The relationship between epidermal growth factor receptor mutations and clinicopathologic features in non-small cell lung cancers.

PURPOSE: Recent studies reported that clinical responsiveness to gefitinib was associated with somatic mutation of epidermal growth factor receptor (EGFR) gene in non-small cell lung cancers (NSCLC). Here, we investigated the relationship between EGFR mutation and clinicopathologic features. EXPERIMENTAL DESIGN: EGFR mutational status of 120 NSCLCs was determined mainly in EGFR exons 18 to 21 by direct sequence and correlated with clinicopathologic parameters. RESULTS: EGFR mutations were present in 38 cases (32%) and the majority of mutations were in-frame deletions of exon 19 (19 cases) and a missense mutation in exon 21 (18 cases). EGFR mutations were frequently associated with adenocarcinoma (P < 0.0001), never smoker (P < 0.0001), and female gender (P = 0.0001). Of interest, increasing smoke exposure was inversely related to the rate of EGFR mutation (P < 0.0001). Multivariate analysis showed that smoking and histology were independent variables. Furthermore, gender difference was observed for the mutational location (P = 0.01) dominance of exon 19 for males and exon 21 for females. Twenty-one cases were treated with gefitinib and found that EGFR mutation was significantly related to gefitinib responsiveness (P = 0.002). In addition, median survival times of patients with and without EGFR mutations treated with gefitinib were 25.1 and 14.0 months, respectively. Patients with EGFR mutations had approximately 2-fold survival advantage; however, the difference was not significant. CONCLUSIONS: We show that EGFR mutations were significantly related to histology and smoke exposure and were a strong predictive factor for gefitinib responsiveness in NSCLC.     

Role of SCOX in determination of Drosophila melanogaster lifespan

In man, COX (cytochrome c oxidase) deficiency is reported to be related to mutation of the SCO2 (synthesis of cytochrome c oxidase 2) gene, which encodes one of the copper-donor chaperones involved in the assembly of mitochondrial cytochrome c oxidase. Such COX deficiency due to the genetic condition leads to heart disease and the Leigh syndrome and is frequently fatal in childhood. Synthesis of cytochrome c oxidase X (SCOX) is a Drosophila orthologue of human SCO2. Here, we generated SCOX-knockdown flies and the full length SCOX transgenic flies to investigate the in vivo roles of SCOX. Our results demonstrated knockdown of SCOX gene in all cells and tissues to be associated with lethality at larval or pupal stages and this correlated with a decrease in ATP level. In contrast, the full length SCOX transgenic flies showed a longer lifespan than wild type flies and control flies carrying Act5C-GAL4 alone and this correlated with an increase in ATP level. Finally, when cultured on paraquat-added medium, full length SCOX transgenic flies also exhibited an elongated lifespan. Therefore, we hypothesized that SCOX plays an important role in ATP production and consumption, which helps to prevent production of mitochondrial reactive oxygen species and/or impairment of mitochondrial activity under oxidative stress.     

Laterality of vestibular evoked myogenic potentials

To clarify the laterality of acoustically evoked vestibulocollic reflexes with a short latency (vestibular evoked myogenic potentials, VEMPs), responses on the bilateral sternocleidomastoid muscles (SCMs) to unilateral acoustic stimulation were studied. Twenty-one healthy volunteers were enrolled. Surface electrodes were placed on the upper half of each SCM (active) and on the lateral end of the upper sternum (reference). Clicks and 500-Hz tone-bursts (95 dB nHL) were used. All subjects showed positive-negative biphasic responses on the ipsilateral SCM by clicks and tone-bursts. Click-stimulation of 41 of the 42 ears did not evoke any response on the contralateral SCM. However, in one ear, positive-negative biphasic responses were evoked on the contralateral SCM. Recordings on the contralateral SCM by tonebursts showed no response in 32 ears, small positive-nega-tive biphasic responses in four ears, and small negative-positive biphasic responses in six ears. These findings show that VEMPs are ipsilateral-dominant, basically consistent with the hypothesis that they are of saccular origin.     

Primary Cardiac Lymphoma: Echocardiography and F‐18‐Fluorodeoxyglucose Positron Emission Tomography in Selection of a Biopsy Site

A 63‐year‐old man was referred to our hospital because of a cardiac tumor. Transthoracic echocardiography revealed a rough, mobile tumor in the dilated right atrium, and transesophageal echocardiography showed that the tumor consisted of small, botryoidal masses. Catheter‐based biopsy carried a high risk of embolism. Therefore, we used F‐18‐fluorodeoxyglucose positron emission tomography (FDG‐PET), which revealed an abnormal accumulation in the right cervical lymph nodes, as well as in the heart. We safely performed biopsy of the lymph nodes and diagnosed the patient with primary cardiac lymphoma. We concluded that echocardiography and FDG‐PET are useful for selecting an appropriate biopsy site in primary cardiac lymphoma.     

False Tendon‐Related Polymorphic Ventricular Tachycardia

A 39‐year‐old woman showed nonsustained polymorphic ventricular tachycardia (PVT) during light physical activity. Cardiac multidetector row computed tomography demonstrated false tendons, one of which proved to be the focus triggering premature ventricular contraction (PVC) in electrophysiological studies. The triggered PVC arose during the diastolic period, which might have caused tension in the false tendon. Radiofrequency catheter ablation targeting the triggered PVC by pace mapping was performed and proved partially effective against PVT. (PACE 2012;35:e341–e344)     

Whole‐exome sequencing and host cell reactivation assay lead to a diagnosis of xeroderma pigmentosum group D with mild ultraviolet radiation sensitivity

A case of xeroderma pigmentosum (XP) group D in a 39‐year‐old Japanese man is reported. The patient had suffered from moderate to severe solar sensitivity and freckle‐like pigmented macules in sun‐exposed areas since 6 years of age, and developed skin malignancies such as squamous cell carcinoma, actinic keratosis, Bowen’s disease and basal cell carcinoma. The minimal erythema dose for ultraviolet (UV) radiation was decreased with a delayed peak reaction. The level of unscheduled DNA synthesis of fibroblasts from the patient was 70% of normal, while they expressed POLH, a gene product responsible for the XP variant. Whole‐exome sequencing indicated that the patient harbored a homozygous mutation of c.1802G>T, p.Arg601Leu in ERCC2. A genetic complementation test was carried out by host cell reactivation assay, which showed that the patient’s fibroblasts recovered only when they were transfected with XPD cDNA, confirming the diagnosis of XP‐D. Arg601Leu mutation in ERCC2 may be related to mild UV radiation sensitivity and moderate skin lesions.     

Pharmacodynamic analysis of apremilast in Japanese patients with moderate to severe psoriasis: Results from a phase 2b randomized trial

We evaluated the pharmacodynamic effects of apremilast in 69 patients who were included in biomarker subanalyses of a phase 2b study that demonstrated the long‐term safety and efficacy of apremilast in Japanese adults with moderate to severe psoriasis. The association between cytokine levels and Psoriasis Area and Severity Index (PASI) improvement was evaluated using linear regression and Spearman’s rank correlation coefficient analysis. At baseline, median plasma levels of interleukin (IL)‐17A, IL‐17F and IL‐22 were elevated versus reference values for healthy individuals, whereas tumor necrosis factor‐α levels were close to normal. With apremilast 30 mg b.i.d., there were significant associations between percentage change in PASI score and percentage change in IL‐17A, IL‐17F and IL‐22 levels at week 16. Findings demonstrate that the efficacy of apremilast in psoriasis is associated with inhibition of key cytokines involved in the pathology of psoriasis.     

Serum levels of anti‐Fcγ receptor IIB/C antibodies are increased in patients with systemic sclerosis

Systemic sclerosis (SSc) is a systemic autoimmune disorder that results in fibrosis of the skin and multiple internal organs. Although the precise mechanism is unknown, it appears to result from the overproduction of extracellular matrix proteins and aberrant immune activations. Receptors for the Fc region of immunoglobulin (Ig)G (FcγR) are members of the Ig superfamily that modulate both activation and inhibition of immune responses. FcγRIIB is the sole inhibitory member, which has an intrinsic cytoplasmic immunoreceptor tyrosine‐based inhibitory motif. The present study was undertaken to investigate the circulating concentrations of anti‐FcγRIIB/C antibodies (Ab) in patients with SSc. Serum levels of anti‐FcγRIIB/C Ab were significantly increased in patients with SSc compared to those in controls and in patients with localized scleroderma. Serum levels of anti‐FcγRIIB/C Ab in patients with limited cutaneous SSc were similar to those in patients with diffuse cutaneous SSc. Among SSc patients, serum levels of anti‐FcγRIIB/C Ab were increased in those with nail‐fold bleeding and decreased in those with diffuse pigmentation and calcinosis. These findings support the notion that increased serum anti‐FcγRIIB/C Ab levels are involved in aberrant immune responses in SSc.