Despite an initial good response to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), resistance to treatment eventually develops. Although several resistance mechanisms have been discovered, little data exist regarding Asian patient populations.
Among patients at a tertiary referral hospital in Korea who initially responded well to gefitinib and later acquired resistance to treatment, we selected those with enough tissues obtained before EGFR-TKI treatment and after the onset of resistance to examine mutations by mass spectrometric genotyping technology (Asan-Panel), MET amplification by fluorescence in situ hybridization (FISH), and analysis of AXL status, epithelial-to-mesenchymal transition (EMT) and neuroendocrine markers by immunohistochemistry.
Twenty-six patients were enrolled, all of whom were diagnosed with adenocarcinoma with EGFR mutations (19del: 16, L858R: 10) except one (squamous cell carcinoma with 19del). Secondary T790M mutation was detected in 11 subjects (42.3%) and four of these patients had other co-existing resistance mechanisms; increased AXL expression was observed in 5/26 patients (19.2%), MET gene amplification was noted in 3/26 (11.5%), and one patient acquired a mutation in the phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha isoform (PIK3CA) gene. None of the patients exhibited EMT; however, increased CD56 expression suggesting neuroendocrine differentiation was observed in two patients. Interestingly, conversion from L858R-mutant to wild-type EGFR occurred in one patient. Seven patients (26.9%) did not exhibit any known resistance mechanisms. Patients with a T790M mutation showed a more favorable prognosis.
The mechanisms and frequency of acquired EGFR-TKI resistance in Koreans are comparable to those observed in Western populations; however, more data regarding the mechanisms that drive EGFR-TKI resistance are necessary.
Non-small cell lung carcinoma; Epidermal growth factor receptor mutation; EGFR tyrosine kinase inhibitor; Acquired resistance; Resistant mechanism; Mass spectrometric genotyping
Helicobacter pylori (H pylori) infection induces a chronic inflammatory response, which promotes gastric carcinogenesis. 15-hydroxyprostaglandin dehydrogenase (15–PGDH) plays a key role as a tumor suppressor in gastrointestinal cancers. The aim of this study was to elucidate the role of 15-PGDH in gastric carcinogenesis associated with H pylori. 15-PGDH expression in gastric biopsies from H pylori-infected (n=25) and non-infected (n=15) subjects was analyzed by quantitative real-time PCR, western blot analysis, and immunohistochemisty. 15-PGDH DNA methylation was evaluated by methylation specific PCR and pyrosequencing. The expression of 15-PGDH, Snail, ERK1/2, TLR4 and MyD88 in response to H pylori infection was assessed by immunoblot analysis. Compared to negative specimens, H pylori positive specimens had 2-fold lower 15-PGDH mRNA levels and significantly less 15-PGDH protein. In four H pylori infected subjects with longitudinal follow-up, the suppression of 15-PGDH expression was reversed by H pylori eradication therapy. In parallel with suppressing 15-PGDH expression, H pylori infection activated expression of TLR4 and MyD88 expression, increased levels of phospho-ERK1/2, and increased expression of epidermal growth factor receptor (EGFR)-Snail. Inhibition of Snail and MyD88 reversed suppression of 15-PGDH expression and small interfering Myd88 reduced phosphorylated ERK1/2. Similarly, treatment with an ERK1/2 and EGFR inhibitor also restored 15-PGDH expression. Heliocobacter pylori appeared to promote gastric carcinogenesis by suppressing15-PGDH. This process is mediated by the TLR4/MyD88 pathway via ERK1/2 or EGFR - Snail transcriptional regulation. 15-PGDH may be a useful marker and a potential therapeutic target in H pylori-induced gastric carcinogenesis.
Gastric cancer; Helicobacter pylori; 15-prostaglandin dehydrogenase
A series of N-(2-amino-6-trifluoromethyl-pyridin-3-ylmethyl) 2-(3-fluoro-4-methylsulfonylaminophenyl) propanamides were designed combining previously identified pharmacophoric elements and evaluated as hTRPV1 antagonists. The SAR analysis indicated that specific hydrophobic interactions of the 2-amino substituents in the C-region of the ligand were critical for high hTRPV1binding potency. In particular, compound 49S was an excellent TRPV1 antagonist (Ki(CAP) = 0.2 nM; IC50(pH) = 6.3 nM) and was thus ca. 100- and 20-fold more potent, respectively, than the parent compounds 2 and 3 for capsaicin antagonism. Furthermore, it demonstrated strong analgesic activity in the rat neuropathic model superior to 2 with almost no side effects. Compound 49S antagonized capsaicin induced hypothermia in mice, but showed TRPV1-related hyperthermia. The basis for the high potency of 49S compared to 2 is suggested by docking analysis with our hTRPV1 homology model in which the 4-methylpiperidinyl group in the C-region of 49S made additional hydrophobic interactions with the hydrophobic region.
Achalasia is classified into 3 types according to the Chicago classification. The aim of this study was to investigate characteristics and treatment outcomes of 3 achalasia subtypes in Korean patients.
Fifty-five patients diagnosed with achalasia based on conventional or high-resolution esophageal manometry were consecutively enrolled. Their clinical characteristics, manometric, endoscopic and esophagographic findings and treatment responses were analyzed among the 3 subtypes of achalasia.
Of 55 patients, 21 (38.2%) patients had type I, 28 (50.9%) patients had type II and 6 (10.9%) patients had type III. The median follow-up period was 22.4 (interquartile range, 3.6-67.4) months. Type III patients were older than type I and II patients (70.0 vs. 46.2 and 47.6 years, P = 0.023). The width of the esophagus in type I patients was wider with more frequent bird's beak appearance on esophagogram than the other 2 types (P = 0.010 and 0.006, respectively). Of the 50 patients who received the evaluation for treatment response at 3 months, 7 patients (36.8% vs. 26.9%) were treated with pneumatic dilatation and 4 patients (21.1% vs. 15.4%) with laparoscopic Heller's myotomy in type I and II groups, respectively. The treatment responses of pneumatic dilatation and Heller's myotomy in type I group were 71.4 and 50.0% and in type II were 85.7 and 75.0%, respectively, and all 5 patients in type III group showed good response to medical therapy.
Clinical characteristics of 3 achalasia subtypes in Korean patients are consistent with other studies. Treatment outcomes are variable among 3 subtypes.
Esophageal achalasia; Esophageal motility disorders; Manometry
The increasing trend of antibiotic resistance requires effective second-line Helicobacter pylori (H. pylori) treatment in high prevalence area of H. pylori. The aim of our study was to evaluate the reinfection rate of H. pylori after second-line treatment that would determine the long-term follow up effect of the rescue therapy.
A total of 648 patients who had failed previous H. pylori eradication on standard triple therapy were randomized into two regimens: 1, esomeprazole (20 mg b.i.d), tripotassium dicitrate bismuthate (300 mg q.i.d), metronidazole (500 mg t.i.d), and tetracycline (500 mg q.i.d) (EBMT) or 2, moxifloxacin (400 mg q.d.), esomeprazole (20 mg b.i.d), and amoxicillin (1000 mg b.i.d.) (MEA). At four weeks after completion of eradication therapy, H. pylori tests were performed with 13C urea breath test or invasive tests. In patients who maintained continuous H. pylori negativity for the first year after eradication therapy, H. pylori status was assessed every year. For the evaluation of risk factors of reinfection, gender, age, clinical diagnosis, histological atrophic gastritis or intestinal metaplasia were analyzed.
The recrudescence rate of the EBMT was 1.7% and of the MEA group 3.3% (p = 0.67). The annual reinfection rate of H. pylori of EBMT was found to be 4.45% and the MEA group 6.46%. Univariate analysis (Log-rank test) showed no association with any clinical risk factor for reinfection.
The long-term reinfection rate of H. pylori stayed low in both of bismuth-containing quadruple therapy and moxifloxacin-based triple therapy; thus reinfection cannot affect the choice of second-line treatment.
Clinical Trial Registration Number NCT01792700
Helicobacter pylori; Reinfection; Quadruple; Moxifloxacin; Second-line
To compare the accuracy of computed tomography (CT) with that of gastroscopy for the extent of evaluation of longitudinal tumor and type-specific diagnosis of Borrmann type IV gastric cancer.
Materials and Methods
Fifty-nine patients (35 men with mean age of 60 years and 24 women with mean age of 55 years) who underwent surgical resection of Borrmann type IV gastric cancer were included in this study. Histopathological analysis data was used as a reference standard to confirm the clinical interpretations of gastroscopy and CT for the diagnosis of Borrmann type IV and evaluation of longitudinal tumor extent. For the evaluation of longitudinal extent, gastroscopic and CT results were classified as underestimated, accurate, or overestimated. The McNemar test was used to identify statistically significant differences in the accuracy between gastroscopy and CT.
For the diagnosis of Borrmann type IV gastric cancer, the accuracy of CT was significantly higher than that of gastroscopy (74.6% [44/59] vs. 44.1% [26/59], p < 0.001). CT was significantly more accurate in assessing the overall tumor extent than gastroscopy (61.4% [35/57] vs. 28.1% [16/57], p < 0.001). The proximal (75.4% [43/57] vs. 50.9% [29/57], p = 0.003) and distal tumor extent (71.9% [41/57] vs. 43.9% [25/57], p < 0.05) were more accurately predicted by CT compared with gastroscopy. The underestimation of tumor extent was a major source of error in both examinations.
CT was found to be more predictive than gastroscopy in type-specific diagnosis and the evaluation of longitudinal tumor extent in patients with Borrmann type IV gastric cancer.
Stomach; Cancer; CT; Gastroscopy; Borrmann type IV; Linitis plastica
This study evaluated the effect of Helicobacter pylori eradication on functional dyspepsia (FD), and the relationship between the changes of histological gastritis and FD symptom responses.
A total of 213 FD patients diagnosed by Rome III criteria were consecutively enrolled. H. pylori tests and gastritis grade by the Sydney system were performed before and 1 year after the proton pump based-eradication therapy for 7 days. Serum levels of pepsinogen, and genetic polymorphisms IL-6, IL-8 and IL-10 were investigated.
Total of 91 patients completed the 1 year follow-up. When the response rate of dyspepsia was compared at 1 year between the non-eradicated group (n = 24) and eradicated group (n = 67), each group showed complete response of 62.5% and 62.7%; satisfactory response (≥ 50%) of 0.0% and 19.4%; partial response (< 50%) of 12.5% and 11.9%; and refractory response of 25.0% and 6.0%, respectively (P = 0.015). In addition, the responder group (complete + satisfactory response) at 1 year showed improvement of activity and chronic inflammation in both the antrum and corpus (all P < 0.001). Multivariate analysis showed that H. pylori eradication (OR, 5.81; 95% CI, 1.07-31.59) and symptom improvement at 3 month (OR, 28.90; 95% CI, 5.29-157.82) were associated with the improvement of dyspepsia at 1 year. Among the successfully eradicated FD patients (n = 67), male (P = 0.013) and higher initial BMI (P = 0.016) were associated with the improvement of dyspepsia at 1 year.
H. pylori eradication improved FD symptoms, as well as gastritis at 1 year, suggesting that inflammation mediates FD.
Eradication; Functional dyspepsia; Helicobacter pylori
This study was performed to investigate the cost effectiveness of Helicobacter pylori screening/eradication in South Korean patients treated with nonsteroidal anti-inflammatory drugs (NSAIDs) and/or aspirin.
A decision Markov model was used to estimate the effectiveness and economic impact of an H. pylori screening/eradication strategy compared to a no-screening strategy among patients who were included in the model at the age of 40 years. Utility weights were applied to four of the health status groups to reflect quality-adjusted life years (QALY). The costs of screening, H. pylori eradication, and managing peptic ulcer and ulcer complications were obtained from South Korea-specific data.
The total costs per patient were US $2,454 for the H. pylori screening/eradication and US $3,182 for the no-screening strategy. The QALYs for the two strategies were 16.05 and 15.73, respectively. The results were robust for the analyses of all different cohort groups who entered the model at the age of 30, 50, or 60 years and for NSAIDs-naïve patients. Through the probabilistic sensitivity analysis, the robustness of our study's results was also determined.
The H. pylori screening/eradication strategy was found to be less expensive and more effective compared to the no-screening strategy among South Korean patients taking NSAIDs and/or aspirin.
Cost-benefit analysis; Helicobacter pylori; Mass screening
Human NSCLCs with activating mutations in EGFR frequently respond to treatment with EGFR tyrosine kinase inhibitors (TKIs) such as erlotinib but responses are not durable as tumors acquire resistance. Secondary mutations in EGFR (T790M) or upregulation of the MET kinase are found in over 50% of resistant tumors. Here, we report increased activation of AXL and evidence of epithelial-to-mesenchymal transition (EMT) in multiple in vitro and in vivo EGFR-mutant lung cancer models with erlotinib acquired resistance in the absence of EGFR T790M or MET activation. Genetic or pharmacologic inhibition of AXL restored sensitivity to erlotinib in these tumor models. Increased expression of AXL, and in some cases its ligand GAS6, was found in EGFR-mutant lung cancers obtained from patients with EGFR TKI acquired resistance. These data identify AXL as a promising therapeutic target whose inhibition could prevent or overcome EGFR TKI acquired resistance in EGFR-mutant lung cancer patients.
To compare gastroesophageal reflux disease (GERD) symptoms and response to proton pump inhibitor (PPI) in patients with erosive esophagitis (EE), non-erosive reflux disease (NERD) or functional heartburn (FH) using GERD impact scale (GIS) questionnaire.
Total 126 patients with GERD symptoms were diagnosed as EE (n = 62), NERD (n = 34) and FH (n = 30) by endoscopy, 24-hour esophageal pH testing and Bernstein test, prospectively. Analysis of risk factors and GIS questionnaire for GERD symptoms and quality of life were performed before and 8 weeks after PPI treatment.
EE group had a higher proportion of men, frequent alcohol consumption, smoking, hiatal hernia, body mass index ≥ 25 kg/m2 and triglyceride levels (≥ 150 mg/dL) than the other groups (all P < 0.05). On the other hand, both psychiatric treatment and psychopharmacotherapy were more frequent in patients with FH than in those with EE and NERD (both P < 0.05). Among GERD symptoms, chest pain was more frequent in FH group than in EE and NERD groups (P < 0.05). Eating problems and limitation of productive daily activities occurred frequently in FH group and NERD group, respectively. GIS after 8 week PPI treatment showed improvement in all of the GERD symptoms in EE (all P < 0.05) and in acid regurgitation, epigastric pain and hoarseness in NERD group (all P < 0.05). In terms of quality of life, PPI treatment improved sleep disturbance in EE (P = 0.031) and limitation of productive activity in the NERD group (P = 0.001).
GIS questionnaire showed that different characteristics and symptoms improved after PPI therapy among patients with EE, NERD and FH, demonstrating the usefulness of the GIS questionnaire.
Functional heartburn; Gastroesophageal reflux; Proton pump inhibitors; Quality of life; Questionnaires
Intestinal metaplasia (IM) is a premalignant condition. This study aimed to evaluate the correlation between endoscopic and histological findings of IM.
The cases of IM were graded by conventional endoscopy, and biopsies were taken from the antrum and body of 1,333 subjects for histological IM diagnosis. Multivariate analyses were performed to identify the factors that affect the sensitivity of endoscopic IM diagnosis.
The sensitivity/specificity of endoscopic IM diagnosis based on histology was 24.0%/91.9% for the antrum and 24.2%/88.0% for the body. As indicated by multivariate analysis, the presence of endoscopic atrophic gastritis (AG) (odds ratio [OR], 4.73; 95% confidence interval [CI], 2.07 to 10.79) and the activity of mucosal inflammation (OR, 2.21; 95% CI, 1.08 to 4.54) were associated with the sensitivity of endoscopic IM diagnosis in the antrum, while the presence of endoscopic AG (OR, 8.02; 95% CI, 4.55 to 14.15), dysplasia (OR, 2.40; 95% CI, 1.07 to 5.39), and benign gastric ulcers (OR, 0.35; 95% CI, 0.15 to 0.081) were associated with the sensitivity of endoscopic IM diagnosis in the body.
As the sensitivity of endoscopic IM diagnosis was low, a high index of suspicion for IM is necessary in the presence of atrophy, and confirmation by histology is also necessary.
Diagnosis; Endoscopy; Histology; Intestinal metaplasia
This study presents an advanced multipoint vision-based system for dynamic displacement measurement of civil infrastructures. The proposed system consists of commercial camcorders, frame grabbers, low-cost PCs, and a wireless LAN access point. The images of target panels attached to a structure are captured by camcorders and streamed into the PC via frame grabbers. Then the displacements of targets are calculated using image processing techniques with premeasured calibration parameters. This system can simultaneously support two camcorders at the subsystem level for dynamic real-time displacement measurement. The data of each subsystem including system time are wirelessly transferred from the subsystem PCs to master PC and vice versa. Furthermore, synchronization process is implemented to ensure the time synchronization between the master PC and subsystem PCs. Several shaking table tests were conducted to verify the effectiveness of the proposed system, and the results showed very good agreement with those from a conventional sensor with an error of less than 2%.
Several children presenting with mild symptoms of respiratory tract infection were diagnosed with unclassified interstitial pneumonia with fibrosis. Their clinical and radiological findings were similar to those of acute interstitial pneumonia, but there were some differences in the pathological findings. Unclassified interstitial pneumonia with fibrosis is characterized by histological findings of centrilobular distribution of alveolar damage and bronchiolar destruction with bronchiolar obliteration. This report describes two different series of familial cases of unclassified interstitial pneumonia with fibrosis, which developed almost simultaneously in the spring. Some of the individual cases showed rapidly progressive respiratory failure of unknown cause, with comparable clinical courses and similar radiological and pathological features, including lung fibrosis. Each family member was affected almost simultaneously in the spring, different kinds of viruses were detected in two patients, and all members were negative for bacterial infection, environmental and occupational agents, drugs, and radiation. These findings implicate a viral infection and/or processes related to a viral infection, such as an exaggerated or altered immune response, or an unknown inhaled environmental agent in the pathogenesis of unclassified interstitial pneumonia with fibrosis.
Interstitial pneumonia; family; fibrosis; respiratory tract infections; environment
Intestinal metaplasia (IM) has been regarded as a premalignant condition. This study evaluated the role of the transforming factor CDX2 according to the severity and type of IM.
This analysis was performed on 383 subjects with IM in the antrum and/or body, with diagnoses that were categorized as controls, dysplasias, and gastric cancers. The IM grades were classified into four groups as negative, mild, moderate or severe using the updated Sydney scoring system. The IM subtypes were categorized as type I, type II, and type III using high iron diamine and alcian blue (pH 2.5) staining. The CDX2 expression in the IM foci was evaluated using immunohistochemistry in specimens from the antrum and/or body.
CDX2 expression increased according to IM severity (p=0.001) but was not associated with the IM subtype (p=0.881) in the antrum specimens. Similarly, CDX2 expression increased according to the IM grade (p=0.001) but was not associated with the IM subtype (p=0.755) in the body specimens. CDX2 expression was also increased according to baseline disease in the antrum, especially dysplastic and GC group (p=0.003), but not in the body (p=0.582). However, status of Helicobacter pylori infection was not associated with CDX2 expression in the antrum (p=0.692) and body (p=0.271).
These results show that CDX2 expression is associated with the IM grade regardless of the IM subtype and that it was more frequent in the dysplasia group. These results suggest that CDX2 expression might play an important role in the progression of IM in various environments that can affect neoplastic change.
Helicobacter pylori; Intestinal metaplasia; CDX2; Grade; Subtype
Eradication of Helicobacter pylori is widely accepted as initial therapy for low-grade gastric mucosa-associated lymphoid tissue (MALT) lymphoma. However, approximately 20% of patients with this disease are not responsive to H. pylori eradication therapy. The aim of this study was to assess remission and relapse rates of low-grade gastric MALT lymphoma after H. pylori eradication and identify the clinical factors that affect remission.
Thirty-nine patients diagnosed with gastric MALT lymphoma (May 2003 to May 2010) were retrospectively analyzed.
Of the 39 patients, 30 (77%) had a H. pylori infection. There were 35/39 (90%) patients with stage I. Among stage I, 25 patients with the infection underwent eradication therapy and 22/25 (88%) achieved remission. The total regression rate with eradication only in stage I was 24/28 (86%). The median time to remission was 98 days (range, 22 to 397 days). Age, tumor location, invasion depth, H. pylori burden, and severity of mononuclear leukocyte and neutrophil infiltration were not related to remission. However, patients with less neutrophil infiltration were more likely to achieve a successful first H. pylori eradication (p=0.049).
The results show that the rate of low-grade gastric MALT lymphoma regression (86%) with H. pylori eradication alone was higher than that in Western studies (77.8%) and that neutrophil infiltration was inversely related to success of the first H. pylori eradication procedure.
Mucosa-associated lymphoid tissue; Lymphoma; Helicobacter pylori; Eradication; Remission
The purpose of this study was to evaluate the efficacy and tolerability of dual therapy consisting of esomeprazole and amoxicillin as a rescue therapy for Helicobacter pylori infection.
From December 2009 to August 2010, 21 patients who experienced two consecutive eradication failures were included. They received esomeprazole (40 mg, b.i.d.) and amoxicillin (1,000 mg, b.i.d.) for 14 days as a third eradication regimen. Compliance and side effects were determined from an interview. H. pylori status was evaluated using the 13C urea breath test at least 6 weeks after treatment.
The mean age of the patients was 59 years and included 52% males. Indications for treatment were functional dyspepsia (61.9%), peptic ulcer disease (28.6%), and gastric adenoma (9.5%). H. pylori was eradicated in 14 of 21 (66.7%) patients. Minor side effects were reported in three of the 21 patients (14.3%). These side effects consisted mainly of nausea and epigastric discomfort.
A 2-week course of dual therapy failed to show satisfactory results in third-line H. pylori eradication, but it was very safe and tolerable. Therefore, dual therapy constitutes an encouraging empirical strategy for the elderly and infirm patients with multiple previous eradication failures.
Helicobacter pylori; Therapy; Proton pump inhibitor; Amoxicillin
Sparganosis is a rare parasitic infection affecting various organs, including the central nervous system, especially the lumbar epidural space. This report describes the identification of disease and different strategies of treatments with preoperative information. A 42-year-old man presented with a 2-year history of urinary incontinence and impotence. He had a history of ingesting raw frogs 40 years ago. Magnetic resonance (MR) imaging showed an intramedullary nodular mass at conus medullaris and severe inflammation in the cauda equina. A 51-year-old woman was admitted with acute pain in the left inguinal area. We observed a lesion which seemed to be a tumor of the lumbar epidural space on MR imaging. She also had a history of ingesting inadequately cooked snakes 10 years ago. In the first patient, mass removal was attempted through laminectomy and parasite infection was identified during intra-operative frozen biopsy. Total removal could not be performed because of severe arachnoiditis and adhesion. We therefore decided to terminate the operation and final histology confirmed dead sparganum infection. We also concluded further surgical trial for total removal of the dead worm and inflammatory grannulation totally. However, after seeing another physician at different hospital, he was operated again which resulted in worsening of pain and neurological deficit. In the second patient, we totally removed dorsal epidural mass. Final histology and enzyme-linked immunosorbent assay (ELISA) confirmed living sparganum infection and her pain disappeared. Although the treatment of choice is surgical resection of living sparganum with inflammation, the attempt to remove dead worm and adhesive granulation tissue may cause unwanted complications to the patients. Therefore, the result of preoperative ELISA, as well as the information from image and history, must be considered as important factors to decide whether a surgery is necessary or not.
Sparganosis; Sparganosis in the lumbar vertebrae; Enzyme-linked immunosorbent assay
Minimally invasive surgical procedures offer advantages of smaller incisions, decreased hospital length of stay, and rapid postoperative recovery to the patient. Surgical robots improve access and visualization intraoperatively and have expanded the indications for minimally invasive procedures. A limitation of the DaVinci surgical robot is a lack of sensory feedback to the operative surgeon. Experienced robotic surgeons use visual interpretation of tissue and suture deformation as a surrogate for tactile feedback. A difficulty encountered during robotic surgery is maintaining adequate suture tension while tying knots or following a running anastomotic suture. Displaying suture strain in real time has potential to decrease the learning curve and improve the performance and safety of robotic surgical procedures. Conventional strain measurement methods involve installation of complex sensors on the robotic instruments. This paper presents a noninvasive video processing-based method to determine strain in surgical sutures. The method accurately calculates strain in suture by processing video from the existing surgical camera, making implementation uncomplicated. The video analysis method was developed and validated using video of suture strain standards on a servohydraulic testing system. The video-based suture strain algorithm is shown capable of measuring suture strains of 0.2% with subpixel resolution and proven reliability under various conditions.
Mediastinal lymphadenopathy associated with extrathoracic malignancy or a metastasis of unknown origin (MUO) requires pathological verification. Surgical exploration or endoscopic ultrasound-guided fine needle aspiration is limited to application. We investigated the effectiveness of endobronchial ultrasound-guided transbronchial needle biopsy (EBUS-TBNA) for evaluating mediastinal lymphadenopathy in patients with an extrathoracic malignancy. We retrospectively analyzed data from 59 patients who underwent EBUS-TBNA with a core biopsy because of a suspected mediastinal metastasis between September 2008 and August 2010. All patients had previously been diagnosed with an extrathoracic malignancy (n = 39, 66.1%) or a suspected MUO without a thoracic lesion (n = 20, 33.9%). A total of 88 lymph nodes was analyzed. EBUS-TBNA findings indicated malignancies in 34 patients (57.6%). The EBUS-TBNA sensitivity and specificity for the detection of mediastinal malignancy in patients with a previous extrathoracic malignancy were 96.3% and 100%, respectively. For MUO patients without a thoracic lesion, the sensitivity and specificity were 61.5% and 100%, respectively. The overall sensitivity and specificity were 81.0% and 100%, respectively (P = 0.053). EBUS-TBNA is a safe and effective modality for evaluating mediastinal lymphadenopathy in patients with a previous extrathoracic malignancy or a MUO without a thoracic lesion. The application of this diagnostic tool is likely to have significant clinical implications.
EBUS; Extrathoracic Malignancy; Mediastinal Adenopathy; Metastatic Cancer of Unknown Primary Site; MUO
The levels of pepsinogen (PG) I and the PGI/II ratio are useful serologic markers for chronic atrophic gastritis. This study evaluated the performance and clinical implications of these markers in patients undergoing endoscopic mucosectomy.
We enrolled 142 consecutive patients with early gastric tumors and Helicobacter pylori infection who were eligible for mucosectomy. Chronic gastritis and atrophy were assessed using four defined biopsy procedures. Serum PGs were measured by an enzyme immunoassay. Optimal diagnostic cut-offs and performance were determined using receiver operating characteristic curves.
The PGI level and the PGI/II ratio decreased with corpus-dominant gastritis and as atrophy advanced toward the corpus greater curvature (GC). For the presence of corpus GC atrophy, the areas under the PGI and PGI/II-ratio curves were 0.82 and 0.77, respectively. The optimal cut-off levels were 59.3µg/L for PGI (sensitivity, 83.3%; specificity, 78.4%) and 3.6µg/L for PGI/II ratio (sensitivity, 70.0%; specificity, 78.4%). Using these serologic cut-off levels, we found that the frequency of corpus tumor location differed significantly (32.9% vs 11.1% for PGI <59.3 and ≥59.3µg/L, respectively; and 31.1% vs 14.8% for PGI/II ratio <3.5 and ≥3.5, respectively; p<0.05).
A low PGI level and PGI/II ratio are valuable serologic markers for predicting corpus GC atrophy, and have clinical implications with respect to the corpus location of tumors in mucosectomy patients.
Pepsinogens; Atrophic gastritis; Stomach neoplasia; Helicobacter pylori; Endoscopy
Early tumor detection is crucial for the prevention of colon cancer. Near-infrared fluorescence (NIRF) imaging using a target-activatable probe may permit earlier disease detection. Matrix metalloproteinases (MMPs) participate in tumorigenesis and tumor growth. The aim of this study was to determine whether NIRF imaging using an MMP-activatable probe can detect colon tumors at early stages.
We utilized two murine colon cancer models: a sporadic colon cancer model induced by azoxymethane (AOM), and a colitis-associated cancer model induced by a combination of AOM and dextran sodium sulfate (DSS). Colonic lesions were analyzed by histologic examination, Western blotting, immunohistochemical staining, and NIRF imaging using an MMP-activatable probe.
Multiple variable-sized tumors developed in both models and progressed from adenomas to adenocarcinomas over time. At the early stage of the AOM/DSS model, diffuse inflammation was observed within the tumors. MMP expression increased progressively through normal, inflammation, adenoma, and adenocarcionoma stages. NIRF signal intensities were strongly correlated with each tumor stage from adenoma to adenocarcinoma. NIRF imaging also distinguished tumors from inflamed mucosa.
NIRF imaging using a protease-activatable probe may be a useful tool for early tumor detection. This approach could translate to improve the endoscopic detection of colon tumors, especially in patients with inflammatory bowel disease.
Colon cancer; Inflammatory bowel disease; Near-infrared fluorescence; Matrix metalloproteinases
Morphological studies on presbycusis, or age-related hearing loss, have been performed in several different strains of mice that demonstrate hearing loss with auditory pathology. The C57BL/6 (C57) mouse is a known model of early onset presbycusis, while the CBA mouse is characterized by relatively late onset hearing loss. We performed this study to further understand how early onset hearing loss is related with the aging process of the cochlea.
We compared C57 cochlear pathology and its accompanying apoptotic processes to those in CBA mice. Hearing thresholds and outer hair cell functions have been evaluated by auditory brainstem response (ABR) recordings and distortion product otoacoustic emission (DPOAE).
ABR recordings and DPOAE studies demonstrated high frequency hearing loss in C57 mice at P3mo of age. Cochlear morphologic studies of P1mo C57 and CBA mice did not show differences in the organ of Corti, spiral ganglion, or stria vascularis. However, from P3mo and onwards, a predominant early outer hair cell degeneration at the basal turn of the cochlea in C57 mice without definitive degeneration of spiral ganglion cells and stria vascularis/spiral ligament, compared with CBA mice, was observed. Additionally, apoptotic processes in the C57 mice also demonstrated an earlier progression.
These data suggest that the C57 mouse could be an excellent animal model for early onset 'sensory' presbycusis in their young age until P6mo. Further studies to investigate the intrinsic or extrinsic etiologic factors that lead to the early degeneration of organ of Corti, especially in the high frequency region, in C57 mice may provide a possible pathological mechanism of early onset hearing loss.
Cochlea; Morphology; Hearing; Aging; Apoptosis
Patients with various chronic liver diseases frequently have increased body iron stores. Prohepcidin is an easily measurable precursor of hepcidin, which is a key regulator of iron homeostasis. This study investigated the serum prohepcidin levels in patients with various chronic liver diseases with various etiologies.
Serum prohepcidin levels were measured in patients with chronic hepatitis C (CH-C) (n=28), nonalcoholic fatty liver disease (NAFLD) (n=24), and alcoholic liver disease (ALD) (n=22), and in healthy controls (n=25) using commercial ELISA. Serum interleukin 6 (IL-6) levels and blood iron indices were also measured.
The serum levels of both prohepcidin and IL-6 were significantly higher in CH-C patients than in healthy controls, and there was a positive correlation between the IL-6 and prohepcidin levels (r=0.505, p=0.020). The prohepcidin levels in ALD patients did not differ from those in controls, despite their significantly elevated IL-6 levels. There was a tendency for a negative correlation between serum prohepcidin levels and transferrin saturation in ALD patients (r=-0.420, p=0.051). Neither prohepcidin nor IL-6 was significantly elevated in the NAFLD group, despite the presence of elevated serum iron and ferritin levels.
The role of prohepcidin may differ in different human liver diseases. In the setting of CH-C, both the serum prohepcidin and IL-6 levels were significantly elevated and were positively correlated with each other.
Prohepcidin; Hepatitis C; Fatty liver; Alcohol; IL-6
Gastroesophageal reflux disease is one of the most common and frequent chronic disease requiring considerable cost. We investigated the medical care costs in the erosive reflux disease (ERD) and non-erosive reflux disease (NERD).
The risk factors and the direct medical care costs were analyzed retrospectively in the ERD (178 patients) and NERD (183 patients) groups for a follow up period of 2 years.
Logistic regression analysis showed that the ERD was more frequent in the groups of male gender, alcohol consumption, higher body mass index (≥25 kg/m2), hiatal hernia, and higher triglyceride levels (≥150 mg/dL). The direct medical care costs per person for 2 years were found to be $384.8 (ERD) and $412.9 (NERD) without statistically significant differences (p = 0.364). However, 9.3% (17/183) of the NERD patients had visited the emergency room compared to 3.4% (6/178) of the ERD patients (p = 0.029). In addition, more NERD patients were hospitalized than ERD patients (p = 0.006), and because of the longer hospitalization period, the medical costs in NERD patients were higher than ERD patients (p = 0.038).
In spite of the different risk factors for ERD and NERD, total direct medical care costs were similar between the ERD and NERD group. However, more visits to emergency room and longer hospitalization period with more hospitalization costs in NERD patients account for the differences in medical service and usage distribution between the 2 groups.
Gastroesophageal reflux; Health care costs; Risk factors
There has been a controversy regarding the usefulness of biofeedback therapy for functional constipation or fecal incontinence. This study was performed to investigate the long-term clinical efficacy of biofeedback therapy.
Sixty-four patients with constipation or fecal incontinence received biofeedback therapy for 4 weeks. Symptom improvements were evaluated immediately after the completion of biofeedback therapy and during the follow-up period of about 12 to 64 months.
Twenty-five patients in the constipation group [mean age of 52.1 years, 16 men (64.0%)] received 6.2 sessions of biofeedback therapy. Improvement of constipation after the completion of biofeedback therapy was as follows: major response (or improvement) in 3 patients (12.0%), fair in 6 (24.0%), minor in 11 (44.0%) and none in 5 (20.0%). Among 9 patients who showed major or fair improvement, 8 patients (88.9%) maintained the symptom improvement through the long term follow-up periods. Thirty-nine patients in the fecal incontinence group [59.7 years old, 15 men (38.5%)] received 6.8 sessions of biofeedback therapy. Improvement of incontinence after the completion of biofeedback therapy was as follows: major improvement in 6 patients (15.4%), fair in 14 (35.9%), minor in 14 (35.9%), and none in 5 (12.8%). All 11 patients with major or fair improvement maintained the symptom improvement to the end of follow-up periods.
Symptom improvements after biofeedback therapy were disappointing in both the constipation and incontinence group. However, when the symptom improvements were classified as major or fair, the improvements continued for at least a year.
Biofeedback; Therapy; Constipation; Fecal incontinence