Effect of tumor burden and growth rate on treatment outcomes of nivolumab in head and neck cancer.

BACKGROUND: Nivolumab improves overall survival (OS) in patients with platinum-refractory recurrent and metastatic head and neck squamous cell carcinoma (R/M HNSCC). In one study, however, Kaplan-Meier OS and progression-free survival (PFS) curves for the nivolumab and cytotoxic agent arms crossed at 3-6 months, suggesting that patients with initial resistance to immunotherapy might have better outcomes with cytotoxic treatment. Here, we explored the conditions and candidates which are predictive of nivolumab outcomes in R/M HNSCC. METHODS: We retrospectively reviewed the clinical records of 27 consecutive R/M HNSCC patients treated with nivolumab from 2014 to 2018. Tumor size was evaluated by RECIST ver.1.1. Tumor growth rate (Gr) was defined as 3log(D0/Dpre)/t, where D0 and Dpre are the sum of the diameters of the target lesions (SumTLs) at baseline and pre-baseline, and t is time, with 1t defined as 4 weeks. RESULTS: Twenty-five patients were enrolled. Survival was significantly worse in patients with disease progression within 3 months. Outcomes appeared poorer in patients with higher pre-treatment Gr and bigger SumTLs at baseline. We therefore explored the association between prognosis, Gr and SumTLs. Recursive partitioning analysis showed that the characteristics of patients with disease progression after 3 months were Gr < 0.76 and SumTLs < 31.0 mm. Further, Gr < 0.76 and SumTLs < 31.0 mm was associated with significantly longer PFS (p = 0.01) and OS (p < 0.01). CONCLUSIONS: These results suggest that Gr and SumTLs at baseline are significantly associated with OS and PFS in R/M HNSCC patients treated with nivolumab.

Anomalous Temperature Behavior of the Chiral Spin Helix in CrNb_{3}S_{6} Thin Lamellae.

Using Lorentz transmission electron microscopy and small-angle electron scattering techniques, we investigate the temperature-dependent evolution of a magnetic stripe pattern period in thin-film lamellae of the prototype monoaxial chiral helimagnet CrNb_{3}S_{6}. The sinusoidal stripe pattern appears due to formation of a chiral helimagnetic order (CHM) in this material. We found that as the temperature increases, the CHM period is initially independent of temperature and then starts to shrink above the temperature of about 90 K, which is far below the magnetic phase transition temperature for the bulk material T_{c} (123 K). The stripe order disappears at around 140 K, far above T_{c}. We argue that this cascade of transitions reflects a three-stage hierarchical behavior of melting in two dimensions.

Microscopic Investigation into the Electric Field Effect on Proximity-Induced Magnetism in Pt.

Electric field effects on magnetism in metals have attracted widespread attention, but the microscopic mechanism is still controversial. We experimentally show the relevancy between the electric field effect on magnetism and on the electronic structure in Pt in a ferromagnetic state using element-specific measurements: x-ray magnetic circular dichroism (XMCD) and x-ray absorption spectroscopy (XAS). Electric fields are applied to the surface of ultrathin metallic Pt, in which a magnetic moment is induced by the ferromagnetic proximity effect resulting from a Co underlayer. XMCD and XAS measurements performed under the application of electric fields reveal that both the spin and orbital magnetic moments of Pt atoms are electrically modulated, which can be explained not only by the electric-field-induced shift of the Fermi level but also by the change in the orbital hybridizations.

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.

Trends in incidence and mortality of tuberculosis in Japan: a population-based study, 1997-2016.

Japan is still a medium-burden tuberculosis (TB) country. We aimed to examine trends in newly notified active TB incidence and TB-related mortality in the last two decades in Japan. This is a population-based study using Japanese Vital Statistics and Japan Tuberculosis Surveillance from 1997 to 2016. We determined active TB incidence and mortality rates (per 100 000 population) by sex, age and disease categories. Joinpoint regression was applied to calculate the annual percentage change (APC) in age-adjusted mortality rates and to identify the years showing significant trend changes. Crude and age-adjusted incidence rates reduced from 33.9 to 13.9 and 37.3 to 11.3 per 100 000 population, respectively. Also, crude and age-adjusted mortality rates reduced from 2.2 to 1.5 and 2.8 to 1.0 per 100 000 population, respectively. Average APC in the incidence and mortality rates showed significant decline both in men (-6.2% and -5.4%, respectively) and women (-5.7% and -4.6%, respectively). Age-specific analysis demonstrated decreases in incidence and mortality rates for every age category, except for the incidence trend in the younger population. Although trends in active TB incidence and mortality rates in Japan have favourably decreased, the rate of decline is far from achieving TB elimination by 2035.

Relationship between the administration of nicardipine hydrochloride and the development of delirium in patients on mechanical ventilation.

A history of hypertension is a known risk factor for delirium in patients in intensive care units, but the effect of antihypertensive agents on delirium development is unclear. Nicardipine, a calcium channel blocker, is widely used in ICU as a treatment agent for hypertensive emergency. This study investigated the relationship between the administration of nicardipine hydrochloride and delirium development in patients under mechanical ventilation. We conducted a medical chart review of 103 patients, who were divided into two groups according to the use of nicardipine hydrochloride. The prevalence of delirium was compared with respect to factors such as age, sex, laboratory data, and medical history, by multivariate analysis. 21 patients (20.4 %) were treated with nicardipine hydrochloride in 103 patients. The treatment and non-treatment groups differed significantly in age (72 vs. 65 years) and history of high blood pressure (57% vs. 11%). Multivariate analysis revealed that patients in the treatment group developed delirium significantly less often than those in the non-treatment group (19% vs. 48%). These results suggested that treatment of high blood pressure with nicardipine hydrochloride is a possible method for preventing the development of delirium.

More Judicious Use of Expectant Management for Localized Prostate Cancer during the Last 2 Decades.

PURPOSE: Urologists have been criticized for overtreating men with low risk prostate cancer and for passively observing older men with higher risk disease. Proponents of active surveillance for low risk disease and critics of watchful waiting for higher risk disease have advocated for more judicious use of observation. Thus, we compared 2 population based cohorts to determine how expectant management has evolved during the last 2 decades. MATERIALS AND METHODS: A total of 5,871 men with localized prostate cancer were enrolled in the PCOS (Prostate Cancer Outcomes Study) or the CEASAR (Comparative Effectiveness Analysis of Surgery and Radiation) study. We compared the use of definitive treatment vs expectant management (watchful waiting or active surveillance) across cohorts, focusing on the influence of disease risk, age and comorbidities. RESULTS: Use of watchful waiting or active surveillance was similar in PCOS and CEASAR (14% in each). Compared to the PCOS, more men in the CEASAR study with low risk disease selected watchful waiting or active surveillance (25% vs 15%, respectively), whereas fewer men with intermediate (7% vs 14%) and high risk (3% vs 10%) disease chose watchful waiting or active surveillance (p <0.001 for each). The association of disease risk with watchful waiting or active surveillance was significantly larger in CEASAR than in PCOS (OR 7.3, 95% CI 3.4 to 15.7). Older age was associated with watchful waiting or active surveillance in both cohorts but there was no association between comorbidity and watchful waiting or active surveillance in the CEASAR study. CONCLUSIONS: Use of watchful waiting or active surveillance was more aligned with disease risk in CEASAR compared to PCOS, suggesting there has been a pivot from watchful waiting to active surveillance. While older men were more likely to be observed, comorbidity had little, if any, influence.

Chiral Surface Twists and Skyrmion Stability in Nanolayers of Cubic Helimagnets.

Theoretical analysis and Lorentz transmission electron microscopy (LTEM) investigations in an FeGe wedge demonstrate that chiral twists arising near the surfaces of noncentrosymmetric ferromagnets [Meynell et al., Phys. Rev. B 90, 014406 (2014)] provide a stabilization mechanism for magnetic Skyrmion lattices and helicoids in cubic helimagnet nanolayers. The magnetic phase diagram obtained for freestanding cubic helimagnet nanolayers shows that magnetization processes differ fundamentally from those in bulk cubic helimagnets and are characterized by the first-order transitions between modulated phases. LTEM investigations exhibit a series of hysteretic transformation processes among the modulated phases, which results in the formation of the multidomain patterns.

Respiratory Pores on Ostrich Struthio camelus (Aves: Struthionidae) Eggshells.

Respiratory pores are essential for the survival of the embryo within the eggshell. Distribution patterns of such pores on ostrich (Struthio camelus) eggshells show remarkable variations in bird group. Eggshells preserved in the museum of New Zealand have long, superficial, winding grooves and ridges, with pores distributed densely in the bottom of grooves. Both the grooves and ridges that separate them are twisted. By contrast, the surfaces of eggs from farmed ostriches are mostly smooth, with only occasional, short grooves, and respiratory pores distributed more evenly. The cause of ridging and grooving of the surface of eggs from wild birds is unclear but may be due to the need for stronger shells and effects of environmental stresses. It appears that the arrangement of respiratory pores on ostrich eggshells seems to be changeable by surrounding stresses.

Geographic body size variation in the periodical cicadas Magicicada: implications for life cycle divergence and local adaptation.

Seven species in three species groups (Decim, Cassini and Decula) of periodical cicadas (Magicicada) occupy a wide latitudinal range in the eastern United States. To clarify how adult body size, a key trait affecting fitness, varies geographically with climate conditions and life cycle, we analysed the relationships of population mean head width to geographic variables (latitude, longitude, altitude), habitat annual mean temperature (AMT), life cycle and species differences. Within species, body size was larger in females than males and decreased with increasing latitude (and decreasing habitat AMT), following the converse Bergmann's rule. For the pair of recently diverged 13- and 17-year species in each group, 13-year cicadas were equal in size or slightly smaller on average than their 17-year counterparts despite their shorter developmental time. This fact suggests that, under the same climatic conditions, 17-year cicadas have lowered growth rates compared to their 13-years counterparts, allowing 13-year cicadas with faster growth rates to achieve body sizes equivalent to those of their 17-year counterparts at the same locations. However, in the Decim group, which includes two 13-year species, the more southerly, anciently diverged 13-year species (Magicicada tredecim) was characterized by a larger body size than the other, more northerly 13- and 17-year species, suggesting that local adaptation in warmer habitats may ultimately lead to evolution of larger body sizes. Our results demonstrate how geographic clines in body size may be maintained in sister species possessing different life cycles.

Ten-year experience of recombinant activated factor VII use in surgical patients with congenital haemophilia with inhibitors or acquired haemophilia in Japan.

Patients with congenital haemophilia with inhibitors or acquired haemophilia are at risk of bleeding complications during surgery. In these patients, replacement therapy for the missing coagulation factor is ineffective, and a bypassing agent such as recombinant activated factor VII (rFVIIa) is required to manage bleeding. To evaluate the safety and haemostatic efficacy of rFVIIa treatment in Japanese patients with congenital haemophilia with inhibitors to FVIII/FIX or acquired haemophilia undergoing surgery. Postmarketing surveillance data from May 2000 to March 2010 were analysed to assess the haemostatic efficacy of 38 procedures in 22 patients with congenital haemophilia A, 13 procedures in seven patients with congenital haemophilia B, and five procedures in five patients with acquired haemophilia. Postoperative bleeding control was judged to be effective (bleeding was stopped completely or reduced considerably) for 34/38 procedures (89%) in patients with congenital haemophilia A, 10/13 procedures (77%) in patients with congenital haemophilia B, and 4/5 procedures (80%) in patients with acquired haemophilia. Tranexamic acid was used concomitantly for 36/56 procedures (64%). Safety was analysed for 66 procedures in 37 patients. Adverse effects potentially related to rFVIIa treatment included mild superficial thrombophlebitis, mild decrease in platelet count, and mild elevation of the serum alanine transaminase level in one patient each. All adverse effects resolved without treatment. Administration of rFVIIa provided adequate haemostasis without serious adverse effects in the majority of cases. The efficacy and safety data in Japanese patients were similar to previously published data from other countries.

Relationship between Cnm-positive Streptococcus mutans and cerebral microbleeds in humans.

OBJECTIVE: Cerebral hemorrhage has been shown to occur in animals experimentally infected with Streptococcus mutans carrying the collagen-binding Cnm gene. However, the relationship between cerebral microbleeds and oral hygiene, with a focus on Cnm gene-positive S. mutans infection, remains unclear. MATERIAL AND METHODS: One hundred and thirty-nine subjects participated. The presence or absence of Cnm-positive S. mutans and its collagen-binding activity were investigated using saliva samples, and relationship with cerebral microbleeds detected on MRI investigated, including clinical information and oral parameters. RESULTS: Fifty-one subjects were identified as Cnm-positive S. mutans carriers (36.7%), with cerebral microbleeds being detected in 43 (30.9%). A significantly larger number of subjects carried Cnm-positive S. mutans in the cerebral microbleeds (+) group. S. mutans with Cnm collagen-binding ability was detected in 39 (28.1%) of all subjects, and the adjusted odds ratio for cerebral microbleeds in the Cnm-positive group was 14.4. Regarding the presence of cerebral microbleeds, no significant differences were noted in the number of remaining teeth, dental caries, or in classic arteriosclerosis risk factors. CONCLUSIONS: The occurrence of cerebral microbleeds was higher in subjects carrying Cnm-positive S. mutans, indicating that the presence of Cnm-positive S. mutans increases cerebral microbleeds, and is an independent risk for the development of cerebrovascular disorders.

A randomized trial of the effects of nebulized albuterol on pulmonary edema in brain-dead organ donors.

Donor lung utilization rates are persistently low primarily due to donor lung dysfunction. We hypothesized that a treatment that enhances the resolution of pulmonary edema by stimulating the rate of alveolar fluid clearance would improve donor oxygenation and increase donor lung utilization. We conducted a randomized, blinded, placebo-controlled trial of aerosolized albuterol (5mg q4h) versus saline placebo during active donor management in 506 organ donors.The primary outcome was change in oxygenation arterial partial pressure of oxygen/fraction of inspired oxygen [PaO2/FiO2] from enrollment to organ procurement.The albuterol (n»260) and placebo (n»246)groups were well matched for age, gender, ethnicity,smoking, and cause of brain death. The change in PaO2/FiO2 from enrollment to organ procurement did not differ between treatment groups (p»0.54) nor did donor lung utilization (albuterol 29% vs. placebo 32%,p»0.44). Donors in the albuterol versus placebo groups were more likely to have the study drug dose reduced (13% vs. 1%, p<0.001) or stopped (8% vs. 0%,p<0.001) for tachycardia. In summary, treatment with high dose inhaled albuterol during the donor management period did not improve donor oxygenation or increase donor lung utilization but did cause tachycardia.High dose aerosolized albuterol should not be used in donors to enhance the resolution of pulmonary edema.

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.

κ-Opioid receptor mediates the antinociceptive effect of nitrous oxide in mice.

BACKGROUND: Our previous reports demonstrated that genetic deletion of µ-opioid receptor has no influence on the anaesthetic and antinociceptive effects of nitrous oxide (N2O) in mice, and that an antagonist selective for κ-opioid receptor (KOP), but not that selective for δ-opioid receptor, suppresses the antinociceptive effect of N2O. However, it is not known whether genetic deletion of KOP affects the N2O actions. METHODS: We measured the minimum alveolar concentration (MAC) of volatile anaesthetics in the absence and presence of N2O. The antinociceptive action of N2O was tested by an acetic acid-writhing test and a hot-plate test. The number of c-Fos-immunopositive cells in sections from the lumbar spinal cord was counted to test whether the descending inhibitory system participates in the pharmacological action of N2O. The hypnotic action of N2O was assessed by measuring the N2O-induced decrease in the EC50 for loss of the righting reflex (EC50-LORR) of sevoflurane. RESULTS: Sevoflurane MAC was not significantly reduced by N2O and its antinociceptive action was almost completely abolished in KOP-knockout (KO) mice. The N2O-induced increase in c-Fos-immunopositive cells in laminae III-IV of the lumbar spinal cord was significant in wild-type (WT), but not in KOP-KO mice. In contrast, sevoflurane EC50-LORR was similarly reduced by N2O in WT and KOP-KO mice. CONCLUSIONS: Our study suggests that N2O demonstrates its antinociceptive action and reduces sevoflurane MAC in mice through KOP activation, whereas its hypnotic potency is not dependent on KOP activation.

A phase II trial of paclitaxel plus biweekly cetuximab for patients with recurrent or metastatic head and neck cancer previously treated with both platinum-based chemotherapy and anti-PD-1 antibody.

BACKGROUND: An important unmet need for new treatment options remains for patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M-HNSCC) previously treated with both platinum-based chemotherapy and anti-programmed cell death protein 1 (PD-1) antibody. Retrospective studies suggest that previous treatment with immune checkpoint inhibitor might augment the efficacy of subsequent chemotherapy. Here, we conducted a phase II trial aimed to evaluate the efficacy and safety of paclitaxel plus biweekly cetuximab for patients in this setting. PATIENTS AND METHODS: This was a single-arm, multicenter, phase II trial. Key eligibility criteria were R/M-HNSCC, and previous treatment with both platinum-based chemotherapy and PD-1 antibody. Paclitaxel plus biweekly cetuximab consisted of weekly paclitaxel 100 mg/m2 (days 1, 8, 15) and biweekly cetuximab 500 mg/m2 (days 1, 15) with a cycle of 28 days until progression or unacceptable toxicity. Primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and adverse events (AEs) (Common Terminology Criteria for Adverse Events version 5.0). RESULTS: Between August 2020 and August 2022, 35 patients were enrolled, of whom 33 were assessable for response. ORR was 69.6% (95% confidence interval 51.2% to 84.4%). With a median follow-up period for survivors of 16.6 months, median PFS and OS were 5.5 and 13.3 months, respectively. DCR was 93.7%. Twenty-three patients (65%) experienced grade 3 or 4 AEs, including neutropenia (34%), infection (14%), leukopenia (11%), mucositis (8%), and pneumonitis (8%). Eight patients discontinued study treatment due to treatment-related AEs, and no treatment-related death was observed. CONCLUSIONS: Paclitaxel plus biweekly cetuximab showed highly encouraging efficacy and manageable toxicities in R/M-HNSCC patients previously treated with both platinum-based chemotherapy and PD-1 antibody. This combination therapy warrants further investigation in this setting.

The impact of rare cancer and early-line treatments on the benefit of comprehensive genome profiling-based precision oncology.

BACKGROUND: Comprehensive genome profiling (CGP) serves as a guide for suitable genomically matched therapies for patients with cancer. However, little is known about the impact of the timing and types of cancer on the therapeutic benefit of CGP. MATERIALS AND METHODS: A single hospital-based pan-cancer prospective study (TOP-GEAR; UMIN000011141) was conducted to examine the benefit of CGP with respect to the timing and types of cancer. Patients with advanced solid tumors (>30 types) who either progressed with or without standard treatments were genotyped using a single CGP test. The subjects were followed up for a median duration of 590 days to examine therapeutic response, using progression-free survival (PFS), PFS ratio, and factors associated with therapeutic response. RESULTS: Among the 507 patients, 62 (12.2%) received matched therapies with an overall response rate (ORR) of 32.3%. The PFS ratios (≥1.3) were observed in 46.3% (19/41) of the evaluated patients. The proportion of subjects receiving such therapies in the rare cancer cohort was lower than that in the non-rare cancer cohort (9.6% and 17.4%, respectively; P = 0.010). However, ORR of the rare cancer patients was higher than that in the non-rare cancer cohort (43.8% and 20.0%, respectively; P = 0.046). Moreover, ORR of matched therapies in the first or second line after receiving the CGP test was higher than that in the third or later lines (62.5% and 21.7%, respectively; P = 0.003). Rare cancer and early-line treatment were significantly and independently associated with ORR of matched therapies in multivariable analysis (P = 0.017 and 0.004, respectively). CONCLUSION: Patients with rare cancer preferentially benefited from tumor mutation profiling by increasing the chances of therapeutic response to matched therapies. Early-line treatments after profiling increase the therapeutic benefit, irrespective of tumor types.

Electronic phase transition and an anomalous ordered phase in Ba2Ti13O22 with 3d1 ions on a triangle-based lattice.

We found that Ba(2)Ti(13)O(22) with Ti(3+) (3d(1)) ions on a triangle-based lattice exhibits a phase transition at T(c)~200 K, below which the increase of electrical resistivity and decrease of magnetic susceptibility were observed. Transmission electron microscopy and optical reflectivity measurements indicate that the low-temperature phase of the present compound shares characteristics in common with a charge-density-wave state with remnant carriers, although a commensurate wave vector of the modulation and a linear temperature dependence of the magnetic susceptibility below T(c) suggest an exotic ordered state.

Identification and characterization of an adenine to guanine transition within intron 10 of the factor VIII gene as a causative mutation in a patient with mild haemophilia A.

Haemophilia A is caused by various genetic mutations in the factor VIII gene (F8). However, after conventional analysis, no candidate mutation could be identified in the F8 of about 2% of haemophilia A patients. The F8 of a patient with mild congenital haemophilia A, in whom no candidate mutation was found in the exons or their flanking regions, was analysed in detail to identify the patient's aetiological genetic abnormality. We also characterized anti-FVIII antibody (inhibitor) development in this patient. Genomic DNA analysis revealed an adenine to guanine transition deep inside intron 10 (c.1478 + 325A>G) of F8 as a causative mutation. Analysis of the transcripts demonstrated that the majority of the patient's transcript was abnormal, with 226 bp of the intronic sequence inserted between exon 10 and 11. However, the analysis also indicated the existence of a small amount of normal transcript. Semi-quantification of ectopic F8 mRNA showed that about one-tenth of the normal mRNA level was present in the patient. After the use of a recombinant FVIII concentrate, the presence of an inhibitor was confirmed. The inhibitor was characterized as oligoclonal immunoglobulin IgG4 directed against both the A2 domain and light chain of the FVIII molecule with type I reaction kinetics of inhibition of FVIII activity. When no mutations are found by conventional analysis, deep intronic nucleotide substitutions may be responsible for mild haemophilia. The inhibitor development mechanism of the patient producing some normal FVIII was thought to be of interest.