Purpose

Ras/Raf/MEK/ERK signaling is critical for tumor cell proliferation and survival. Selumetinib is a potent, selective, and orally available MEK1/2 inhibitor. In the current study, we evaluated the therapeutic efficacy of selumetinib alone or with cediranib, an orally available potent inhibitor of all three VEGFR tyrosine kinases, in murine orthotopic NSCLC models.

Experimental Design

NCI-H441 or NCI-H460 KRAS-mutant human NSCLC cells were injected into the lungs of mice. Mice were randomly assigned to treatment with selumetinib, cediranib, paclitaxel, selumetinib plus cediranib, or control. When controls became moribund, all animals were sacrificed and assessed for lung tumor burden and locoregional metastasis. Lung tumors and adjacent normal tissues were subjected to immunohistochemical analyses.

Results

Selumetinib inhibited lung tumor growth and, particularly at higher dose, reduced locoregional metastasis, as did cediranib. Combining selumetinib and cediranib markedly enhanced their antitumor effects, with near complete suppression of metastasis. Immunohistochemistry of tumor tissues revealed that selumetinib alone or with cediranib reduced ERK phosphorylation, angiogenesis, and tumor cell proliferation and increased apoptosis. The antiangiogenic and apoptotic effects were substantially enhanced when the agents were combined. Selumetinib also inhibited lung tumor VEGF production and VEGFR signaling.

Conclusions

In the current study, we evaluated therapy directed against MEK combined with antiangiogenic therapy in distinct orthotopic NSCLC models. MEK inhibition resulted in potent antiangiogenic effects with decreased VEGF expression and signaling. Combining selumetinib with cediranib enhanced their anti-tumor and antiangiogenic effects. We conclude that combining selumetinib and cediranib represents a promising strategy for the treatment of NSCLC.

Background

Symptoms of an adverse reaction to contrast agents for computed tomography are diverse ranging, and sometimes serious. The goal of this study is to create a scoring rule to predict adverse reactions to contrast agents used in computed tomography.

Methods

This was a retrospective cohort study of all adult patients undergoing contrast enhanced CT scan for 7 years. The subjects were randomly divided into either a derivation or validation group. Baseline data and clinically relevant factors were collected from the electronic chart. Primary outcome was any acute adverse reactions to contrast media, observed for during 24 hours after administration. All potential candidate predictors were included in a forward stepwise logistic regression model. Prediction scores were assigned based on β coefficient. A receiver operating characteristic (ROC) curve was drawn, and the area under the curve (AUC) and incidence of acute adverse reactions at each point were obtained. The same process was performed in the validation group.

Results

36,472 patients underwent enhanced CT imaging: 20,000 patients in the derivation group and 16,472 in the validation group. A total of 409 (2.0%, 95% CI:1.9-2.3) and 347 (2.1%, 95% CI:1.9-2.3) acute adverse reactions were seen in the derivation and validation groups. Logistic regression analysis revealed that prior adverse reaction to contrast agents, urticaria, an allergic history to drugs other than contrast agents, contrast agent concentration >70%, age <50 years, and total contrast agent dose >65 g were significant predictors of an acute adverse reaction. AUC was 0.70 (95% CI:0.67-0.73) and 0.67 (95% CI:0.64-0.70) in the derivation and validation groups.

Conclusions

We suggest a prediction model consisting of six predictors for acute adverse reactions to contrast agents used in CT.

Background

Gastric cancer is one of the most significant diseases, and esophago-gastro-duodenoscopy (EGD) is one of screening methods for gastric cancer. This study was conducted to identify the optimal screening interval for gastric cancer using EGD in healthy adults.

Methods

A retrospective cohort study was conducted on 3,723 healthy participants without a known diagnosis of gastric cancer at baseline from January 2005 to December 2010. Participants underwent annual health screenings, including EGD, at the Center for Preventive Medicine at St Luke’s International Hospital, a community teaching hospital in Japan. Participants with cytological abnormalities underwent further examination. A generalized estimating equation (GEE) was used to analyze the longitudinal data. We decided 0.5% of incidence of gastric cancer as a cutoff point for interval.

Results

The mean age (SD) of the participants was 55 (11) years, and 1,879 (50.5%) were male. During the study period, gastric cancer was detected in 35 participants. However, the incidence varied based on their ages. In the age groups <40, 40–49, 50–59, 60–69 and ≥70 years old, the 5-year cumulative incidences (95%CI) of gastric cancer were 0% (0-0%), 0.3% (0.1-1.0%), 1.0% (0.5-1.8%), 1.4% (0.8-2.4%) and 1.9% (0.8-3.8%), respectively. The odds ratios of the incidence of gastric cancer per year, which were evaluated using GEE models for the age groups 40–49, 50–59, 60–69 and ≥70 years old, were 1.51 (95%CI: 0.91-2.49), 1.94 (95%CI: 1.31-2.86), 1.59 (95%CI: 1.23-2.06) and 1.46 (95%CI: 1.06-2.02), respectively.

Conclusions

A screening for gastric cancer using EGD may be appropriate annually for healthy people over 70 years old, every two or three years for people 60–69 years old and every four years for people 50–59 years old. People younger than 50 years old may only need repeat screenings every five years or more.

Introduction

Internal hernia within the falciform ligament is exceedingly rare. A literature search revealed only 14 cases of internal herniation of the small bowel through a congenital defect of the falciform ligament, most of which were found intra-operatively.

Case presentation

A 77-year-old Japanese woman presented to our emergency department with sudden hematemesis, occurring at least four to five times over a 12-hour period. No ulcer or gastrointestinal bleeding was detected on gastroendoscopy. A 40mm mass in the inferior lobe of the right lung was found on a chest X-ray, and our patient’s symptoms were therefore initially ascribed to aspirated blood from lung tumor-associated hemoptysis. However, our patient continued to show signs of severe abdominal pain and decreased urine output despite aggressive hydration, leading her examining physicians to search for a possibly severe, occult abdominal pathology. On emergent computed tomography imaging, we found an acute strangulated internal hernia within the falciform ligament. Diagnosis was made by helical computed tomography, permitting rapid surgical intervention.

Conclusions

Our findings on computed tomography imaging assisted with the pre-operative diagnosis and enabled us to make a rapid surgical intervention. Early diagnosis may help preclude significant strangulation with unnecessary resection.

Background

Accidental falls among inpatients are a substantial cause of hospital injury. A number of successful experimental studies on fall prevention have shown the importance and efficacy of multifactorial intervention, though success rates vary. However, the importance of staff compliance with these effective, but often time-consuming, multifactorial interventions has not been fully investigated in a routine clinical setting. The purpose of this observational study was to describe the effectiveness of a multidisciplinary quality improvement (QI) activity for accidental fall prevention, with particular focus on staff compliance in a non-experimental clinical setting.

Methods

This observational study was conducted from July 2004 through December 2010 at St. Luke’s International Hospital in Tokyo, Japan. The QI activity for in-patient falls prevention consisted of: 1) the fall risk assessment tool, 2) an intervention protocol to prevent in-patient falls, 3) specific environmental safety interventions, 4) staff education, and 5) multidisciplinary healthcare staff compliance monitoring and feedback mechanisms.

Results

The overall fall rate was 2.13 falls per 1000 patient days (350/164331) in 2004 versus 1.53 falls per 1000 patient days (263/172325) in 2010, representing a significant decrease (p = 0.039). In the first 6 months, compliance with use of the falling risk assessment tool at admission was 91.5% in 2007 (3998/4368), increasing to 97.6% in 2010 (10564/10828). The staff compliance rate of implementing an appropriate intervention plan was 85.9% in 2007, increasing to 95.3% in 2010.

Conclusion

In our study we observed a substantial decrease in patient fall rates and an increase of staff compliance with a newly implemented falls prevention program. A systematized QI approach that closely involves, encourages, and educates healthcare staff at multiple levels is effective.

OBJECTIVE

To evaluate the optimal interval for rechecking A1C levels below the diagnostic threshold of 6.5% for healthy adults.

RESEARCH DESIGN AND METHODS

This was a retrospective cohort study. Participants were 16,313 apparently healthy Japanese adults not taking glucose-lowering medications at baseline. Annual A1C measures from 2005 to 2008 at the Center for Preventive Medicine, a community teaching hospital in Japan, estimated cumulative incidence of diabetes.

RESULTS

Mean age (±SD) of participants was 49.7 ± 12.3 years, and 53% were male. Mean A1C at baseline was 5.4 ± 0.5%. At 3 years, for those with A1C at baseline of <5.0%, 5.0–5.4%, 5.5–5.9%, and 6.0–6.4%, cumulative incidence (95% CI) was 0.05% (0.001–0.3), 0.05% (0.01–0.11), 1.2% (0.9–1.6), and 20% (18–23), respectively.

CONCLUSIONS

In those with an A1C <6.0%, rescreening at intervals shorter than 3 years identifies few individuals (∼≤1%) with an A1C ≥6.5%.

Introduction Discriminating acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) from cardiogenic pulmonary edema (CPE) using the plasma level of brain natriuretic peptide (BNP) alone remains controversial. The aim of this study was to determine the diagnostic utility of combination measurements of BNP and C-reactive protein (CRP) in critically ill patients with pulmonary edema.

Methods

This was a cross-sectional study. BNP and CRP data from 147 patients who presented to the emergency department due to acute respiratory failure with bilateral pulmonary infiltrates were analyzed.

Results

There were 53 patients with ALI/ARDS, 71 with CPE, and 23 with mixed edema. Median BNP and CRP levels were 202 (interquartile range 95-439) pg/mL and 119 (62-165) mg/L in ALI/ARDS, and 691 (416-1,194) pg/mL (p < 0.001) and 8 (2-42) mg/L (p < 0.001) in CPE. BNP or CRP alone offered good discriminatory performance (C-statistics 0.831 and 0.887), but the combination offered greater one [C-statistics 0.931 (p < 0.001 versus BNP) (p = 0.030 versus CRP)]. In multiple logistic-regression, BNP and CRP were independent predictors for the diagnosis after adjusting for other variables.

Conclusions

Measurement of CRP is useful as well as that of BNP for distinguishing ALI/ARDS from CPE. Furthermore, a combination of BNP and CRP can provide higher accuracy for the diagnosis.

Background

The mu event-related desynchronization (ERD) is supposed to reflect motor preparation and appear during motor imagery. The aim of this study is to examine the modulation of ERD with transcranial direct current stimulation (tDCS).

Methods

Six healthy subjects were asked to imagine their right hand grasping something after receiving a visual cue. Electroencephalograms (EEGs) were recorded near the left M1. ERD of the mu rhythm (mu ERD) by right hand motor imagery was measured. tDCS (10 min, 1 mA) was used to modulate the cortical excitability of M1. Anodal, cathodal, and sham tDCS were tested in each subject with a randomized sequence on different days. Each condition was separated from the preceding one by more than 1 week in the same subject. Before and after tDCS, mu ERD was assessed. The motor thresholds (MT) of the left M1 were also measured with transcranial magnetic stimulation.

Results

Mu ERD significantly increased after anodal stimulation, whereas it significantly decreased after cathodal stimulation. There was a significant correlation between mu ERD and MT.

Conclusions

Opposing effects on mu ERD based on the orientation of the stimulation suggest that mu ERD is affected by cortical excitability.

ABSTRACT

BACKGROUND

The Ministry of Health, Labour and Welfare of Japan has been promoting participation in scholarly activities for physicians during residency training. However, there is debate regarding whether this is worthwhile for residents.

OBJECTIVE

To evaluate residents’ opinions of engaging in scholarly activities and identify factors associated with overall satisfaction with their training program.

DESIGN

Cross-sectional national survey.

PARTICIPANTS

1,124 second-year residents in teaching hospitals in Japan in 2007

MEASUREMENTS

Collected data included demographics, teaching hospital characteristics and resources, residents’ research experiences, including type of activities, barriers to performing scholarly activities, residents’ opinions of scholarly requirements, and resident satisfaction with their residency program.

RESULTS

1,124 residents/1,500 responded for a response rate of 74.9%. Our data showed that 60.2% of Japanese residents engaged in some type of scholarly activity. Barriers included: “No resident time”; “No mentor;” and “No resident interest.” Sixty-three percent of residents thought that research should be a residency requirement. In multivariate logistic analysis, residents’ overall satisfaction with their residency program was significantly associated with participation in research activity (odds ratio (OR), 1.5; 95% confidence interval (CI), 1.1–2.1); male gender (OR, 1.5; 95% CI: 1.1–2.2); satisfaction with residency compensation (OR, 3.8; 95% CI, 2.6–5.0), and satisfaction with the residency curriculum (OR, 19.5; 95% CI, 13.7–27.7).

CONCLUSIONS

The majority of residents surveyed thought that research activity was worthwhile. Residents’ participation in research activity was associated with higher levels of satisfaction with residency training. Implementing measures to overcome existing barriers may have educational benefits for residents.

Background

We investigated the views of newly graduating physicians on their preparedness for postgraduate clinical training, and evaluated the relationship of preparedness with the educational environment and the pass rate on the National Medical Licensure Examination (NMLE).

Methods

Data were obtained from 2429 PGY-1 physicians-in-training (response rate, 36%) using a mailed cross-sectional survey. The Dundee Ready Education Environment Measure (DREEM) inventory was used to assess the learning environment at 80 Japanese medical schools. Preparedness was assessed based on 6 clinical areas related to the Association of American Medical Colleges Graduation Questionnaire.

Results

Only 17% of the physicians-in-training felt prepared in the area of general clinical skills, 29% in basic knowledge of diagnosis and management of common conditions, 48% in communication skills, 19% in skills associated with evidence-based medicine, 54% in professionalism, and 37% in basic skills required for a physical examination. There were substantial differences among the medical schools in the perceived preparedness of their graduates. Significant positive correlations were found between preparedness for all clinical areas and a better educational environment (all p < 0.01), but there were no significant associations between the pass rate on the NMLE and perceived preparedness for any clinical area, as well as pass rate and educational environment (all p > 0.05).

Conclusion

Different educational environments among universities may be partly responsible for the differences in perceived preparedness of medical students for postgraduate clinical training. This study also highlights the poor correlation between self-assessed preparedness for practice and the NMLE.

The cerebellum is one of the regions that contribute to urinary dysfunction in humans. A 43-year-old woman at age 35 had an acute onset of encephalitis that led to fever, generalized convulsion and coma. Six months after the disease onset, she regained consciousness and developed generalized myoclonus, cerebellar ataxia and overactive bladder, e.g., urinary urgency, daytime urinary frequency, and urinary incontinence. Eight years after the disease onset, she was revealed to have cerebellar atrophy on MRI, cerebellar hypoperfusion on SPECT, and detrusor overactivity on urodynamic study. Selective inflammation in the cerebellum seemed to produce cerebellar ataxia and overactive bladder in our case.

Background

Health locus of control influences health-related behaviour, but its association with healthcare use is unclear.

Aim

To investigate the association between individuals' health locus of control and the use of conventional and alternative health care.

Design of study

Prospective cohort study.

Setting

A nationally representative random sample of community-dwelling adult households in Japan.

Method

Health locus of control, symptom-related visits to physicians, and the use of dietary and physical complementary and alternative medicine (CAM) was measured. Dietary CAM included supplements, such as herbs and vitamins. Physical CAM included manipulations, such as acupuncture and acupressure.

Results

Of the 2453 adult participants studied, 2103 (86%; 95% CI [confidence interval] = 84 to 88%) developed at least one symptom during the 31-day study period. Of these symptomatic adults, 639 visited physicians (30%; 95% CI = 28 to 32%), 480 used dietary CAM (23%; 95% CI = 21 to 25%), and 156 (7%; 95% CI = 6 to 9%) used physical CAM. The likelihood of visiting a physician was not related significantly to individuals' health locus of control. Increased use of dietary CAM was weakly associated with control by spiritual powers (P = 0.028), internal control (P = 0.013), and less control by professionals (P = 0.020). Increased use of physical CAM was significantly associated with control by spiritual powers (P = 0.009) indicating a belief that supernatural forces control individuals' health status.

Conclusion

The likelihood of visiting a physician is not affected by individuals' health locus of control. Control by spiritual powers is involved with increased CAM use. Internal control is weakly associated with greater use of dietary CAM; professional control is weakly associated with less use of dietary CAM.

Background

The government-led "evidence-based guidelines for cataract treatment" labelled pirenoxine and glutathione eye drops, which have been regarded as the standard care for cataracts in Japan, as lacking evidence of effectiveness, causing great upset among ophthalmologists and professional ophthalmology societies. This study investigated the reasons why such "scientific evidence of treatment effectiveness" is not easily accepted by physicians, and thus, why they do not change their clinical practices to reflect such evidence.

Methods

We conducted a qualitative study based on grounded theory to explore physicians' awareness of "scientific evidence" and evidence-supported treatment in relation to pirenoxine and glutathione eye drops, and to identify current barriers to the implementation of evidence-based policies in clinical practice. Interviews were conducted with 35 ophthalmologists and 3 general practitioners on their prescribing behaviours, perceptions of eye drop effectiveness, attitudes toward the eye drop guideline recommendations, and their perceptions of "scientific evidence."

Results

Although few physicians believed that eye drops are remarkably effective, the majority of participants reported that they prescribed eye drops to patients who asked for them, and that such patients accounted for a considerable proportion of those with cataracts. Physicians seldom attempted to explain to patients the limitations of effectiveness or to encourage them to stop taking the eye drops. Physicians also acknowledged the benefits of prescribing such drugs, which ultimately outweighed any uncertainty of their effectiveness. These benefits included economic incentives and a desire to be appreciated by patients. Changes in clinical practice were considered to bring little benefit to physicians or patients. Government approval, rarity of side effects, and low cost of the drops also encouraged prescription.

Conclusion

Physicians occasionally provide treatment without expecting remarkable therapeutic effectiveness, as exemplified by the use of eye drops. This finding highlights that scientific evidence alone cannot easily change physicians' clinical practices, unless evidence-based practices are accepted by the general public and supported by health policy.