JCOG0911 INTEGRA study: a randomized screening phase II trial of interferonβ plus temozolomide in comparison with temozolomide alone for newly diagnosed glioblastoma

Purpose

This study explored the superiority of temozolomide (TMZ)?+?interferonβ (IFNβ) to standard TMZ as treatment for newly diagnosed glioblastoma (GBM) via randomized phase II screening design.

Experimental design

Eligibility criteria included histologically proven GBM, with 50% of the tumor located in supratentorial areas, without involvement of the optic, olfactory nerves, and pituitary gland and without multiple lesions and dissemination. Patients in the TMZ?+?radiotherapy (RT) arm received RT (2.0 Gy/fr/day, 30 fr) with TMZ (75 mg/m², daily) followed by TMZ maintenance (100–200 mg/m²/day, days 1–5, every 4 weeks) for 2 years. Patients in the TMZ?+?IFNβ?+?RT arm intravenously received IFNβ (3 MU/body, alternative days during RT and day 1, every 4 weeks during maintenance period) and TMZ?+?RT. The primary endpoint was overall survival (OS). The planned sample size was 120 (one-sided alpha 0.2; power 0.8).

Results

Between Apr 2010 and Jan 2012, 122 patients were randomized. The median OS with TMZ?+?RT and TMZ?+?IFNβ?+?RT was 20.3 and 24.0 months (HR 1.00, 95% CI 0.65–1.55; one-sided log rank P?=?0.51). The median progression-free survival times were 10.1 and 8.5 months (HR 1.25, 95% CI 0.85–1.84). The incidence of neutropenia with the TMZ?+?RT and the TMZ?+?IFNβ?+?RT (grade 3–4, CTCAE version 3.0) was 12.7 versus 20.7% during concomitant period and was 3.6 versus 9.3% during maintenance period. The incidence of lymphopenia was 54.0 versus 63.8% and 34.5 versus 41.9%.

Conclusions

TMZ?+?IFNβ?+?RT is not considered as a candidate for the following phase III trial, and TMZ?+?RT remained to be a most promising treatment. This trial was registered with the UMIN Clinical Trials Registry: UMIN000003466.

     

Association of serum chloride level with mortality and cardiovascular events in chronic kidney disease: the CKD-ROUTE study

Clinical and Experimental Nephrology - Electrolyte abnormalities, particularly dysnatremia, are independent predictors of adverse outcome in individuals with and without renal failure. However, the...     

Significant on-call misses by radiology residents interpreting computed tomographic studies: Perception versus cognition

The purpose of this study was to evaluate the etiology of significant false-negative computed tomographic (CT) interpretations by radiology residents on-call. Over a 1-year period, significant on-call false-negative CT interpretations were analyzed to determine whether errors were perceptual (i.e., the resident did not see the finding or findings) or cognitive (i.e., the resident did not recognize the implications or misinterpreted a finding or findings). Significant misses were defined as errors that delayed surgical treatment or misdirected management in a potentially life-threatening manner.A total of 12 significant false-negative interpretations occurred over a 1-year period. All head CT misses (extraaxial hemorrhage, pneumocephalus, contusion, subarachnoid hemorrhage due to ruptured aneurysm) were perceptual errors. Misses on thoracic, abdominal, and pelvic CT scans (2 abscesses, abdominal aortic aneurysm rupture, superior vena cava perforation due to catheter placement, ischemic bowel, liver laceration, hypoperfusion syndrome, appendicitis) were mixed (4 cognitive and 4 perceptual errors).Since the diagnostic possibilities of emergency head CT scans are limited, residents missed only subtle, perceptual manifestations and had little difficulty interpreting findings when they were correctly recognized. The gamut of diagnostic possibilities in the thorax, abdomen, and pelvis was more challenging to residents on-call; errors in both perception and interpretation arose with equal frequency, and the significant error rate was higher than that for head CT interpretation. Junior residents, who make most of the significant on-call errors, commonly feel overwhelmed in attempting to assimilate the knowledge required to take call. Prepartion needs to be extensive, yet it should be focused on areas that will engender optimal impact on after-hours performance. When preparing residents to interpret on-call CT studies, perceptual manifestations of neuroradiology should be emphasized, whereas a more comprehensive approach to thoracic, abdominal, and pelvic disorders needs to be stressed.Presented at the 8th Annual Meeting of the American Society of Emergency Radiology, New Orleans, March 20, 1997     

Failed spinal anaesthesia: cause identified by MRI

Purpose

To determine the cause of failed spinal anaesthesia, magnetic resonance images of the lumbar spine were examined.

Clinical futures

A 28-yr-old woman, scheduled for closure of a rectal fistula under spinal anaesthesia, hyperbaric tetracaine 12.5 mg injected into the subarachnoid space at L_3–4 repeatedly resulted in restricted sacral spread. Magnetic resonance imaging showed that the cylindrical dimension of the lumbar spinal canal was wider than in normal subjects, suggesting a larger volume of CSF within the dural sac below the termination of the cord. The summit of the lumbar convexity was located at L₃, which was more cephalad than the L_3–4 puncture site.

Conclusion

The uncommon anatomical characteristics of the lumbar spinal canal identified by magnetic resonance imaging were considered to be the reason for the restricted sacral spread observed repeatedly in this patient.     

Sevoflurane anaesthesia for a patient with adult polyglucosan body disease

Purpose

Adult polyglucosan body disease (APBD) is a rare neurological disorder of unknown cause characterized by four manifestations: upper motor neuron signs, peripheral neuropathy with motor and sensory loss, urinary incontinence, and dementia. The purpose of this report is to present a patient with APBD anaesthetized successfully with sevoflurane and nitrous oxide.

Clinical feature

A 51-yr-old man with APBD was scheduled for haemorrhoidectomy. Paraesthesia, dysaesthesia, distal muscular atrophy and fasciculation were recognized in the extremities. Dementia, bulbar paralysis and respiratory insufficiency were absent. Anaesthesia was induced with inhalation of sevoflurane and nitrous oxide, and the trachea was intubated without the use of muscle re taxants. Maintenance of anaesthesia was performed with sevoflurane (inspired concentration: 1.5–2.5 %) and nitrous oxide (50%). Emergence from anaesthesia and the postoperative course were uneventful, and no exacerbation of neurological signs and symptoms was recognized. No postoperative analgesia was required.

Conclusion

General anaesthesia and tracheal intubation with sevoflurane and nitrous oxide provided safe anaesthesia for a patient with APBD.     

NGF-induced phosphatidylinositol 3-kinase signaling pathway prevents thapsigargin-triggered ER stress-mediated apoptosis in PC12 cells

Tunicamycin, an inhibitor of the glycosylation of newly biosynthesized proteins, induces endoplasmic reticulum (ER) stress and subsequent apoptosis, and caspase family proteases are activated during the process of ER stress-mediated apoptosis. In the present study, we showed that thapsigargin (Th), an inhibitor of the sarcoplasmic/endoplasmic reticulum Ca(2+) ATPase (SERCA), also induced ER stress-mediated apoptosis, and nerve growth factor (NGF) prevented the apoptosis in PC12 cells. We also found that LY 294002, an inhibitor of phosphatidylinositol 3-kinase (PI 3-K), reduced the survival of cells treated with NGF for 24h in the presence of Th. We discovered that the activities of caspase-3, -9 and -12 were increased time-dependently after the treatment with Th, and NGF suppressed the Th-triggered activation of caspase-3, -9 and -12. LY 294002 diminished the effect of NGF on the inactivation of all these caspases. These results indicate that the NGF-induced PI 3-K signaling pathway prevents Th-triggered ER stress-specific apoptosis via inhibition of caspase-mediated apoptotic signal.     

Perception of apparent motion in depth: a high-density electrical mapping study in humans

We evaluated brain activity using 64-channel visual evoked potentials (VEPs) while subjects perceived apparent motion in depth. Checkerboard patterns (CBPs) within small and large circles were presented in turn as experimental conditions. Motion in depth was perceived when the CBP in the large circle was coarser than in the small circle; when coarseness did not change, no motion in depth was perceived. As control conditions only fine or coarse CBPs were presented. We used ANOVA to compare VEPs associated with experimental vs. control conditions and with coarse vs. fine CBPs. Negative potentials at a latency near 190 ms showed statistically significant interactions between these comparisons in the right lateral occipital and posterior parietal areas when apparent motion in depth was perceived. This suggests that higher tiers of the dorsal stream mediate this motion perception.     

Alteration of intestinal intraepithelial lymphocytes and increased bacterial translocation in a murine model of cirrhosis

Alterations in immunological defense in the gut may lead to the bacterial infection that is frequently associated with cirrhosis of the liver. The aim of this study was to investigate the changes in distribution and function of intestinal intraepithelial lymphocytes (IELs) in relation to intestinal barrier dysfunction in experimental cirrhosis. Cirrhosis was induced in mice by treatment with carbon tetrachloride (CCl4) intraperitoneally with 5% alcohol in drinking water for 12 weeks. Bacterial translocation was assessed in mesenteric lymph nodes (MLNs) by the transport of fluorescence-labeled latex beads and by bacteriological cultures. The lymphocyte subpopulation was compared in three groups (cirrhosis, alcohol alone and controls). IFN-gamma production from isolated IELs was determined by ELISA after stimulation with anti-CD3 or IL-12/IL-18. The total number of IELs significantly increased in the cirrhosis and alcohol groups. There was a preferential increase in TCRgammadelta+CD8+ population in the alcohol group, but no change in cirrhosis. Bacterial translocation was negative in the control group, and a small number was noted in the alcohol group, whereas it was significantly noted in the cirrhosis group. Although the number of IEL was significantly increased in the cirrhosis group, their proliferative response was decreased, and IFN-gamma production from each IEL was markedly diminished in either stimulation by anti-CD3 or IL-12/IL-18. These changes were more remarkable in the cirrhosis group than in the alcohol group. In conclusion, bacterial translocation due to intestinal barrier dysfunction in cirrhosis may be closely correlated with the alteration of the immune function in IELs.     

Mechanisms of mechanical heart valve cavitation in an electrohydraulic total artificial heart

Until now, we have estimated cavitation for mechanical heart valves (MHV) mounted in an electrohydraulic total artificial heart (EHTAH) with tap water as a working fluid. However, tap water at room temperature is not a proper substitute for blood at 37 degrees C. We therefore investigated MHV cavitation using a glycerin solution that was identical in viscosity and vapor pressure to blood at body temperature. In this study, six different kinds of monoleaflet and bileaflet valves were mounted in the mitral position in an EHTAH, and we investigated the mechanisms for MHV cavitation. The valve closing velocity, pressure drop measurements, and a high-speed video camera were used to investigate the mechanism for MHV cavitation and to select the best MHV for our EHTAH. The closing velocity of the bileaflet valves was slower than that of the monoleaflet valves. Cavitation bubbles were concentrated on the edge of the valve stop and along the leaflet tip. It was established that squeeze flow holds the key to MHV cavitation in our study. Cavitation intensity increased with an increase in the valve closing velocity and the valve stop area. With regard to squeeze flow, the Bj?rk-Shiley valve, because it is associated with slow squeeze flow, and the bileaflet valve with low valve closing velocity and small valve stop areas are better able to prevent blood cell damage than the monoleaflet valves.     

Population-Based Observational Study of Adverse Drug Event-Related Mortality in the Super-Aged Society of Japan

Introduction

Adverse drug events (ADEs) are a major cause of mortality.

Objective

We examined long-term trends for ADE-related deaths in Japan.

Methods

This observational study was conducted using the Japanese Vital Statistics from 1999 to 2016. Data for all ADE-related deaths were extracted using International Classification of Diseases, Tenth Revision codes. We analysed ADE-related deaths by age and sex and calculated crude and age-standardised mortality rates (ASMR) per 100,000 people. We used Joinpoint regression analysis to identify significant changing points in mortality trends and to estimate annual percentage change (APC).

Results

In total, 16,417 ADE-related deaths were identified. The crude mortality rate for individuals aged ≥ 65 years was higher than that of young individuals. The ASMR per 100,000 people increased from 0.44 in 1999 to 0.64 in 2016. The crude mortality rate increased from 0.44 in 1999 to 1.01 in 2016. The APC of ASMR increased at a rate of 2.8% (95% confidence interval [CI] 1.4–4.2) throughout the study period. In addition, crude mortality increased at a rate of 5.7% (95% CI 4.2–7.3) annually from 1999 to 2016. The ADE-related mortality rate was higher for men than for women during the study period.

Conclusions

The number of and trend in ADE-related deaths increased in Japan from 1999 to 2016, particularly in the older population.