Analysis of Clinical Predictive Factors Affecting the Outcome of Second-Line Chemotherapy for Gemcitabine-Refractory Advanced Pancreatic Cancer.

Background/Aims: The benefit of second-line chemotherapy (SL) after failed first-line chemotherapy (FL) in patients with advanced pancreatic cancer has not yet been established. We evaluated the clinical characteristics affecting the benefits of SL compared to best supportive care (BSC), identified the prognostic factors, and ultimately devised a model of clinical parameters to assist in making decision between SL and BSC after the failure of gemcitabine-based FL. Methods: The records of patients who received gemcitabinebased FL for advanced pancreatic cancer at Yonsei University Hospital between January 2010 and December 2015 were retrospectively reviewed. Significant clinical parameters were assessed for their potential as predictive factors. Results: SL patients received a longer duration of FL compared with BSC patients with median duration being 16.0 weeks (range, 8.0 to 26.0 weeks) and 8.0 weeks (range, 4.0 to 16.0 weeks), respectively (p<0.001). When the SL group was stratified by their modified overall survival (mOS) (longer and shorter than 6 months), we found significant differences for several clinical factors, namely, metastasis to the peritoneum (p<0.001), number of metastases (p<0.001), thrombotic events (p=0.003), and level of carbohydrate antigen 19-9 (CA19- 9; p=0.011). In multivariate analysis, more than one site of metastasis, occurrence of thrombotic event during FL, and a CA19-9 level above 90 U/mL were significant independent prognostic factors for mOS in the SL group (p<0.05). When an attempt was made to devise a prognostic nomogram, Harrell's C-index of the final prognosis prediction model was 0.62. Conclusions: SL may be beneficial for patients without peritoneal metastasis or thrombotic events who have a single metastasis and a level of CA19-9 less than 90 U/mL. This prognostic nomogram can be used to predict mOS before the administration of SL after the failure of gemcitabinebased FL.

Morphologic Restoration After Peroral Endoscopic Myotomy in Sigmoid-type Achalasia.

BACKGROUND/AIMS: Achalasia is a chronic, progressive motility disorder of the esophagus. The sigmoid-type achalasia is an advanced stage of achalasia characterized by severe dilatation and tortuous angulation of the esophageal body. Peroral endoscopic myotomy (POEM) has been reported to provide excellent clinical outcomes for achalasia, including the sigmoid type, but the restoration of esophageal morphology and function remain poorly described. The aim of our study is to investigate esophageal restoration after POEM for sigmoid-type achalasia. METHODS: From 98 patients with achalasia who underwent POEM in the Yonsei University Health System from 2013 to 2018, we recruited 13 patients with sigmoid-type achalasia (7 male; mean age 53.3 years) and assessed morphological and manometric changes in the esophagus. RESULTS: Clinical success (Eckardt score < 3) was achieved in all cases. After POEM, the average angle of esophageal tortuosity became more obtuse (91.5° vs 114.6°, P = 0.046), esophageal body diameter decreased (67.6 vs 49.8 mm, P = 0.002), and esophagogastric junction opening widened (6.4 vs 9.5 mm, P = 0.048). Patients whose esophageal tortuosity did not improve had longer durations of symptoms than patients with improvement (80.2 vs 636 months, P < 0.001). An absence of peristalsis was observed in all patients pre- and post-POEM. CONCLUSIONS: POEM resulted in excellent clinical outcomes and morphologic improvement in sigmoid-type achalasia. These results suggest that the improvement of esophageal tortuosity through POEM reflects a reduced esophageal burden.

Noninvasive prediction model for diagnosing gastrointestinal stromal tumors using contrast-enhanced harmonic endoscopic ultrasound.

BACKGROUND & AIMS: Subepithelial tumors (SETs) are difficult to diagnose accurately without invasive pathological confirmation. We created a noninvasive prediction model for diagnosing gastrointestinal stromal tumors (GISTs) using contrast-enhanced harmonic endoscopic ultrasound (CEH-EUS). METHODS: We retrospectively reviewed 176 patients who underwent CEH-EUS from October 2011 to August 2017. Seventy patients with a diagnosis of GIST (n = 37) or leiomyoma (n = 33) were included. The long-to-short axis ratio (LSR) and enhancement patterns (vascularity, diffuse enhancement) on CEH-EUS were assessed. Logistic regression and classification and regression tree (CART) analyses were performed. RESULTS: The mean age of all patients was 54.9 ±â€¯13.68 years. The GIST group showed significantly higher rates of positive vascularity (81.1% vs. 15.2%, p < 0.001) and diffuse enhancement (51.4% vs. 15.2%, p = 0.001), and lower LSR (1.30 vs. 1.76, p < 0.001). In multivariate logistic regression, positive vascularity (odds ratio [OR] 27.765, 95% confidence interval [CI] 5.336-144.458) and low LSR (OR 18.940, 95% CI 3.623-99.007) were independent predictors of GIST. A noninvasive prediction model for GISTs was developed using the CART model, by allocating patients according to statistically significant variables. CONCLUSIONS: The LSR and vascularity of SETs on CEH-EUS can be used as parameters for a noninvasive prediction model of GISTs. This model may be helpful in the early identification and treatment of GISTs.

Incidence and risk factors of delayed postpolypectomy bleeding in patients with chronic liver disease.

OBJECTIVE: Hepatologists and colonoscopists often hesitate to perform a colonoscopic polypectomy in patients with chronic liver disease (CLD), especially those with cirrhosis, because of the risk of postpolypectomy bleeding (PPB). We aimed to investigate the incidence and risk factors of delayed PPB after a colonoscopic polypectomy in patients with CLD. MATERIALS AND METHODS: In total, 152 patients with CLD who underwent colonoscopic polypectomy from December 2005 to December 2012 were retrospectively reviewed. RESULTS: Cirrhosis was identified in 80 (52.6%) patients. During the study period, 442 polyps were removed and delayed PPB developed in 14 (9.2%) patients. The incidence of delayed PPB was significantly higher in patients with cirrhosis than in those without the disease (13.8% [n = 11] vs. 4.2% [n = 3], p = 0.041). The polyp size (odds ratio, 1.087; 95% confidence interval, 1.009-1.172) and cirrhosis (odds ratio, 8.535; 95% confidence interval, 2.417-30.140) were independent risk factors for delayed PPB. In patients with cirrhosis, the optimal cut-off size to identify high-risk polyps for delayed PPB was 10 mm (area under the receiver operating characteristics curve, 0.737; sensitivity, 52%; specificity, 88%). CONCLUSION: Caution is needed when colonoscopic polypectomy is planned in patients with CLD who have larger polyps and cirrhosis.

Propyl gallate inhibits adipogenesis by stimulating extracellular signal-related kinases in human adipose tissue-derived mesenchymal stem cells.

Propyl gallate (PG) used as an additive in various foods has antioxidant and anti-inflammatory effects. Although the functional roles of PG in various cell types are well characterized, it is unknown whether PG has effect on stem cell differentiation. In this study, we demonstrated that PG could inhibit adipogenic differentiation in human adipose tissue-derived mesenchymal stem cells (hAMSCs) by decreasing the accumulation of intracellular lipid droplets. In addition, PG significantly reduced the expression of adipocyte-specific markers including peroxisome proliferator-activated receptor-γ (PPAR-γ), CCAAT enhancer binding protein-α (C/EBP-α), lipoprotein lipase (LPL), and adipocyte fatty acid-binding protein 2 (aP2). PG inhibited adipogenesis in hAMSCs through extracellular regulated kinase (ERK) pathway. Decreased adipogenesis following PG treatment was recovered in response to ERK blocking. Taken together, these results suggest a novel effect of PG on adipocyte differentiation in hAMSCs, supporting a negative role of ERK1/2 pathway in adipogenic differentiation.

Chlormadinone acetate promotes osteoblast differentiation of human mesenchymal stem cells through the ERK signaling pathway.

Bone is continuously remodeled throughout life, and this remodeling is regulated by osteoclasts and osteoblasts. Bone-forming osteoblasts are derived from mesenchymal stem cells in bone marrow. Here, we have identified a new function of chlormadinone acetate (CMA) as an osteogenic activator in human bone marrow-derived mesenchymal stem cells (hBMSCs). To date, CMA has been used as an oral contraceptive and is known to have antiandrogenic activity. Our results show that CMA promotes osteoblast differentiation and calcium deposition in hBMSCs, whereas CMA treatment suppresses adipogenesis of hBMSCs. CMA activates and potentiates the phosphorylation of extracellular signal-regulated kinases (ERK1/2) in an osteogenic differentiation conditions. In addition, CMA-stimulated osteoblast differentiation is suppressed by inhibiting the ERK pathway, suggesting that CMA promotes the osteogenic differentiation program of hBMSCs through the ERK activation. Taken together, these results suggest a novel function of CMA as an osteogenic activator and intracellular signaling pathway mediated by CMA in osteoblast differentiation.

Atrial septal defect with normal pulmonary arterial pressure in adult cyanotic patient.

A 22-year-old male presented with recurrent stroke, central cyanosis, and dyspnea. Transesophageal echocardiography and cardiac catheterization revealed bidirectional shunt flow through atrial septal defect (ASD) without pulmonary arterial hypertension. The orifice of inferior vena cava facing towards ASD opening led partially right to left shunt resulting in cyanosis with normal pulmonary arterial pressure.

Periostin-binding DNA aptamer inhibits breast cancer growth and metastasis.

Periostin is an extracellular matrix (ECM) protein that is overexpressed in a variety of human cancers, and its functions appear to be linked to tumor growth, metastasis, and angiogenesis. Recent clinical evidence suggests that aberrant periostin expression is correlated with poor outcome in patients with breast cancer. To identify novel tools to regulate the functional role of periostin, we generated benzyl-d(U)TP-modified DNA aptamers that were directed against human periostin (PNDAs) and characterized their functional roles in breast cancer progression. PNDA-3 selectively bound to the FAS-1 domain of periostin with nanomolar affinity and disrupted the interaction between periostin and its cell surface receptors, αvß3 and αvß5 integrins. PNDA-3 markedly antagonized the periostin-induced adhesion, migration, and invasion of breast cancer cells and blocked the activation of various components of the αvß3 and αvß5 integrin signal transduction pathways. In a 4T1 orthotopic mouse model, PNDA-3 administration significantly reduced primary tumor growth and distant metastasis. Thus, our results demonstrated that periostin-integrin signaling regulates breast cancer progression at multiple levels in tumor cells and the tumor microenvironment. DNA aptamers targeting periostin may potentially be used to inhibit breast cancer progression.

Phospholipase C-γ1 involved in brain disorders.

Phosphoinositide-specific phospholipase C-γ1 (PLC-γ1) is an important signaling regulator involved in various cellular processes. In brain, PLC-γ1 is highly expressed and participates in neuronal cell functions mediated by neurotrophins. Consistent with essential roles of PLC-γ1, it is involved in development of brain and synaptic transmission. Significantly, abnormal expression and activation of PLC-γ1 appears in various brain disorders such as epilepsy, depression, Huntington's disease and Alzheimer's disease. Thus, PLC-γ1 has been implicated in brain functions as well as related brain disorders. In this review, we discuss the roles of PLC-γ1 in neuronal functions and its pathological relevance to diverse brain diseases.

Double antiangiogenic protein, DAAP, targeting VEGF-A and angiopoietins in tumor angiogenesis, metastasis, and vascular leakage.

Two vascular growth factor families, VEGF and the angiopoietins, play critical and coordinate roles in tumor progression and metastasis. A single inhibitor targeting both VEGF and angiopoietins is not available. Here, we developed a chimeric decoy receptor, namely double anti-angiogenic protein (DAAP), which can simultaneously bind VEGF-A and angiopoietins, blocking their actions. Compared to VEGF-Trap or Tie2-Fc, which block either VEGF-A or angiopoietins alone, we believe DAAP is a highly effective molecule for regressing tumor angiogenesis and metastasis in implanted and spontaneous solid tumors; it can also effectively reduce ascites formation and vascular leakage in an ovarian carcinoma model. Thus, simultaneous blockade of VEGF-A and angiopoietins with DAAP is an effective therapeutic strategy for blocking tumor angiogenesis, metastasis, and vascular leakage.

Expression pattern of sulfated glycoprotein-2 (SGP-2) mRNA in rat testes exposed to endocrine disruptors.

Sulfated glycoprotein-2 (SGP-2) is secreted in Sertoli cells and epididymal epithelial cells and plays important roles in the regulation of spermatogenesis and sperm maturation. To investigate whether endocrine disruptors affect spermatogenesis through an SGP-2-dependent mechanism, daily oral doses of testosterone (50, 200 and 1,000 microg/kg), flutamide (1, 5 and 25 mg/kg), ketoconazole (0.2, 1, 5 and 25 mg/kg), diethylhexylphthalate (10, 50 and 250 mg/kg), nonylphenol (10, 50, 100 and 250 mg/kg), octylphenol (10, 50 and 250 mg/kg), diethylstilbesterol (10, 20 and 40 microg/kg) or corn oil (control) were administered to 5 week-old, male Sprague-Dawley rats for 3 weeks. Following treatment with these endocrine disruptors, testicular expression of SGP-2 mRNA was analyzed using reverse transcription-polymerase chain reaction. Compared with the control, the lowest dose of testosterone (50 microg/kg/day) significantly increased expression of SGP-2 mRNA, whereas 200 and 1,000 microg/kg/day testosterone significantly decreased the expression (P<0.05). Flutamide, ketoconazole, diethylhexylphthalate, nonylphenol, octylphenol and diethylstilbesterol significantly decreased SGP-2 mRNA expression in testes at all doses studied, with the exception of 1 mg/kg/day flutamide (P<0.05). These results suggest that endocrine disruptors might decrease spermatogenesis in testes by decreasing expression of SGP-2 mRNA.

Differential expression of 3beta-hydroxysteroid dehydrogenase mRNA in rat testes exposed to endocrine disruptors.

Expression of 3beta-hydroxysteroid dehydrogenase (3beta-HSD) is mainly found in the Leydig cells from which steroid hormones are biosynthesized in the testes. To investigate whether endocrine disruptors affect the microenvironment of the testes, the mRNA expression of 3beta-HSD as a molecular marker for androgen biosynthesis was analyzed in rat testes exposed to several endocrine disruptors using a reverse transcription-polymerase chain reaction technique. Testosterone [50, 200 and 1,000 microg/kg body weight (BW)], flutamide (1, 5 and 25 mg/kg BW), ketoconazole (0.2, 1, 5 and 25 mg/kg BW), diethylhexyl phthalate (10, 50 and 250 mg/kg BW), nonylphenol (10, 50, 100 and 250 mg/kg BW), octylphenol (10, 50 and 250 mg/kg BW), and diethylstilbestrol (10, 20 and 40 microg/kg BW) were orally administered to 4-week-old Sprague-Dawley rats for 3 weeks daily. Although testosterone at a low dose (50 microg/kg/day) increased the expression of 3beta-HSD mRNA, it was significantly decreased in the rats treated with 200 or 1,000 microg/kg/day testosterone compared with the control group (P<0.05). Furthermore, ketoconazole, diethylhexyl phthalate, nonylphenol, octylphenol and diethylstilbestrol caused significant downregulation of 3beta-HSD mRNA in the testes at all doses (P<0.05). However, flutamide remarkably increased the level of 3beta-HSD mRNA in the testes (P<0.05). These results suggest that endocrine disruptors may influence androgen biosynthesis in the testes by alteration of 3beta-HSD mRNA expression.

Six fractions per week of external beam radiotherapy and high-dose-rate brachytherapy for carcinoma of the uterine cervix: A phase I/II study.

PURPOSE: This study evaluated the treatment results of external beam radiotherapy administered in six fractions per week and high-dose-rate (HDR) brachytherapy for the treatment of cervical cancer. METHODS AND MATERIALS: From July 2000 to July 2003, 43 patients were enrolled in this study. The patients received 45 Gy from a 10-MV photon beam using four-field box or anterior-posterior beams. Parametrial regions and the pelvic side walls were boosted with up to 50.4 Gy using a midline block. The daily fraction dose was 1.8 Gy administered in six-weekly fractions, from Monday to Saturday. HDR brachytherapy was also delivered at doses of 24 Gy to point A in six fractions twice a week. The median follow-up time was 37 months (range, 9-60 months). RESULTS: The median overall treatment time was 51 days for all patients (range, 44-62 days). Thirty-four patients (79.1%) achieved complete remission and 8 (18.6%) achieved partial remission after radiotherapy. Locoregional recurrence occurred in 5 patients (11.6%), and a distant metastasis was encountered in 6 patients (13.9%). The 3-year overall survival, locoregional, and distant metastasis-free survival rates were 74.7%, 87.8%, and 84.7%, respectively. Grade 2 and 3 late rectal complications were encountered in 3 (6.5%) and 1 (2.2%), respectively. There were no Grade 3 late bladder complications. CONCLUSIONS: Six fractions per week of external beam radiotherapy and HDR brachytherapy is an effective treatment for patients with a carcinoma of the uterine cervix and can be used as a possible alternative to concomitant chemoradiotherapy in elderly patients or in patients with co-morbidity.

Variation of small bowel sparing with small bowel displacement system according to the physiological status of the bladder during radiotherapy for cervical cancer.

OBJECTIVE: To evaluate the reproducibility of small bowel displacement system (SBDS) volumetrically using weekly CT throughout a regimen of radiotherapy for the treatment of cervical cancer. METHODS: From October 2004 to January 2005, 10 consecutive patients who received pelvic radiation therapy for uterine cervical carcinoma with the SBDS were included in this study. With the patient laid prone on the conventional simulator table, the Styrofoam compression device is placed under the lower abdomen of the patient. Next, CT scan images, first two sets of without and with the SBDS, followed by with SBDS once a week for 3 weeks consecutively after the beginning of radiotherapy, were taken. Radiation planning was performed using standard pelvic box fields in 3-dimensional radiation treatment planning system. In each CT sets, we measured the identified organ volumes and the volume of small bowel irradiated in treatment portals. We used the regression analysis to know the correlation of the volume of small bowel irradiated according to the volume variation of bladder during radiotherapy. RESULTS: The mean small bowel volume with SBDS of 10 patients during radiotherapy was reduced by 60.5% (from 32.5% to 78.2%), comparing to the small bowel volume without SBDS. The variation of small bowel volume reduction in each patient was ranged from 7.3% to 38.5% (mean: 20.5%). In spite of using the SBDS, the volume reduction of small bowel irradiated was affected significantly by the volume of bladder during radiotherapy. The variation of small bowel irradiated for five patients who had more than 10% small bowel volume variation was significantly correlated with the volume of bladder, but not for five patients less than 10% small bowel volume variation. CONCLUSION: We confirm that in spite of the variation of bladder volume during radiotherapy, the SBDS is an effective method that can be used to displace the small bowel continuously away from the irradiated field for cervical cancer.

Radical radiotherapy for locally advanced cancer of uterine cervix.

PURPOSE: This study was performed to evaluate the treatment results, prognostic factors and complication rates in patients with locally advanced cancer of uterine cervix after radiotherapy with high-dose rate (HDR) brachytherapy. MATERIALS AND METHODS: One hundred and twenty patients with a locally advanced (stages IIB approximately IVA according to FIGO classification) carcinoma of the uterine cervix were treated with radiotherapy at the Department of Radiation Oncology, Samsung Medical Center between September 1994 and December 2001. The median age of the patients was 61 years (range 29 to 81). Sixty-one, 56 and 3 patients had FIGO stage IIB, III, and IV diseases, respectively. All patients were given external beam radiotherapy over the whole pelvis (median 50.4 Gy) and HDR intracavitary brachytherapy, with a median of 4 Gy per fraction, to point A. Twenty-one patients received chemotherapy, of which 13 and 21 received neoadjuvant chemotherapy and concurrent chemotherapy, respectively, during the first and fourth weeks of external beam radiotherapy. The chemotherapy was not randomly assigned and the median follow-up time was 28.5 months (range: 6 approximately 100 months). RESULTS: The three- and 5-year overall survival (OS) and disease-free survival (DFS) rates were 64.4 and 57.0%, and 63.7 and 60.2%, respectively. The 5-year OS and DFS rates of the patients at stages IIB, III and IV were 60.2, 57.9 and 33.3%, and 57.4, 65.4 and 33.3%, respectively. Univariate analysis indicated that the FIGO stage, overall treatment time (OTT) and treatment response were significant variables for the OS (p=0.035, p=0.0649 and p=0.0009) and of the DFS (p=0.0009, p=0.0359 and p=0.0363). Multivariate analysis showed that the treatment response was the only significant variable for the OS (p=0.0018) and OTT for the DFS (p=0.0360). The overall incidence of late complications in the rectum and bladder were 11.7 and 6.7%, respectively. In addition, insufficiency fractures were observed in 7 patients (5.8%). CONCLUSION: The results of this study suggest that radical radiotherapy with HDR brachytherapy was appropriate for the treatment of locally advanced uterine cervix cancer. Also, the response after treatment and OTT are significant prognostic factors.

The N-terminal cysteine pair of yeast sulfhydryl oxidase Erv1p is essential for in vivo activity and interacts with the primary redox centre.

Yeast Erv1p is a ubiquitous FAD-dependent sulfhydryl oxidase, located in the intermembrane space of mitochondria. The dimeric enzyme is essential for survival of the cell. Besides the redox-active CXXC motif close to the FAD, Erv1p harbours two additional cysteine pairs. Site-directed mutagenesis has identified all three cysteine pairs as essential for normal function. The C-terminal cysteine pair is of structural importance as it contributes to the correct arrangement of the FAD-binding fold. Variations in dimer formation and unique colour changes of mutant proteins argue in favour of an interaction between the N-terminal cysteine pair with the redox centre of the partner monomer.

Induction of telomerase activity during an early burst of proliferation in pancreatic regeneration.

Telomerase activity (TA) and telomerase reverse transcriptase (rTERT) were investigated in Sprague-Dawley rats, killed at 6 and 12 h, and 1, 2, 3, 7, and 14 days after 90% pancreatectomy (px), by TRAPeze enzyme-linked immunosorbent assay telomerase detection and reverse transcriptase-polymerase chain reaction. TA increased at 2 days and reached a maximum at 3 days after px, when the small ductules showed the highest proliferation activity. After 3 days, TA decreased to basal levels as the ductules differentiated into new endocrine and exocrine pancreas. The expression of rTERT showed a correlation with TA. These results suggest telomerase is actively regulated during pancreatic regeneration.