Comparative outcomes for three‐dimensional conformal versus intensity‐modulated radiation therapy for esophageal cancer

Emerging data suggests a benefit for using intensity modulated radiation therapy (IMRT) for the management of esophageal cancer. We retrospectively reviewed patients treated at our institution who received definitive or preoperative chemoradiation with either IMRT or 3D conformal radiation therapy (3DCRT) between October 2000 and January 2012. Kaplan Meier analysis and the Cox proportional hazard model were used to evaluate survival outcomes. We evaluated a total of 232 patients (138 IMRT, 94 3DCRT) who received a median dose of 50.4 Gy (range, 44–64.8) to gross disease. Median follow up for all patients, IMRT patients alone, and 3DCRT patients alone was 18.5 (range, 2.5–124.2), 16.5 (range, 3–59), and 25.9 months (range, 2.5–124.2), respectively. We observed no significant difference based on radiation technique (3DCRT vs. IMRT) with respect to median overall survival (OS) (median 29 vs. 32 months; P = 0.74) or median relapse free survival (median 20 vs. 25 months; P = 0.66). On multivariable analysis (MVA), surgical resection resulted in improved OS (HR 0.444; P < 0.0001). Superior OS was also associated on MVA with stage I/II disease (HR 0.523; P = 0.010) and tumor length ≤5 cm (HR 0.567; P = 0.006). IMRT was also associated on univariate analysis with a significant decrease in acute weight loss (mean 6% + 4.3% vs 9% + 7.4%, P = 0.012) and on MVA with a decrease in objective grade ≥3 toxicity, defined as any hospitalization, feeding tube, or >20% weight loss (OR 0.51; P = 0.050). Our data suggest that while IMRT‐based chemoradiation for esophageal cancer does not impact survival there was significantly less toxicity. In the IMRT group there was significant decrease in weight loss and grade ≥3 toxicity compared to 3DCRT.     

Detection of D‐3‐phosphoglycerate dehydrogenase autoantibodies in patients with autoimmune hepatitis: Clinical significance evaluation

Aim: D‐3‐phosphoglycerate dehydrogenase (3‐PHGDH) was identified as a putative target of autoantibodies in autoimmune hepatitis (AIH). The aims of the present study were to detect anti‐3‐PHGDH in patients with AIH and other chronic liver diseases and to analyze their clinical relevance. Methods: Human 3‐PHGDH gene was cloned and expressed in Escherichia coli and used in enzyme‐linked immunosorbent assays and Western blots. Serum from patients with AIH (n = 101), primary biliary cirrhosis (PBC, n = 122), chronic hepatitis C (CHC, n = 117), chronic hepatitis B (CHB, n = 112), and from patients with other autoimmune disease (n = 125) were investigated. Results: The highest incidence and activity of anti‐PHGDH was observed in AIH patients. Thirty‐two of 40 untreated (80%) and 37 of 61 AIH patients treated with corticosteroid (60.7%) were positive. Antibody titers decreased significantly during corticosteroid treatment. 15.8% of PBC patients, 9.8% of CHB and 12.8% of CHC patients, were anti‐PHGDH‐positive, with less than 12% of patients positive with other autoimmune diseases via reactions with recombinant 3‐PHGDH protein. Conclusion: Anti‐PHGDH were detected in chronic liver diseases. They occur predominantly in AIH, and corticosteroid treatment seems to decrease antibody titers. Whether the antibodies are primary or secondary phenomena and whether they are related to the etiology or pathogenesis, at least in a subgroup of patients with chronic liver diseases, has still to be evaluated.     

Three‐Dimensional Echocardiographic Assessment of Patent Foramen Ovale in Platypnea‐Orthodeoxia

Platypnea‐orthodeoxia is an uncommon syndrome characterized by positional dyspnea and hypoxia when upright that improves with lying down. We present a 75‐year‐old man with platypnea‐orthodeoxia in the setting of a patent foramen ovale (PFO) and a 2.1 cm highly mobile atrial septal aneurysm with 2 cm bowing. Prior reports have established the use of three‐dimensional echocardiography to facilitate percutaneous closure of PFO and atrial septal defect, but its use in patients with platypnea‐orthodeoxia is unclear. We document three‐dimensional echocardiographic images that accurately estimated PFO defect size and confirmed placement of the occluder device.     

Effects of 1‐O‐hexyl‐2,3,5‐trimethylhydroquinone on carbon tetrachloride‐induced hepatic cirrhosis in rats

Aim: The present study was undertaken to evaluate the effects of 1‐O‐hexyl‐2,3,5‐trimethylhydroquinone (HTHQ), a synthesized vitamin E derivative, on carbon tetrachloride (CCl₄)‐induced cirrhosis. Methods: Rats were treated with hypodermic injections of CCl₄ twice a week to induce the hepatic cirrhosis, and given drinking water containing HTHQ or solvent. Primary cultures of rat hepatocytes were performed to evaluate the effects of HTHQ on the expression of inducible nitric oxide synthase (iNOS). Results: Masson's staining of rat livers showed fibrosis around pseudo‐lobules in the CCl₄ group, the lesions being reduced in the CCl₄ HTHQ group. Increases in liver tissue hydroxyproline and α₁(I) collagen, α‐smooth muscle actin and iNOS induced by CCl₄, were also markedly diminished by HTHQ. Furthermore, both HTHQ and vitamin E attenuated interleukin‐1β‐induced iNOS protein expression in cultured hepatocytes, the potency of HTHQ being 10‐times higher than that of vitamin E. Conclusion: HTHQ may inhibit development of hepatic cirrhosis in rats, more potently than vitamin E, by inhibiting the iNOS expression in hepatocytes. Because vitamin E has a radical scavenging action, roles of NO and peroxynitrite will be discussed in the effects of HTHQ on the fibrosis.     

Real‐world effectiveness of ombitasvir/paritaprevir/ritonavir±dasabuvir±ribavirin in patients with hepatitis C virus genotype 1 or 4 infection: A meta‐analysis

The direct‐acting antiviral regimen of ombitasvir (OBV)/paritaprevir (PTV)/ritonavir (r)±dasabuvir (DSV)±ribavirin (RBV) demonstrated high rates of sustained viral response at post‐treatment week 12 (SVR12) in clinical trials for treatment of hepatitis C virus (HCV) genotypes (GT) 1 and 4. To confirm the effectiveness of this regimen in the real world, we conducted meta‐analyses of published literature on 30 April 2016. Freeman‐Tukey transformation determined the SVR rate within GTs 1a, 1b and 4, as well as specific SVR rates by cirrhosis or prior treatment experience status. Rates of virologic relapse, hepatic decompensation, drug discontinuation and serious adverse events were also analysed. In total, 20 cohorts across 12 countries were identified, totalling 5158 patients. The overall SVR12 rates were 96.8% (95% CI 95.8‐97.7) for GT1 and 98.9% (95% CI 94.2‐100) for GT4. For GT1a patients, the SVR rates were 94% and 97% for those with or without cirrhosis, and 94% overall. For GT1b patients, the SVR rates were 98% and 99% for those with or without cirrhosis, and 98% overall. The virologic relapse rate of GT1 patients was 1.3%, across 3524 patients in nine studies that reported this parameter. The rate of hepatic decompensation was less than 1% across five studies, including 3440 patients, 70% of which had cirrhosis. Conclusions: Real‐world SVR12 rates for OBV/PTV/r±DSV±RBV were consistently high across HCV GT1 and four irrespective of cirrhosis status or prior HCV treatment experience, confirming effectiveness within a diverse patient population across multiple cohorts and countries.     

Stress echocardiography using real‐time three‐dimensional imaging

Two‐dimensional (2D) stress echocardiography is well established in the assessment of patients with ischemic heart disease. However, in a number of patients, this technique results in nondiagnostic tests due to limited time available at peak stress to capture wall motion abnormalities. In order to obtain all segments of the left ventricle, the sonographer is expected to acquire multiple echocardiography views from multiple windows. The changes in heart rate during acquisition and the technical challenges in exactly matching the stress with the baseline 2D echocardiographic views may adversely impact the sensitivity of the test. Real‐time three‐dimensional (3D) stress echocardiography offers advantages in acquisition of all images from one echo window in a single capture, with the technique relatively easy to master. The current review will describe the 3D stress echocardiography technique, its advantages, and limitations. Additionally, the future direction of 3D stress echocardiography in detecting ischemia in patients with coronary artery disease will be discussed.     

Melatonin‐induced calbindin‐D9k expression reduces hydrogen peroxide‐mediated cell death in rat pituitary GH3 cells

Abstract: In this study, we investigated whether calbindin‐D9k (CaBP‐9k) expression was regulated by melatonin during hydrogen peroxide (H₂O₂)‐induced cell death in rat pituitary GH3 cells. CaBP‐9k expression was increased by melatonin in a dose‐ and time‐dependent manner, indicating that CaBP‐9k expression is regulated by melatonin. Cell survival was increased approximately 27–30% where H₂O₂‐treated cells (0.25 or 0.5 mm ) were also incubated with 1 mm melatonin, when compared with H₂O₂ alone or H₂O₂ plus 0.5 mm melatonin. This result was consistent with 4,6‐diamidino‐2‐phenylindole staining. CaBP‐9k expression was also augmented by co‐treatment with H₂O₂ and 1 mm melatonin, suggesting a functional relationship between increased cell death and melatonin‐induced CaBP‐9k expression during H₂O₂‐mediated apoptosis. Bcl‐2‐associated protein expression increased following treatment with H₂O₂ alone, whereas Bcl‐2 expression was elevated following treatment with melatonin alone, or H₂O₂ plus melatonin. The expression of p53 was depressed by treatment with melatonin alone, or co‐treatment with H₂O₂ plus melatonin. These results correlated with CaBP‐9k expression levels and activation of the mitogen‐activated protein kinase/extracellular signal‐regulated kinase signaling pathway. Knockdown of CaBP‐9k expression using a small inhibitory RNA resulted in an elevation of H₂O₂‐induced cell death, whereas cell survival was increased in cells that overexpressed CaBP‐9k, providing additional evidence that the induction of CaBP‐9k expression may be associated with survival signaling during H₂O₂‐mediated oxidative cell death. CaBP‐9k appears to interact with p53, suggesting a possible role for this interaction in cell proliferation and cell cycle progression.     

Effect of genipin on cholestasis induced by estradiol‐17β‐glucuronide and lithocholate‐3‐O‐glucuornide in rats

Aim: Genipin is reported to stimulate the insertion of multidrug resistance protein 2 (Mrp2) in the bile canalicular membrane, thereby causing choleresis by the increased the biliary excretion of glutathione, which has been considered to be a substrate of Mrp2. In the present study, we examined the effect of genipin on cholestasis induced by estradiol‐17β‐glucuronide and lithocholate‐3‐O‐glucuronide, Mrp2 substrates, in rats. Further, the effect of genipin on the biliary excretion of substrates of P‐glycoprotein (P‐gp), vinblastine and erythromycin, was also studied. Methods: The effect of genipin infusion at the rate of 0.5 µmol/min/100 g on cholestasis induced by estradiol‐17β‐glucuronide (0.075 µmol/min/100 g for 20 min) and lithocholate‐3‐O‐glucuronide (0.15 µmol/min/100 g for 40 min) was studied. The effect of genipin infusion on the biliary excretion of a tracer dose of vinblastine and erythromycin infused at the rate of 0.1 µmol/min/100 g was also studied. Results: Genipin relieved estradiol‐17β‐glucuronide‐induced cholestasis, and cumulative biliary estradiol‐17β‐glucuronide excretion for 120 min was increased from 50 ± 20%–81 ± 20% dose. In contrast, genipin had no effect on lithocholate‐3‐O‐glucuronide‐induced cholestasis. Biliary excretion of a tracer dose of vinblastine and the maximum biliary excretion of erythromycin were significantly decreased by genipin. Conclusions: Genipin protected estradiol‐17β‐glucuronide‐induced cholestasis. The mechanism of the protection of cholestasis by genipin is unknown, but it is speculated to be due to a conformational change of P‐gp by genipin, in addition to the stimulation of Mrp2 insertion into the bile canaliculi.