Antiplatelet drugs may increase the risk for checkpoint inhibitor-related pneumonitis in advanced cancer patients.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are indicated for various cancers and are the mainstay of cancer immunotherapy. They are often associated with ICI-related pneumonitis (CIP), however, hindering a favorable clinical course. Recently, non-oncology concomitant drugs have been reported to affect the efficacy and toxicity of ICIs; however, the association between these drugs and the risk for CIP is uncertain. The aim of this study was to assess the impact of baseline concomitant drugs on CIP incidence in ICI-treated advanced cancer patients. PATIENTS AND METHODS: This was a single-center retrospective study that included a cohort of 511 patients with advanced cancer (melanoma and non-small-cell lung, head and neck, genitourinary, and other types of cancer) treated with ICIs. Univariable analysis was conducted to identify baseline co-medications associated with CIP incidence. A propensity score matching analysis was used to adjust for potential CIP risk factors, and multivariable analysis was carried out to assess the impact of the identified co-medications on CIP risk. RESULTS: Forty-seven (9.2%) patients developed CIP. In these patients, the organizing pneumonia pattern was the dominant radiological phenotype, and 42.6% had grade ≥3 CIP, including one patient with grade 5. Of the investigated baseline co-medications, the proportion of antiplatelet drugs (n = 50, 9.8%) was higher in patients with CIP (23.4% versus 8.4%). After propensity score matching, the CIP incidence was higher in patients with baseline antiplatelet drugs (22% versus 6%). Finally, baseline antiplatelet drug use was demonstrated to increase the risk for CIP incidence regardless of cancer type (hazard ratio, 3.46; 95% confidence interval 1.21-9.86). CONCLUSIONS: An association between concomitant antiplatelet drug use at baseline and an increased risk for CIP was seen in our database. This implies the importance of assessing concomitant medications for CIP risk management.

Unusually strong electronic correlation and field-induced ordered phase in YbCo2.

We report the first study of electrical resistivity, magnetization, and specific heat on YbCo2. The measurements on a single-phased sample of YbCo2bring no evidence of magnetic ordering down to 0.3 K in a zero magnetic field. The manifestations of low Kondo temperature are observed. The specific heat value divided by temperature,C/T, keeps increasing logarithmically beyond 7 J/mol K2with decreasing temperature down to 0.3 K without no sign of magnetic ordering, suggesting a very large electronic specific heat. Analysis of the magnetic specific heat indicates that the large portion of the low-temperature specific heat is not explained simply by the low Kondo temperature but is due to the strong intersite magnetic correlation in both the 3dand 4felectrons. Temperature-dependent measurements under static magnetic fields up to 7 T are carried out, which show the evolution of field-induced transition above 2 T. The transition temperature increases with increasing field, pointing to a ferromagnetic character. The extrapolation of the transition temperature to zero field suggests that YbCo2is in the very proximity of the quantum critical point. These results indicate that in the unique case of YbCo2, the itinerant electron magnetism of Co 3d-electrons and the Kondo effect within the vicinity of quantum criticality of Yb 4f-local moments can both play a role.

Adequate Protein Intake on Comprehensive Frailty in Older Adults: Kyoto-Kameoka Study.

OBJECTIVES: Defining an adequate protein intake in older adults remains unresolved. We examined the association between calibrated protein intake and comprehensive frailty by sex in the Kyoto-Kameoka study. DESIGN: Cross-sectional study of baseline data. SETTING AND PARTICIPANTS: The study included 5679 Japanese participants aged 65 years or older. METHODS: Calibration coefficients were estimated from food frequency questionnaires and 7-day dietary records as a reference. Comprehensive frailty was evaluated using the 25-item Kihon Checklist (KCL) and defined as a total KCL score of ≥7points. Sex-specific calibrated protein intakes were presented as % of energy, per kg of actual body weight (BW), and per kg of ideal BW. RESULTS: Multiple logistic regression analysis showed that calibrated protein intake is inversely associated with comprehensive frailty. The association between protein intake and comprehensive frailty was also evaluated using curve fitting with non-linear regression, a weak U-shaped association was found in males and an L-shaped association in females. Men had a low prevalence of frailty at a calibrated protein intake of 15-17% energy from protein, 1.2 g/kg actual BW/day, or 1.4 g/kg ideal BW/day, and women had a low prevalence of frailty at 17-21% energy from protein or 1.6 g/kg ideal BW/day, with the prevalence of frailty remaining unchanged at higher protein intakes. Meanwhile, the inverse relationship between protein intake per ABW and frailty showed a gradual decrease at 1.4 g/kg ABW/day for protein in women. CONCLUSIONS AND IMPLICATIONS: A non-linear relationship was found between calibrated protein intake and frailty, with a U-shaped association in men and an L-shaped association in women. Adequate protein intake in healthy Japanese older adults was higher than the current recommended daily allowance.

Radiofrequency identification tag system improves the efficiency of closed vitrification for cryopreservation and thawing of bovine ovarian tissues.

PURPOSE: A radiofrequency identification (RFID) tag system was designed to streamline cryopreservation and thawing procedures. This study evaluated the usefulness of the RFID tag system for improving the efficiency of cryopreserving/thawing bovine ovarian tissue by the closed vitrification protocol. METHODS: Six participants carried out closed vitrification and thawing of bovine ovarian tissues procedures using either the conventional or the new RFID tag method, and the time required to perform each step of the respective methods was measured. After normality of data was confirmed by the Shapiro-Wilk test, the significance of differences was assessed by the unpaired t test. RESULTS: When closed vitrification was performed, the time required for each step showed a significant difference between the two methods (t(4) = 2.938, p = 0.042, d = 2.40), and the total cryopreservation time was 11 min shorter using the RFID tag system. When thawing was performed, the time required for each step also showed a significant difference between the two methods (t(4) = 2.797, p = 0.049, d = 2.28), and the total thawing time was 2 min shorter using the RFID tag system. CONCLUSION: The RFID tag system tested in this study seems to be suitable for managing biological samples stored in liquid nitrogen. Adoption of an RFID tag system by fertility centers may not only improve the efficiency of cryopreserving/thawing reproductive tissues but could also reduce human error.

Facial nerve paralysis after super-selective intra-arterial chemotherapy for oral cancer.

Facial nerve paralysis (FNP) after super-selective intra-arterial chemotherapy (SSIAC) is a relatively rare local side effect of SSIAC to the maxillary artery (MA) or the middle meningeal artery (MMA). The incidence and prognosis of FNP after SSIAC in 381 patients with oral cancer (133 with catheterization of the MA, 248 without) was investigated retrospectively. Only three patients (two male and one female) had FNP, for an incidence of 0.8%. All patients with FNP had undergone catheterization of the MA, and the incidence of FNP in this group was 2.3% (3/133). One of the three patients with FNP had paralysis of the third branch of the trigeminal nerve. FNP occurred a mean of 8.7 days (range 5-11 days) after initial SSIAC, and the mean total dose of cisplatin was 55.8mg (range 42.5-67.2mg) and of docetaxel was 25.4mg (range 17.0-33.6mg). FNP resolved completely a mean of 12.7 months (range 6-19 months) after onset. Because the administration of anticancer agents via the MA or MMA carries a risk of FNP, this information will be useful when obtaining informed consent from patients before treatment.

Note: Absolute detection efficiency of a tapered microchannel plate for Ne⁺ ions.

The absolute detection efficiency of a tapered microchannel plate with an open-area ratio of 90% was measured for Ne(+) with energies up to 5 keV, and comparison with the results for Xe(+) was made. As in the case of Xe(+), the maximum detection efficiency was 90%. The energy dependence of the efficiency curves normalized with respect to the open-area ratios was examined based on the scaling law proposed previously.

Radiation therapy with concurrent retrograde superselective intra-arterial chemotherapy for gingival carcinoma.

PURPOSE: The aim of this study was to review the efficacy and toxicity of radiation therapy with concurrent retrograde superselective intra-arterial chemotherapy in the treatment of gingival carcinoma. METHODS AND MATERIALS: In all, 34 patients (21 men and 13 women) with squamous cell carcinoma of the gingiva underwent radiation therapy with concurrent retrograde superselective intra-arterial chemotherapy. Treatment consisted of daily external irradiation and concurrent retrograde superselective intra-arterial infusion with cisplatin and docetaxel. A median total dose of 60 Gy in 30 fractions was delivered to tumors. RESULTS: Of the 34 patients, 29 (85 %) achieved a complete response (CR) and 5 had residual tumors. Of the 29 patients with a CR, 2 had local recurrences and 1 had distant metastasis 1-15 months after treatment. Twenty-six of the 36 patients had survived at a median follow-up time of 36 months (range 12-79 months); 4 died of cancer and 4 died of non-cancer-related causes. At both 3 and 5 years after treatment, the overall survival rates were 79 % and the cause-specific survival rates were 85 %. Osteoradionecrosis of the mandibular bone only developed in 1 patient after treatment. CONCLUSION: Radiation therapy with concurrent retrograde superselective intra-arterial chemotherapy was effective and safe in the treatment of gingival carcinoma. This treatment may be a promising curative and organ-preserving treatment option for gingival carcinoma.

Mobilities of Li(+)-attached butanol isomers in He gas.

Mobilities of Li(+)-attached butanol isomers, (n-BuOH)Li(+), (s-BuOH)Li(+), (i-BuOH)Li(+), and (t-BuOH)Li(+), in helium gas were measured over a range of reduced electric fields (E/N = 25-96 Td) at room temperature. Arrival time measurements accurately identified small differences in the measured mobilities of the isomer ions. At low E/N (≤30 Td, corresponding to a mean collision energy ε≤0.05 eV), (n-BuOH)Li(+) showed a mobility about 1.5% greater than that of the other ions, but at high E/N (≥75 Td, ε≥0.1 eV) its mobility was about 1.1% less.

Inhibition of calcitonin gene-related peptide (CGRP) has the potential to extend first-phase insulin secretion.

The neuropeptide calcitonin gene-related peptide (CGRP), known to have a strong vasodilation effect, has also been reported to inhibit insulin secretion. However, the physiological effect of CGRP related to insulin secretion is still unknown. Here, we evaluated the effect of whole-body CGRP inhibition by anti-CGRP antibodies in mice using an oral glucose tolerance test. CGRP has 2 isotypes, alpha-CGRP and beta-CGRP, and we confirmed the antibody used in this study inhibits function of both. Then, we evaluated the effect of CGRP inhibition on insulin secretion and discovered that CGRP inhibition lead to extend first-phase insulin secretion in an antibody dose-dependent manner and nearly plateaued at 10 mg/kg, although the effect was not so large and didn't affect plasma glucose level. We then measured the plasma antibody concentration and it was increased depending on administration dose. So, the effect of first-phase insulin secretion extension was determined to be the result of complete inhibition of CGRP by the antibody. These results indicate that CGRP has the potential to inhibit insulin secretion and shorten first-phase insulin secretion. However the effect of CGRP inhibition was not so large at least on healthy condition, and it indicates the effect of CGRP related to insulin secretion on healthy physiological condition may be limited.

Efficacy and safety of switching from basal insulin to sitagliptin in Japanese type 2 diabetes patients.

Basal-supported oral therapy (BOT) is often used to treat poorly controlled type 2 diabetes. However, patients sometimes experience nocturnal and early morning hypoglycemia. Thus, maintaining targeted glycemic control by BOT is limited in some patients. We assessed the efficacy and safety of replacing basal insulin by sitagliptin therapy in Japanese type 2 diabetes patients on BOT. Forty-nine subjects were sequentially recruited for the 52-week, prospective, single arm study. Patients on BOT therapy were switched from basal insulin to sitagliptin. The primary endpoint was change in HbA1c in 52 weeks. The secondary endpoints were dropout rate, changes in body weight, frequency of hypoglycemia, and relationship between change in HbA1c and insulin secretion capacity evaluated by glucagon loading test. The average dose of basal insulin was 15.0±8.4 units. Sixteen subjects (31.3%) were dropped because replacement by sitagliptin was less effective for glycemic control. In these subjects, diabetes duration was longer, FPG and HbA1c at baseline were higher, and insulin secretion capacity was lower. Change in HbA1c in 52 weeks was - 4 mmol/mol (95% CI - 5 to - 4 mmol/mol) (p<0.05). Change in body weight was - 0.71 kg (95% CI - 1.42 to - 0.004 kg) (p<0.05). Frequency of hypoglycemia was decreased from 1.21±1.05 to 0.06±0.24 times/month. HbA1c level was improved if C-peptide index (CPI) was over 1.19. In conclusion, basal insulin in BOT can be replaced by sitagliptin with a decrease in HbA1c level and frequency of hypoglycemia in cases where insulin secretion capacity was sufficiently preserved.

Sitagliptin add-on to low dosage sulphonylureas: efficacy and safety of combination therapy on glycaemic control and insulin secretion capacity in type 2 diabetes.

AIMS: To assess the efficacy and safety of combination therapy with sitagliptin and low dosage sulphonylureas on glycaemic control and insulin secretion capacity in Japanese type 2 diabetes. METHODS: Eighty-two subjects were sequentially recruited for the 52-week, prospective, single arm study. Sitagliptin was added on to sulphonylureas (glimepride or gliclazide) with or without metformin. The primary endpoint was a change in A1C. The secondary endpoints were changes in BMI, insulin secretion capacity, blood pressure and urinary albumin excretion, unresponsive rate, and hypoglycaemia. Insulin secretion capacity was evaluated by glucagon loading test. RESULTS: Change in A1C was -0.80% (95% CI -0.90 to -0.68) (p < 0.001). Change in BMI, systemic and diastolic blood pressure, and urinary albumin excretion were -0.38 kg/m(2) (95% CI -0.72 to -0.04) (p < 0.05), -6.7/-3.6 mmHg (95% CI -10.0 to -3.4/-4.8 to -2.4) (p < 0.001), and -43.2 mg/gCr (95% CI -65.7 to -20.8) (p < 0.001) respectively. Mild hypoglycaemia was observed in three cases. The unresponsive rate was 6.1%. Glucagon loading test showed that 0-min and 6-min CPR at baseline and 52-week were not significantly changed: 0-min CPR, 1.58 ± 0.58-1.71 ± 0.73 ng/ml; 6-min CPR, 3.48 ± 1.47-3.58 ± 1.21 ng/ml. Insulin secretion capacity, CPI and SUIT index at baseline did not predict the efficacy of the combination therapy. The final dosages of glimepiride and gliclazide were 1.44 ± 0.90 mg and 34.5 ± 15.3 mg respectively. The dosage of sitagliptin was increased from 50 mg to 69.0 ± 24.5 mg in 52-week. CONCLUSIONS: The combination therapy with sitagliptin and low dosage sulphonylureas was safe and effective for glycaemic control. Glucagon loading test indicated that 1 year administration of sitagliptin and sulphonylureas preserved insulin secretion capacity.

Psychological adjustment and psychosocial stress among Japanese couples with a history of recurrent pregnancy loss.

BACKGROUND: Little is known about the effects of recurrent pregnancy loss (RPL) on the psychological adjustment of couples. The aim of this study was to elucidate psychological adjustment and RPL-associated psychosocial stress affecting Japanese couples with a history of RPL, focusing on gender differences and quality of the marital relationship. METHODS: The study included 76 RPL couples who visited the outpatient clinic of a tertiary hospital. They completed self-administered questionnaires that assessed RPL-associated stress, quality of their marital relationship (Quality Marriage Index, QMI), depression (Beck Depression Index) and anxiety (State-Trait Anxiety Inventory). RESULTS: Women showed significantly higher levels of depression, anxiety and RPL-associated personal and social stress compared with men. Although there were no differences in QMI scores and RPL-associated marital stress between men and women, women with a low perception of marital relationship quality (low QMI) had significantly higher levels of depression and anxiety compared with women with a moderate or high QMI. In contrast, depression and anxiety scores did not differ according to the quality of the marital relationship among men. Of 76 couples, 26 men (34%) and 45 women (59%) who had considered professional mental health consultations regarding their RPL status but had not yet initiated the process were more depressed and anxious than 48 men and 24 women, respectively, who had never considered such consultation. CONCLUSIONS: Women were significantly more distressed than men. Poor quality of the marital relationship was significantly associated with impaired psychological adjustment among women, but not among men. These gender discrepancies may foster a mutual worsening of psychological adjustment and marital relationships in RPL couples. The need to seek help not only in women but also in a substantial portion of men suggests the importance of couple-based psychological care in the management of RPL.

A design of backing seat and gasket assembly in diamond anvil cell for accurate single crystal x-ray diffraction to 5 GPa.

We designed a new cell assembly of diamond anvil cells for single crystal x-ray diffraction under pressure and demonstrate the application of the cell to the crystallographic studies for ice VI and ethanol high-pressure (HP) phase at 0.95(5) GPa and 1.95(2) GPa, respectively. The features of the assembly are: (1) the platy anvil and unique-shaped backing seat (called as "Wing seat") allowing the extremely wide opening angle up to ±65°, (2) the PFA-bulk metallic glass composite gasket allowing the easy attenuation correction and less background. Thanks to the designed assembly, the R(int) values after attenuation corrections are fairly good (0.0125 and 0.0460 for ice VI and ethanol HP phase, respectively), and the errors of the refined parameters are satisfactory small even for hydrogen positions, those are comparable to the results which obtained at ambient conditions. The result for ice VI is in excellent agreement with the previous study, and that for ethanol HP phase has remarkable contributions to the revision to its structure; the H12 site, which makes gauche molecules with O1, C2, and C3 sites, may not exist so that only trans conformers are present at least at 1.95(2) GPa. The accurate intensities using the cell assembly allow us to extract the electron density for ethanol HP phase by the maximum entropy method.

Desorption of cluster ions from solid Ne by low-energy ion impact.

We investigated Ne(+) ions and Ne(n)(+) (n = 2-20) cluster ions desorbed from the surface of solid Ne by 1.0 keV Ar(+) ion impact. Kinetic energy analysis shows a considerably narrower energy distribution for Ne(n)(+) (n ≥ 3) ions than for Ne(n)(+) (n = 1, 2) ions. The dependence of ion yields on Ne film thickness indicates that cluster ions (n ≥ 3) are desorbed only from relatively thick films. We conclude that desorbed ions grow into large cluster ions during the outflow of deep bulk atoms to the vacuum.

Potential sputtering of ionic species from rare gas solids by multiply charged ion impact.

The interaction of low-energy multiply charged Ar(q +) (q ≤ 7) ions with a solid Ne surface is experimentally studied. Desorption of very large cluster ions Nen (+) (n > 100) is observed. The size distribution of smaller (n = 1-3) cluster ions depends strongly on the charge state of the incident ion, whereas that of larger (n > 7) cluster ions exhibits no dependence on the charge state, indicating that desorption of large cluster ions is due to kinetic sputtering. The potential sputtering yield is estimated by analyzing the size distribution of the desorbed cluster ions. The results suggest that the ion desorption mechanism, which is known as desorption induced by electronic transitions, can also be applied to explain the present results.

Pulmonary involvement of autoimmune pancreatitis.

BACKGROUND: A wide variety of systemic lesions have been seen in patients with autoimmune pancreatitis. The pulmonary involvement of autoimmune pancreatitis was analysed to clarify the clinicopathological features of pulmonary lesions in comparison with pulmonary sarcoidosis. MATERIALS AND METHODS: Nineteen patients had autoimmune pancreatitis and eight had pulmonary sarcoidosis. The symptoms, laboratory data, chest computed tomography, Gallium-67 scintigraphy, pulmonary function testing and bronchoscopy findings, including the histological IgG4-immunostaining and IgG subclasses in the bronchoalveolar lavage in autoimmune pancreatitis, were collected to compare them with pulmonary sarcoidosis. RESULTS: The serum total protein, IgG and IgG4 levels were found to be significantly elevated in comparison with pulmonary sarcoidosis. In autoimmune pancreatitis, 17 patients showed bilateral hilar lymphadenopathy, while eight showed pulmonary nodules on chest computed tomography. Eighteen of 19 patients on Gallium-67 scintigraphy showed accumulation spots in either the hilar or mediastinal lymph nodes. Six patients with pulmonary nodules demonstrated accumulation spots in the corresponding lesions on chest computed tomography. All eight patients with pulmonary sarcoidosis showed accumulation spots in either the hilar or mediastinal lymph nodes. Bronchoalveolar lavage IgG4 in autoimmune pancreatitis showed a significant increase in comparison with pulmonary sarcoidosis. The histological findings obtained by a transbronchial lung biopsy showed the infiltration of lymphocytes and plasma cells in the thickened interstitum and alveoli with IgG4-positive plasma cell infiltration in patients with autoimmune pancreatitis. CONCLUSION: IgG4 in the bronchoalveolar lavage was seen at remarkably increased levels and IgG4-positive plasma cells were identified in the pulmonary lesions of patients with autoimmune pancreatitis.