Tumor immune microenvironment and nivolumab efficacy in EGFR mutation-positive non-small-cell lung cancer based on T790M status after disease progression during EGFR-TKI treatment.

BACKGROUND: The efficacy of programmed death-1 blockade in epidermal growth factor receptor gene (EGFR) mutation-positive non-small-cell lung cancer (NSCLC) patients with different mechanisms of acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) is unknown. We retrospectively evaluated nivolumab efficacy and immune-related factors in such patients according to their status for the T790M resistance mutation of EGFR. PATIENTS AND METHODS: We identified 25 patients with EGFR mutation-positive NSCLC who were treated with nivolumab after disease progression during EGFR-TKI treatment (cohort A). Programmed death-ligand 1 (PD-L1) expression and tumor-infiltrating lymphocyte (TIL) density in tumor specimens obtained after acquisition of EGFR-TKI resistance were determined by immunohistochemistry. Whole-exome sequencing of tumor DNA was carried out to identify gene alterations. The relation of T790M status to PD-L1 expression or TIL density was also examined in an independent cohort of 60 patients (cohort B). RESULTS: In cohort A, median progression-free survival (PFS) was 2.1 and 1.3 months for T790M-negative and T790M-positive patients, respectively (P = 0.099; hazard ratio of 0.48 with a 95% confidence interval of 0.20-1.24). Median PFS was 2.1 and 1.3 months for patients with a PD-L1 expression level of ≥1% or <1%, respectively (P = 0.084; hazard ratio of 0.37, 95% confidence interval of 0.10-1.21). PFS tended to increase as the PD-L1 expression level increased with cutoff values of ≥10% and ≥50%. The proportion of tumors with a PD-L1 level of ≥10% or ≥50% was higher among T790M-negative patients than among T790M-positive patients of both cohorts A and B. Nivolumab responders had a significantly higher CD8+ TIL density and nonsynonymous mutation burden. CONCLUSION: T790M-negative patients with EGFR mutation-positive NSCLC are more likely to benefit from nivolumab after EGFR-TKI treatment, possibly as a result of a higher PD-L1 expression level, than are T790M-positive patients.

Initial Atomic Motion Immediately Following Femtosecond-Laser Excitation in Phase-Change Materials.

Despite the fact that phase-change materials are widely used for data storage, no consensus exists on the unique mechanism of their ultrafast phase change and its accompanied large and rapid optical change. By using the pump-probe observation method combining a femtosecond optical laser and an x-ray free-electron laser, we substantiate experimentally that, in both GeTe and Ge_{2}Sb_{2}Te_{5} crystals, rattling motion of mainly Ge atoms takes place with keeping the off-center position just after femtosecond-optical-laser irradiation, which eventually leads to a higher symmetry or disordered state. This very initial rattling motion in the undistorted lattice can be related to instantaneous optical change due to the loss of resonant bonding that characterizes GeTe-based phase change materials. Based on the amorphous structure derived by first-principles molecular dynamics simulation, we infer a plausible ultrafast amorphization mechanism via nonmelting.

Hot electron relaxation dynamics in semiconductors: assessing the strength of the electron-phonon coupling from the theoretical and experimental viewpoints.

The rapid development of the computational methods based on density functional theory, on the one hand, and of time-, energy-, and momentum-resolved spectroscopy, on the other hand, allows today an unprecedently detailed insight into the processes governing hot-electron relaxation dynamics, and, in particular, into the role of the electron-phonon coupling. Instead of focusing on the development of a particular method, theoretical or experimental, this review aims to treat the progress in the understanding of the electron-phonon coupling which can be gained from both, on the basis of recently obtained results. We start by defining several regimes of hot electron relaxation via electron-phonon coupling, with respect to the electron excitation energy. We distinguish between energy and momentum relaxation of hot electrons, and summarize, for several semiconductors of the IV and III-V groups, the orders of magnitude of different relaxation times in different regimes, on the basis of known experimental and numerical data. Momentum relaxation times of hot electrons become very short around 1 eV above the bottom of the conduction band, and such ultrafast relaxation mechanisms are measurable only in the most recent pump-probe experiments. Then, we give an overview of the recent progress in the experimental techniques allowing to obtain detailed information on the hot-electron relaxation dynamics, with the main focus on time-, energy-, and momentum-resolved photoemission experiments. The particularities of the experimental approach developed by one of us, which allows to capture time-, energy-, and momentum-resolved hot-electron distributions, as well as to measure momentum relaxation times of the order of 10 fs, are discussed. We further discuss the main advances in the calculation of the electron-phonon scattering times from first principles over the past ten years, in semiconducting materials. Ab initio techniques and efficient interpolation methods provide the possibility to calculate electron-phonon scattering times with high precision at reasonable numerical cost. We highlight the methods of analysis of the obtained numerical results, which allow to give insight into the details of the electron-phonon scattering mechanisms. Finally, we discuss the concept of hot electron ensemble which has been proposed recently to describe the hot-electron relaxation dynamics in GaAs, the applicability of this concept to other materials, and its limitations. We also mention some open problems.

A multicenter study of leukocytapheresis in rheumatoid arthritis.

OBJECTIVE: To evaluate the efficacy and safety of leukocytapheresis (LCAP) in patients with rheumatoid arthritis (RA) that is refractory to disease modifying antirheumatic drugs (DMARDs), we conducted a prospective, multicenter, open-label clinical trial. METHODS: We enrolled 38 active RA patients, including 32 patients who showed an inadequate response to > or = 2 DMARDs and 6 patients with rapidly progressive RA. All patients continued drug therapy and were treated with 5 LCAP sessions conducted at 1-week intervals. The clinical response was evaluated at baseline before starting LCAP and at 4 weeks after the completion of all the LCAP sessions using the American College of Rheumatology (ACR) criteria and the 28-joint disease activity score (DAS28) of the European League Against Rheumatism (EULAR). RESULTS: Of the 35 patients who fulfilled the study's eligibility criteria, 24 (69%), 10 (29%), and 23 (66%) patients achieved 20% (ACR20), 50% (ACR50), and DAS28-C-reactive protein (CRP) EULAR improvement, respectively. The mean DAS28-CRP score of the 35 patients decreased significantly from 5.99 +/- 0.92 at baseline to 4.54 +/- 1.39 after treatment. Comparison analysis of the ACR20 responders and non-responders to LCAP revealed that 22 of 24 responders (92%) concomitantly received methotrexate, whereas significantly fewer, that is, 6 of 11 non-responders (55%) received methotrexate. Less frequent and transient mild-to-moderate adverse events, including nausea and headache, were seen in 12 of 189 LCAP sessions (6.3%). CONCLUSION: These results demonstrate the usefulness of LCAP in combination with DMARDs, particularly methotrexate, as an effective and safe treatment for refractory RA.

A non-acromegalic case of multiple endocrine neoplasia type 1 accompanied by a growth hormone-releasing hormone-producing pancreatic tumor.

Cases of acromegaly due to GHRHproducing pancreatic endocrine tumors have been reported. Here we present a case of a 31-yr-old nonacromegalic man with hyperparathyroidism and elevated serum IGF-I with normal serum GH levels. Serum GH was not suppressed below 1 ng/ml by the glucose tolerance test and increased in response to TR H and GHRH administration. Magnetic resonance imaging (MRI) revealed pituitary hyperplasia and an abdominal computed tomography (CT ) scan showed a tumor in the pancreatic tail. Plasma concentration of GHRH was elevated. Based on these clinical data, multiple endocrine neoplasia (MEN) type 1 was suspected. Three enlarged parathyroid glands were removed and a distal pancreatectomy was performed. Pathological examination of the parathyroid glands and pancreatic tumor showed nodular hyperplasia and a well-differentiated endocrine tumor, respectively, both compatible with MEN features. Immunohistochemistry revealed positive immunoreactivity for GHRH, SS , insulin, glucagon, chromogranin A, and pancreatic polypeptide in the pancreatic tumor. After pancreatic surgery, elevated levels of GHRH and IGF-I were normalized and pituitary hyperplasia definitely decreased in size. In cases of pituitary hyperplasia with elevated IGF-I, ectopic GHRH syndrome must be considered even if physical features of acromegaly are absent. It is also important to measure plasma GHRH concentrations in order to give a diagnosis.

Optical signatures of intrinsic electron localization in amorphous SiO2.

We measure and analyse the optical absorption spectra of three silica glass samples irradiated with 1 MeV electrons at 80 K, where self-trapped holes are stable, and use ab initio calculations to demonstrate that these spectra contain a signature of intrinsic electron traps created as counterparts to the holes. In particular, we argue that optical absorption bands peaking at 3.7, 4.7, and 6.4 eV belong to strongly localised electrons trapped at precursor sites in amorphous structure characterized by strained Si-O bonds and O-Si-O angles greater than 132°. These results are important for our understanding of the properties of silica glass and other silicates as well as the reliability of electronic and optical devices and for luminescence dating.

Sympathomimetic amines having a carbostyril nucleus.

A series of new sympathomimetic amines containing an 8-hydroxycarbostyril moiety was synthesized. These compounds probably exist as resonance hybrids having two acidic hydrogen atoms in locations approximating to those of the hydroxyl groups of catechol-containing adrenergic agents. In an in vitro test, many of these compounds showed potent activity for relaxation of guinea pig tracheal smooth muscle. One of the compounds was 24 000 times more potent than isoproterenol. Their actions on cardiac muscle were also examined in vitro by measuring increase in the beating rate of the right atria of guinea pigs. Several of the compounds appeared to be beta-selective. Some of the compounds seem suitable for use as bronchodilators. The structure-activity relationships of these compounds were discussed in comparison with those of catecholamines.

Multiple myeloma evaluated with 201Tl scintigraphy compared with bone scintigraphy.

UNLABELLED: The purpose of this study was to investigate the clinical usefulness of 201Tl chloride scintigraphy in the diagnostic evaluation of 20 patients with multiple myeloma (19/20 patients) or extramedullary plasmacytoma (1/20 patients) in comparison with bone scintigraphy. METHODS: Both 201Tl and bone scintigraphy were performed to obtain planar images on the same instrument. RESULTS: 201Tl scintigraphy showed increased uptake in 15 of 20 patients (75%) and was negative in 5 of 20 patients (25%). In addition, 201Tl scintigraphy of multiple myeloma was more useful in detecting the lesions in 11 of 17 patients and less useful in 6 of 17 patients than bone scintigraphy. CONCLUSION: The combination of 201Tl and bone scintigraphy, compared with bone scintigraphy alone, shows promise in more accurately diagnosing multiple myeloma.

Production mechanism of crackles in excised normal canine lungs.

Lung crackles may be produced by the opening of small airways or by the sudden expansion of alveoli. We studied the generation of crackles in excised canine lobes ventilated in an airtight box. Total airflow, transairway pressure (Pta), transpulmonary pressure (Ptp), and crackles were recorded simultaneously. Crackles were produced only during inflation and had high-peak frequencies (738 +/- 194 Hz, mean +/- SD). During inflation, crackles were produced from 111 +/- 83 ms (mean +/- SD) prior to the negative peak of Pta, presumably when small airways began to open. When end-expiratory Ptp was set constant between 15 and 20 cmH2O and end-expiratory Ptp was gradually reduced from 5 cmH2O to -15 or -20 cmH2O in a breath-by-breath manner, crackles were produced in the cycles in which end-expiratory Ptp fell below -1 to 1 cmH2O. This pressure was consistent with previously known airway closing pressures. When end-expiratory Ptp was set constant at -10 cmH2O and end inspiratory Ptp was gradually increased from -5 to 15 or 20 cmH2O, crackles were produced in inspiratory phase in which end-inspiratory Ptp exceeded 4-6 cmH2O. This pressure was consistent with previously known airway opening pressures. These results indicate that crackles in excised normal dog lungs are produced by opening of peripheral airways and are not generated by the sudden inflation of groups of alveoli.

Bilateral hypoplastic internal carotid arteries with multiple cerebral aneurysms.

A 60-year-old man with massive subarachnoid hemorrhage is reported. Radiologically, bilateral occlusion of the internal carotid arteries and multiple cerebral aneurysms of the saccular type were detected. Postmortem examination revealed that the internal carotid arteries were markedly diminutive and completely occluded by mesenchymal fibrous tissue. The pathogenesis of the diminutive internal carotid arteries and the cerebral aneurysms were briefly discussed.

Two-year follow up on the protective value of dust masks against farmer's lung disease.

Some advocate moving away from the farm environment for farmers affected with farmer's lung disease (FLD), but most affected farmers still live on farms. In this study, we evaluated the practicality of dust masks and their effectiveness in prevention of FLD. The dust masks we chose were practically used and no new severe episodes of FLD developed in 20 of 21 farmers with FLD using the masks during a 2-year period. When the farmers took off the dust masks in a farming environmental provocation test, statistically significant reductions in FVC (mean 3.43 to 3.351, p < 0.01), DLco (mean 19.6 to 18.2 ml/torr/min, p < 0.01), and DL/VA (mean 5.1 to 4.8 (x10(-3)) 1/torr/min, p < 0.01) were observed several hours after exposure. These findings suggest that the dust masks were used practically during routine dairy farming and were effective in protection against FLD.

Smoking promotes insidious and chronic farmer's lung disease, and deteriorates the clinical outcome.

Although the prevalence of serum precipitating antibodies for farmer's lung disease (FLD) is lower in smokers than in nonsmokers and FLD predominates in nonsmokers, the affects of smoking on the clinical course of the disease is not known. We compared the clinical findings and the prognosis between 12 smokers (SM-FLD) and 31 non-smokers with FLD (NS-FLD). There was no difference in age, sex, working years on farm, clinical symptoms, laboratory findings, radiographic findings, between the two groups. However, for the type of onset on the first visit for FLD, "acute single episode" type was less common, and "recurrent" and "insidious onset" types were more common in SM-FLD than in NS-FLD (8.3 vs 58.1, 91.7 vs 41.9%, respectively, p < 0.05). Although working status and mask wearing status were not significantly different between the two groups after the diagnosis of FLD, patients with symptoms and/or radiographic abnormalities of FLD of more than 6 months were found more frequently in SM-FLD than in NS-FLD (66.7 vs 19.4%, p < 0.005). And also SM-FLD had more recurrences of FLD than NS-FLD after the initial diagnosis of FLD (1.58 +/- 1.56 vs 0.47 +/- 1.07, p < 0.05). SM-FLD tended to have lower % VC than NS-FLD (73.6 +/- 7.4 vs 88.5 +/- 3.9%, respectively, p = 0.06). Regarding the prognosis, the 10-year survival rates were 70.7% in SM-FLD, and 91.5% in NS-FLD (p < 0.05). These results suggest that smoking may make FLD insidious and chronic, and deteriorates the clinical outcome.

Extravasation from anterior choroidal artery in a child with moyamoya disease--case report.

A rare association of moyamoya disease with intra- and periventricular hemorrhage in an 8-year-old girl is presented. Angiography showed that the cause of hemorrhage was extravasation from the dilated anterior choroidal artery. Ventriculoperitoneal shunt and encephalomyosynangiosis have prevented clinical or neurological deficits for over 6 years.

[Determination of blood polyamines in patients with brain tumor -with special reference to relationship between varieties of tumors and concentrations of blood spermidine and spermine (author's transl)].

Examination of blood polyamines in 38 patients with brain tumor and 17 normal volunteers was carried out by columnar chromatography--cellulose acetate membrane electrophoresis. The upper limits of the normal values; M.+2S.D. of the blood polyamine concentrations in 17 normal volunteers, were less than 2.1 mg/ml for spermidine, less than 1.6 mg/ml for spermine, and less than 2.2 mg/ml for spermidine plus spermine. The values of blood polyamines in 21 cases with glioma were significantly higher than those in normal subjects (p less than 0.01). And in 14 out of them, the concentrations of the blood polyamines were higher than the maximum normal value. In one case with reticulum cell sarcoma, the concentrations of the blood polyamines were remarkably increased. In 2 out of 4 cases with metastatic brain tumor the concentration of the blood polyamines were higher than the upper limit of normal amount, and values of the blood polyamines in 4 cases with metastatic brain tumor were significantly higher than those in normal volunteers (p less than 0.05). In none of 2 cases with pituitary adenoma, 3 cases with meningioma, 4 cases with neurinoma, one case with hemangioblastoma, and one case with pinealoma, the values of the blood polyamines were significantly higher than those in normal volunteers. The CSF samples obtained from 9 patients with brain tumor, consisted of 6 gliomas (glioblastoma multiforme 2, anaplastic glioma 4), 1 teratoblastoma, 1 von Recklinghausen's disease (neurinoma and meningioma), and 1 craniopharyngioma, were analyzed for detection of polyamines, but no detectable amount was present in those cases.

[A case of brain metastasis of rhabdomyosarcoma in a child].

We report here a specific case of metastatic brain tumor orienting from rhabdomyosarcoma. An 11-year-old boy came to our hospital with complaints including headache, exophthalmos and tumors in the right frontal and left occipital region. 6 months previously subtotal removal of rhabdomyosarcoma in his right foot had been performed. CT scan demonstrated tumors in the right orbit, right frontal region and left occipital region. The tumors existed bilaterally in the skull and markedly enhanced by contrast medium. But the changes of the cranium were mild, only the dipole was slightly dilated. MRI showed that the tumors were extraaxial masses. Right external carotid angiogram revealed numerous tumor vessels fed by the meningeal artery. On April 3rd, biopsy was performed at the right frontal region. The tumor had spread in the epidural space but the cortical surface seemed to be intact. Histologically, the tumor consisted of small round cells and revealed multinuclear giant cells. It involved the skull bone, dura mater and subdural tissues. Accordingly the tumor was diagnosed as rhabdomyosarcoma. Although tumor increased rapidly, the intracranial region did not change remarkably. It was an interesting phenomenon. Eventually, rhabdomyosarcoma metastasized to the lung, and the patient died due to respiratory distress.

[Correlation between diffuse alpha wave pattern of EEG and hyperfrontal pattern of regional cerebral blood flow].

Regional cerebral blood flow (rCBF) was measured in three groups; (1) 20 healthy subjects, (2) 14 patients with diffuse alpha wave pattern of EEG, (3) 14 patients without diffuse alpha wave pattern matching with ages of group 2. In the group 2, one patient with transient ischemic attack, 7 with reversible ischemic neurological deficit, 3 with vertebro-basilar insufficiency, 2 with minor stroke and one with posttraumatic sequelae were selected for rCBF measurements. In the group 3, 3 patients with transient ischemic attack, 7 with reversible ischemic neurological deficit, 2 with vertebro-basilar insufficiency and 2 with minor stroke were selected for rCBF measurements. Electroencephalographic analyses were performed by using a BERG-Fourier Analyzer, simultaneously with rCBF measurements. All patients in the group 2 had diffuse alpha wave (generalized continuous simple rhythmic alpha wave--Hori et al) pattern of EEG. Regional cerebral blood flow measurement was performed with intracarotid injection method of 133Xe (10 mCi) by using the scintillation camera and on-line computer system. 133Xe clearance curve from the whole hemisphere were computed by height over area method. Regional value were obtained from brain areas of 6 mm X 6 mm. Mean hemispheric values were 59.2 +/- 7.9 ml/100 g/min in the group 1, 47.8 +/- 4.9 ml/100 g/min in the group 2 and 49.0 +/- 3.7 ml/100 g/min in the group 3. Although difference between group 2 and 3 was not significant, difference between group 1 and 2 was significant (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

[Immunological surveillance mechanism of a rat brain tumor model--study of time-lapse changes in the concomitant immunity of peripheral blood lymphocytes by microcytotoxicity assays (author's transl)].

A rat brain tumor model was prepared by semi-stereotactically implanting 1 x 10(6) RG--C6 tumor cells (chemically induced and maintained in vitro) in the right caudate nucleus of inbred WKA rat by a new method "Soft Agar Technique" which we developed. The tumor grew at a nearly fixed rate. We measured the maximum tumor area and the whole brain area of the rat brain which were sectioned coronary in series. We regarded the percentage of the tumor area to the whole area of the same section as tumor growth index. Microcytotoxicity assays of peripheral blood lymphocytes were performed at various stages of the tumor growth. RG--C6 cells were used as target cells, and they mixed with lymphocytes by Takasugi and Klein's method. Cytotoxicity index was higher in 22 cases (80.00 +/- 16.67; tumor growth index, 0--10) than in 28 cases of the control group (67. 25 +/- 19.68) and then gradually decreased with tumor growth (Fig. 2). At last cytotoxicity index went down to 41.55 +/- 24.94 in 11 cases (tumor growth index, over 31). These observations have a strong resemblance to other animal tumor models and suggest that the rat having brain tumor intra-axially have concomitant immunity especially in the first stage of tumor bearing.

[Hemodynamic changes during pneumonectomy especially changes of right ventricular ejection fraction].

Hemodynamic changes were studied in 14 patients during pneumonectomy using a rapid computerized thermodilution catheter, which is capable of measuring right ventricular ejection fraction (RVEF). Measurements were also performed during perioperative period. Ten minutes after clamping pulmonary artery, RVEF, pulmonary artery resistance index (PVRI) and stroke volume index (SVI) showed an increased right ventricular afterload. The RVEF is a useful and fast responding monitor of right ventricular afterload. It has been suggested that the PVRI may be a reliable safety index to decide the indication of pneumonectomy. We conclude that the right ventricular ejection fraction measured by a rapid computerized thermodilution catheter, can be helpful in hemodynamic monitoring during perioperative period of pneumonectomy.

[Neuro-psychiatric involvement in primary Sjögren's syndrome].

Neuro-psychiatric involvement in primary Sjögren's syndrome (PSJS) has been summarized according to the literature. Sjögren's syndrome is an autoimmune disorder with a predilection for multi-system involvement. Recently, disorders of the peripheral nervous system (PNS) and central nervous system (CNS) in PSJS, as well as, other organ involvement has been reported increasingly. However, CNS involvement, including the symptoms mimicking multiple sclerosis in PSJS is a controversial issue. There is discrepancy in the frequency of CNS involvement in PSJS among investigators. As for psychiatric manifestations in PSJS, descriptions have been made by many investigators. Depression and anxiety are the most common psychiatric manifestations in PSJS. About 10% of the patients with SJS have a neuropathy which tends to predilect for trigeminal nerve involvement. Further investigations elucidating the mechanisms of neuro-psychiatric involvement in PSJS is required.