Liver-targeted hydrodynamic gene therapy: Recent advances in the technique

One of the major research focuses in the field of gene therapy is the development of clinically applicable, safe, and effective gene-delivery methods. Since the first case of human gene therapy was performed in 1990, a number of gene-delivery methods have been developed, evaluated for efficacy and safety, and modified for human application. To date, viral-vectormediated deliveries have shown effective therapeutic results. However, the risk of lethal immune response and carcinogenesis have been reported, and it is still controversial to be applied as a standard therapeutic option. On the other hand, delivery methods for nonviral vector systems have been developed, extensively studied, and utilized in in vivo gene-transfer studies. Compared to viral-vector mediated gene transfer, nonviral systems have less risk of biological reactions. However, the lower gene-transfer efficiency was a critical hurdle for applying them to human gene therapy. Among a number of nonviral vector systems, our studies focus on hydrodynamic gene delivery to utilize physical force to deliver naked DNA into the cells in the living animals. This method achieves a high gene-transfer level by DNA solution injections into the tail vein of rodents, especially in the liver. With the development of genome editing methods, in vivo gene-transfer therapy using this method is currently the focus in this research field. This review explains the method principle, efficiency, safety, and procedural modifications to achieve a high level of reproducibility in large-animal models.     

Liquid biopsy in patients with pancreatic cancer: Circulating tumor cells and cell-free nucleic acids

Despite recent advances in surgical techniques and perioperative management, the prognosis of pancreatic cancer(PCa) remains extremely poor. To provide optimal treatment for each patient with Pca, superior biomarkers are urgently needed in all phases of management from early detection to staging, treatment monitoring, and prognosis. In the blood of patients with cancer, circulating tumor cells(CTCs) and cell-free nucleic acids(cf NAs), such as DNA, m RNA, and noncoding RNA have been recognized. In the recent years, their presence in the blood has encouraged researchers to investigate their potential use as novel blood biomarkers, and numerous studies have demonstrated their potential clinical utility as a biomarker for certain types of cancer. This concept, called "liquid biopsy" has been focused on as a less invasive, alternative approach to cancer tissue biopsy for obtaining genetic and epigenetic aberrations that contribute to oncogenesis and cancer progression. In this article, we review the available literature on CTCs and cfN As in patients with cancer, particularly focusing on PCa, and discuss future perspectives in this field.     

Pancreatic adenocarcinoma: MDCT versus MRI in the detection and assessment of locoregional extension

PURPOSE: To compare dynamic-contrast enhanced multirow detector computed tomography (MDCT) including multiplanar reformatted images (MPR) and magnetic resonance imaging (MRI) including magnetic resonance cholangiopancreatography images for the detection and assessment of locoregional extension of pancreatic adenocarcinoma. MATERIALS AND METHODS: Twenty-four patients with and 21 patients without pancreatic adenocarcinoma underwent triple-phase MDCT and MRI. Three radiologists independently attempted to detect pancreatic adenocarcinoma and assess locoregional extension in 3 sessions. First session involved MDCT images. In the second session, radiologists had access to coronal and sagittal MPR images together with the axial images (MDCT + MPR). Third session involved MR images. Results were compared with surgical findings using receiver operating characteristic analysis and kappa statistics. RESULTS: Regarding tumor detection, MDCT + MPR had a significantly higher value for areas under the curve (0.96 +/- 0.02) at receiver operating characteristic analysis compared with those of MRI (0.90 +/- 0.03) and MDCT (0.85 +/- 0.04). MDCT + MPR had the highest mean sensitivity (96%), and MRI had the highest mean specificity (98%). For locoregional extension, MDCT + MPR showed the highest kappa values of the study for all factors evaluated (range, 0.63-0.86). CONCLUSIONS: In conclusion, multiphasic MDCT imaging with MPR images was superior to multiphasic MDCT imaging without MPR images and to comprehensive MRI employing 2-D sequences and magnetic resonance cholangiopancreatography for both the detection and assessment of locoregional extension of pancreatic adenocarcinomas. MRI might be used for further lesion characterization regarding its high specificity.     

Neuroradiologic findings in Sotos syndrome

Sotos syndrome is a well-known anomaly syndrome characterized by overgrowth, characteristic facial gestalt, and developmental delay, and haploinsufficiency of the NSD1 gene has been revealed as one of the major genetic causes. However, there have been only a few reports on neuroradiologic findings by computed tomography (CT) or magnetic resonance imaging (MRI), and functional examination of the brain has not been reported. We examined three cases with typical Sotos syndrome, which also were confirmed by genetic analysis with a specific probe for the NSD1 gene. The results of MRI showed the characteristic features that have been reported previously. The findings obtained by using single-photon emission computed tomography and magnetic resonance spectroscopy suggested an association between mental delay and behavioral tendency in Sotos syndrome and immaturity in frontal brain function.     

Continuous regional arterial infusion effective for children with acute necrotizing pancreatitis even under neutropenia

Severe acute pancreatitis is one of the critical conditions that may develop in children with cancer. The leading cause of death due to acute pancreatitis is infectious pancreatitis or circulation collapse. Therefore, patients who develop acute pancreatitis while undergoing chemotherapy or after hematopoietic transplantation are at risk for a life‐threatening and fatal course. We treated 140 patients with malignancy from April 2002 to March 2009 at our hospital and encountered 3 patients under neutropenia who developed severe acute pancreatitis. Two of them were successfully treated with continuous regional arterial infusion of a protease inhibitor and antibiotic even under agranulocytosis. Another patient was treated with conventional therapy with intravenous antibiotics plus a protease inhibitor and total or partial parenteral nutrition. Even though the two patients treated with continuous regional arterial infusion presented much more severe conditions, their symptoms resolved earlier. In conclusion, acute pancreatitis is one of the severe complications of childhood malignancy. Even under agranulocytosis, continuous regional arterial infusion of a protease inhibitor and antibiotic was well tolerated and effective among our cases and might reduce early death due to pancreatitis.     

Rationale and Design of an International Multicenter Registry of Patients With Repaired Tetralogy of Fallot to Define Risk Factors for Late Adverse Outcomes: The INDICATOR Cohort

Although early survival after tetralogy of Fallot (TOF) repair in the modern era is excellent, studies on late outcomes have shown increasing rates of mortality and morbidity. Despite multiple publications on factors associated with late complications, risk factors for major outcomes (death and sustained ventricular tachycardia [VT]) remain poorly defined. Consequently, the International Multicenter TOF Registry (INDICATOR) was established. This article describes the development, structure, and goals of this registry and characterizes the initial cohort derived from four large congenital heart centers in the United States, Canada, and Europe. A data coordinating center with a core cardiac magnetic resonance (CMR) laboratory and statistical core was established. Subjects with repaired TOF who had CMR imaging performed between 1997 and 2010 and ≥1 year follow-up were included. Clinical end points were death and sustained VT. Demographic, electrophysiologic, exercise, and outcome data were collected. A total of 873 subjects fulfilled inclusion criteria (median age at repair 2.9 years and at CMR imaging 22.8 years). Of these, 9 % had QRS duration >180 ms on electrocardiogram (ECG). On CMR imaging, 38 % had severe right-ventricular (RV) dilatation (≥160 mL/m²), and 6 % had severe RV dysfunction (ejection fraction < 35 %). Of the 551 subjects with exercise testing available, 28 % had severely decreased exercise capacity with <50 % predicted peak oxygen consumption. The INDICATOR cohort allows robust statistical analysis to evaluate major clinical outcomes in patients with repaired TOF. Continued follow-up and further expansion of the registry may provide new insights into innovative therapeutic strategies to improve late outcomes.     

Bilateral Banding of Malpositioned Pulmonary Artery Branches

This report presents two rare cases of malpositioned pulmonary artery branches managed by bilateral banding. The left-branch pulmonary artery, originating from and directly superior to the right branch, entered the posterior mediastinum before heading toward the left pulmonary hilum. The ostium of the left branch could not be visualized by midline sternotomy. Therefore, a double-subtraction technique was used to pass the banding tape around the left branch from the right side. The tape location was adjusted and confirmed by intraoperative echocardiography.     

The first case of lung carcinosarcoma harboring in-frame deletions at exon19 in the EGFR gene

Mutations of the epidermal growth factor receptor (EGFR) gene play a critical role in carcinogenesis of lung cancer, particularly adenocarcinoma. However, to the best of our knowledge, no mutations of the EGFR in patients with lung carcinosarcoma have been identified. We herein report the case of a 61-year-old female referred for a detailed examination of a left pulmonary mass shadow. Although bronchoscopy was performed, it failed to lead to a diagnosis, and video-assisted thoracoscopic surgery was therefore carried out to diagnose the tumor. The pathology revealed biphasic features consisting of both adenocarcinoma and chondrosarcoma. Intriguingly, both the adenocarcinoma and chondrosarcoma components were proven to harbor an exon19 deletion in the EGFR gene. Although carcinosarcoma is a rare malignancy of the lungs, genetic analyses of oncogenic drivers, such as the EGFR gene, should be conducted.     

Definitive radiation therapy for invasive carcinoma of the vagina: impact of high-dose rate intracavitary brachytherapy

Background

This study was designed to evaluate the efficacy of definitive radiation therapy (RT) for invasive carcinoma of the vagina.

Methods

Twenty-six patients with invasive carcinoma of the vagina who received RT were studied retrospectively. The median age was 68 years. The pathologic subtype of vaginal carcinoma was squamous cell carcinoma in 24 patients, adenosquamous cell carcinoma in one patient, and adenocarcinoma in one patient. The distribution of clinical stage according to the International Federation of Gynecology and Obstetrics staging system was as follows: stage I, seven patients; stage II, 10 patients, stage III, seven patients; and stage IVA, two patients. Twenty patients received external beam radiation therapy (EBRT) combined with high-dose rate intracavitary brachytherapy (HDR-ICBT), and three received EBRT alone. The remaining three patients with stage I disease were given HDR-ICBT alone. The median dose was 50 Gy for EBRT, and 23 Gy for HDR-ICBT. Systemic chemotherapy was administered concurrently with RT to three patients.

Results

The median follow-up was 90 months. The initial rate of response to RT was 100%, and complete remission was attained in 21 patients (81%). The 5-year overall survival rate (OS) and the median survival time of the 26 patients were 57% and 97 months, respectively. The 5-year OS for the three patients who received HDR-ICBT alone was 100%. Severe toxicity occurred in three patients—grade 3 rectal hemorrhage in one, grade 3 cystitis in one, and grade 4 cystitis in one.

Conclusions

Our results demonstrated that definitive RT with HDR-ICBT is effective for invasive carcinoma of the vagina, with acceptable toxicity.