regard to the BFFR. The clinical failure-free rates (CFFR) at 3-year follow-up for the elderly and younger groups was 95.8 and 98.5%, respectively; the 2 groups did not differ significantly in regard to the CFFR. The cumulative incidence rates of gastrointestinal toxicity (grade ≥2) and genitourinary toxicity (grade ≥2) at 3-year follow-up were 10.5 and 1.3%, respectively; there was no significant difference between the elderly and younger groups. It was concluded that in prostate cancer patients aged 75 years or older, IMRT has a treatment effect equivalent to that in patients <75 years old; adverse events are also comparable.

11C-methionine positron emission tomography for target delineation of recurrent glioblastoma in re-irradiation planning.

AIM: To define the optimal margin on MRI scans in the re-radiation planning of recurrent glioblastoma using methionine positron emission tomography (MET-PET). BACKGROUND: It would be very useful if the optimal margin on MRI to cover the uptake area on MET-PET is known. MATERIALS AND METHODS: CT, MRI, and MET-PET were performed separately over the course of 2 weeks. Among the MRI scans, we used the contrast-enhanced T1-weighted images (Gd-MRI) and T2-weighted images (T2-MRI). The Gd-MRI-based clinical target volume (CTV) (CTV-Gd) and the T2-MRI-based CTV (CTV-T2) were defined as the contrast-enhanced area on Gd-MRI and the high intensity area on T2-MRI, respectively. We defined CTV x mm (x = 5, 10, 15, 20) as x mm outside the CTV. MET-PET-based CTV (CTV-MPET) was defined as the area of accumulation of MET-PET. We calculated the sensitivity and specificity of CTV-Gd and CTV-T2 following comparison with CTV-MPET, which served as the gold standard in this study. RESULTS: The sensitivity of CTV-T2 5 mm (98%) was significantly higher than CTV-T2 (87%), and there was no significant difference in the sensitivity between CTV-T2 5 mm and CTV T2 10, 15, or 20 mm. The sensitivity of CTV-Gd 20 mm (97%) was lower than that of CTV-T2 5 mm (98%). CONCLUSIONS: A margin of at least 5 mm around the high intensity area on T2-MRI is necessary in the target volume delineation of recurrent glioblastoma for the coverage of MET-PET findings in re-radiation therapy planning.

Imaging of immunogold labeling in cells and tissues by helium ion microscopy.

Helium ion microscopy (HIM) scans samples with a fine ion beam exploiting the very short de Broglie wavelength of helium ions. Because the radiation induces only a small sample region to emit secondary electrons (SEs), very high resolution is expected. In order to explore the applications of SE-HIM in biology, COS7 kidney fibroblast cells and C2C12 myoblast cells cultured on a silicon (Si) nitride (SiN)/Si bilayer were dried and directly observed in high vacuum, without coating or staining. High contrast, high depth-of-field images were obtained revealing the nucleus, endoplasmic reticulum, cytoskeleton and putative mitochondria above a bright background from the support. Gold-tagged antibodies were employed to aid organelle identification. Signals from the gold tags were most clearly distinguishable by secondary electron (SE)-HIM when cells were grown on thin SiN film, and the minimum gap measured between gold particles showed the resolution to be 2 nm. Wheat germ agglutinin-gold labeling revealed clusters of gold particles ~50-200 nm in diameter on COS7 cells, which might represent assemblies of glycosylated proteins, suggesting the formation of membrane raft structures that include membrane proteins. SE-HIM also delivered high contrast images of unstained, uncoated, thin sections of Epon­embedded mouse kidney tissues mounted on a SiN/Si bilayer, revealing the details of sub-tissues and cell organelles. A charge-coupled mechanism explaining the observed SE-HIM contrast is proposed. Ionoluminescence-HIM was also performed targeting zinc oxide particles on cells. In conclusion, the high depth-of-field, high-resolution imaging achieved using HIM may have applications in various fields, including soft materials.

Controlled fabrication of electrically contacted carbon nanoscrolls.

Carbon nanoscrolls (CNS) with their open ended morphology have recently attracted interest due to the potential application in gas capture, biosensors and interconnects. However, CNS currently suffer from the same issue that have hindered widespread integration of CNTs in sensors and devices: formation is done ex situ, and the tubes have to be placed with precision and reliability-a difficult task with low yield. Here, we demonstrate controlled in situ formation of electrically contacted CNS from suspended graphene nanoribbons with slight tensile stress. Formation probability depends on the length to width aspect ratio. Van der Waals interaction between the overlapping layers fixes the nanoscroll once formed. The stability of these CNSs is investigated by helium nano ion beam assisted in situ cutting. The loose stubs remain rolled and mostly suspended unless subject to a moderate helium dose corresponding to a damage rate of 4%-20%. One CNS stub remaining perfectly straight even after touching the SiO2 substrate allows estimation of the bending moment due to van der Waals force between the CNS and the substrate. The bending moment of 5400 eV is comparable to previous theoretical studies. The cut CNSs show long-term stability when not touching the substrate.

Evaluation of electron tomography reconstruction methods for interface roughness measurement.

We evaluate the suitability of simultaneous iterative reconstruction technique (SIRT), filtered back projection, and simultaneous algebraic reconstruction technique methods for buried interface roughness measurements. We also investigate the effect of total electron dose distributed over the entire tilt series on measured roughness values. We investigate the applicability of the dose fractionation theorem by evaluating the effect of an increasing number of images, i.e., decreasing tilt increment size at fixed total electron irradiation dose on the quantitative measurement of buried interface roughness. The results indicate that SIRT is the most suitable method for reconstruction and a 3° to 5° angle is optimal for the roughness measurement.

Structurally Controlled Large-Area 10 nm Pitch Graphene Nanomesh by Focused Helium Ion Beam Milling.

Graphene nanomesh (GNM) is formed by patterning graphene with nanometer-scale pores separated by narrow necks. GNMs are of interest due to their potential semiconducting characteristics when quantum confinement in the necks leads to an energy gap opening. GNMs also have potential for use in phonon control and water filtration. Furthermore, physical phenomena, such as spin qubit, are predicted at pitches below 10 nm fabricated with precise structural control. Current GNM patterning techniques suffer from either large dimensions or a lack of structural control. This work establishes reliable GNM patterning with a sub-10 nm pitch and an < 4 nm pore diameter by the direct helium ion beam milling of suspended monolayer graphene. Due to the simplicity of the method, no postpatterning processing is required. Electrical transport measurements reveal an effective energy gap opening of up to ∼450 meV. The reported technique combines the highest resolution with structural control and opens a path toward GNM-based, room-temperature semiconducting applications.

Treatment outcomes and late toxicities of intensity-modulated radiation therapy for 1091 Japanese patients with localized prostate cancer.

AIM: This study aimed to evaluate the treatment result of intensity-modulated radiation therapy (IMRT) in a large number of Japanese patients with prostate cancer. BACKGROUND: A total of 1091 patients with localized prostate cancer were recruited between March 2006 and July 2014. The patients were stratified into low- (n = 205 [18.8%]), intermediate- (n = 450 [41.2%]), high- (n = 345 [31.6%]), and very high-risk (n = 91 [8.3%]) groups according to the National Comprehensive Cancer Network classification. All patients were irradiated via IMRT at a dose of 74-78 Gy with or without androgen-deprivation therapy. The mean follow-up period was 50 months (range, 2-120 months). RESULTS: The biochemical failure-free rate (BFFR), the clinical failure-free rate, and the overall survival rate at the 5-year follow-up for all patients was 91.3%, 96.2%, and 99.1%, respectively. In univariate analysis, the prostate-specific antigen (PSA) levels (≤20 vs. >20 ng/ml) were significantly correlated with BFFR. A trend toward higher BFFR was noted in patients with a Gleason score (GS) of ≤7 than in patients with GS ≥8. In multivariate analysis, only PSA (≤20 vs. >20 ng/ml) was significantly correlated with BFFR. The cumulative incidence rate of gastrointestinal and genitourinary toxicity (≥grade 2) at the 5-year follow-up was 11.4% and 4.3%, respectively. CONCLUSIONS: The findings of this study indicate that IMRT is well tolerated and is associated with both good long-term tumor control and excellent outcomes in patients with localized prostate cancer.

Does intensity-modulated radiation therapy (IMRT) alter prostate size? Magnetic resonance imaging evaluation of patients undergoing IMRT alone.

AIM: To assess the changes in prostate size in patients with prostate cancer undergoing intensity-modulated radiation therapy (IMRT). BACKGROUND: The effect of size change produced by IMRT is not well known. MATERIALS AND METHODS: We enrolled 72 patients who received IMRT alone without androgen-deprivation therapy and underwent magnetic resonance imaging (MRI) examination before and after IMRT. The diameter of the entire prostate in the anterior-posterior (P-AP) and left-right (P-LR) directions was measured. The transitional zone diameter in the anterior-posterior (T-AP) and left-right (T-LR) directions was also measured. RESULTS: The average relative P-AP values at 3, 6, 12, 24, and 36 months after IMRT compared to the pre-IMRT value were 0.94, 0.90, 0.89, 0.89, and 0.90, respectively; the average relative P-LR values were 0.93, 0.92, 0.91, 0.91, and 0.90, respectively. The average P-AP and P-LR decreased by approximately 10% during the 12 months post-IMRT, and remained unchanged thereafter. The average relative T-AP values at 3, 6, 12, 24, and 36 months after IMRT compared to the pre-IMRT value were 0.93, 0.88, 0.91, 0.87, and 0.89, respectively; the average relative T-LR values were 0.96, 0.90, 0.91, 0.87, and 0.88, respectively. The average T-AP and T-LR also decreased by approximately 10% during the 12 months post-IMRT, and remained unchanged thereafter. At 12 months after IMRT, the average relative T-AP was significantly lower in patients with recurrence than in those without recurrence. CONCLUSIONS: The average prostate diameter decreased by approximately 10% during the 12 months after IMRT; thereafter remained unchanged.

Chronic Graft-versus-host Disease Presenting with Multiple Punctate Intracranial Lesions on Contrast-enhanced Magnetic Resonance Imaging.

Central nervous system graft-versus-host disease can present quite a diagnostic challenge. We herein present a case of histologically-confirmed chronic graft versus host disease (GVHD) involving the central nervous system that occurred at 19 months after peripheral blood stem cell transplantation. Cranial magnetic resonance imaging showed areas of confluent hyperintensity in the deep/subcortical white matter with multiple punctate and curvilinear gadolinium enhancements, suggesting the disruption of the blood-brain barrier. A brain biopsy revealed perivascular CD3-positive T cell infiltration around the small vessels. We propose that the detection of punctate-enhanced lesions by magnetic resonance imaging may be a useful finding that facilitates the early diagnosis of chronic GVHD involving the central nervous system.

Quantum transport localization through graphene.

Localization of atomic defect-induced electronic transport through a single graphene layer is calculated using a full-valence electronic structure description as a function of the defect density and taking into account the atomic-scale deformations of the layer. The elementary electronic destructive interferences leading to Anderson localization are analyzed. The low-voltage current intensity decreases with increasing length and defect density, with a calculated localization length ζ = 3.5 nm for a defect density of 5%. The difference from the experimental defect density of 0.5% required for an oxide surface-supported graphene to obtain the same ζ is discussed, pointing out how interactions of the graphene supporting surface and surface chemical modifications also control electronic transport localization.

Complete Remission in Systemic Skin Interdigitating Dendritic Cell Sarcoma after ABVD Chemotherapy.

Interdigitating dendritic cell sarcoma (IDCS) is a rare and aggressive neoplasm that is thought to arise from dendritic cells. This disease usually involves the lymph nodes and, rarely, extra-nodal sites. We report a 62-year-old man presenting skin nodules in the head, body, and extremities, as well as bone marrow involvement. Morphologic analysis of a biopsied specimen from the skin lesion was consistent with IDCS. Immunohistochemical staining demonstrated that the tumor cells were positive for IDCS-associated antigens such as CD4, CD45, CD68 (KP-1), and S-100 protein. Complete remission was achieved by treatment with 6 cycles of ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine) chemotherapy. Although the optimal treatment of IDSC remains unknown, the experience in the current case supports the notion that ABVD chemotherapy may be effective for IDCS, and further extends this idea to rare patients presenting multiple skin lesions.

[Multiple myeloma recurring as small intestinal polyposis after autologous hematopoietic stem cell transplantation].

A 52-year-old woman was diagnosed with BJP-λ multiple myeloma (MM) in November 2012. She was treated with six cycles of bortezomib and dexamethasone, resulting in a very good partial response. The patient underwent autologous peripheral blood stem cell transplantation (PBSCT) 6 months after the diagnosis, and clearly achieved a complete response thereafter. She again suffered chronic abdominal pain with spontaneous remission 9 months after the PBSCT, and, 2 months thereafter, was hospitalized due to intestinal obstruction. Two small intestinal intussusceptions and polyposis in the small intestine were found on abdominal computed tomography. As conservative treatment produced no improvement, partial resection of the small intestine was performed. The pathologic review clearly demonstrated the polyps to have atypical plasma cell infiltrates in the mucosa of the small intestine involving all layers. Immunohisto-chemistry and FISH analyses yielded positive results for CD138, CD79a, and λ light chain, consistent with extramedullary relapse of MM. It is very rare for MM to present with polyposis in the small intestine. There have been no reports describing such a case after autologous PBSCT.

[Acute painful crisis in a female Nigerian patient with sickle cell disease].

We report a 38-year-old Nigerian woman with sickle cell disease. Sickle cell disease had been diagnosed when she experienced her first sickle cell crisis episode at age 8 years. Thereafter, she had infrequent minor episodes. She visited a hospital presenting with fever, anemia, jaundice, and systemic pain, and was then transferred to our hospital. Together with rehydration and red blood cell transfusion, analgesics and antibiotics were prescribed, and produced gradual improvement of all symptoms and signs. The patient was discharged on day 9 of hospitalization. Sickle cell crisis is an acute painful episode caused by occlusion of arterioles. The degree of pain and accompanying symptoms, as well as the frequencies of crises, are variable. Moreover, one third of individuals with sickle cell disease never experience a crisis. As our society becomes increasingly globalized, the probabilities of encountering sickle cell disease patients will be higher.