Keratinocyte Growth Factor Gene Electroporation into Skeletal Muscle as a Novel Gene Therapeutic Approach for Elastase-Induced Pulmonary Emphysema in Mice

Pulmonary emphysema is a progressive disease with airspace destruction and an effective therapy is needed. Keratinocyte growth factor (KGF) promotes pulmonary epithelial proliferation and has the potential to induce lung regeneration. The aim of this study was to determine the possibility of using KGF gene therapy for treatment of a mouse emphysema model induced by porcine pancreatic elastase (PPE). Eight-week-old BALB/c male mice treated with intra-tracheal PPE administration were transfected with 80 μg of a recombinant human KGF (rhKGF)-expressing FLAG-CMV14 plasmid (pKGF-FLAG gene), or with the pFLAG gene expressing plasmid as a control, into the quadriceps muscle by electroporation. In the lung, the expression of proliferating cell nuclear antigen (PCNA) was augmented, and surfactant protein A (SP-A) and KGF receptor (KGFR) were co-expressed in PCNA-positive cells. Moreover, endogenous KGF and KGFR gene expression increased significantly by pKGF-FLAG gene transfection. Arterial blood gas analysis revealed that the PaO2 level was not significantly reduced on day 14 after PPE instillation with pKGF-FLAG gene transfection compared to that of normal mice. These results indicated that KGF gene therapy with electroporation stimulated lung epithelial proliferation and protected depression of pulmonary function in a mouse emphysema model, suggesting a possible method of treating pulmonary emphysema

Pancreatic Duct-to-mucosa versus Invagination or Complete External Drainage Anastomosis in Case of Small Pancreatic Duct after Pancreaticoduodenectomy: Comparative Historical Review

After pancreaticoduodenectomy (PD), pancreatic duct-to-mucosa anastomosis (PDM) has been usually applied which may prevent risk of pancreatic fistula (PF). In cases with a small pancreatic duct, however, PDM is difficult to complete. Procedures involving the invagination (IV) or complete external tube drainage (CED) are supposed to be alternative options for anastomosis. We retrospectively compared clinical results between PDM and IV or CED in 104 patients with a tiny pancreatic duct who underwent PD. The 77 patients undergoing PDM (the control group) and 27 patients undergoing other procedures, including 19 for CED and 8 for IV, were comparatively examined. Fatty pancreas was commonly observed in CED group. Pancreaticojejunostomy was significantly more frequently applied in CED group, and the operating time in the IV group was significantly longer than in control group (p<0.05). The anastomotic time in CED group tended to be shorter than those in control and IV groups (18 versus 29 and 37 min). The incidences of PF were not significantly different among groups (31% in control, 47% inCED and 14% in IV, respectively); however, a grade B or C level of PF was not observed in the IV group. PDM is often difficult to achieve and inadequate suturing may injure the pancreatic parenchyma in cases of very small pancreatic duct. Re-evaluation of the CED or IV procedure as an alternative option was suggested to be warranted

Intratracheal Administration of Recombinant Human Keratinocyte Growth Factor Promotes Alveolar Epithelial Cell Proliferation during Compensatory Lung Growth in Rat

Keratinocyte growth factor (KGF) is considered to be one of the most important mitogens for lung epithelial cells. The objectives of this study were to confirm the effectiveness of intratracheal injection of recombinant human KGF (rhKGF) during compensatory lung growth and to optimize the instillation protocol. Here, trilobectomy in adult rat was performed, followed by intratracheal rhKGF instillation with low (0.4 mg/kg) and high (4 mg/kg) doses at various time-points. The proliferation of alveolar cells was assessed by the immunostaining for proliferating cell nuclear antigen (PCNA) in the residual lung. We also investigated other immunohistochemical parameters such as KGF, KGF receptor and surfactant protein A as well as terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling. Consequently, intratracheal single injection of rhKGF in high dose group significantly increased PCNA labeling index (LI) of alveolar cells in the remaining lung. Surprisingly, there was no difference in PCNA LI between low and high doses of rhKGF with daily injection, and PCNA LI reached a plateau level with 2 days-consecutive administration (about 60%). Our results indicate that even at low dose, daily intratracheal injection is effective to maintain high proliferative states during the early phase of compensatory lung growth

Keratinocyte growth factor accelerates compensatory growth in the remaining lung after trilobectomy in rats.

OBJECTIVE: In rats pulmonary resection is followed by lung compensatory growth. However, the molecular mechanism underlying lung compensatory growth remains unclear. Keratinocyte growth factor is expressed in lung tissue and is considered a possible mitogen for lung epithelial cells. The objectives of this study were to define the role of keratinocyte growth factor and its receptor in rat lung compensatory growth after trilobectomy and the effect of exogenous keratinocyte growth factor gene transfection. METHODS: Adult Lewis rats were used. Right trilobectomy was performed in the operation group and sham thoracotomy in the sham group. In the operation group, keratinocyte growth factor-FLAG or FLAG expression vector was transfected directly into the lung by means of electroporation. Expression of keratinocyte growth factor and its receptor and alveolar cell proliferation index based on proliferating cell nuclear antigen levels were measured in the right lung at day 14 after the operation. RESULTS: Proliferating cell nuclear antigen, keratinocyte growth factor, and keratinocyte growth factor receptor expression in lung epithelial cells was significantly increased at day 4 after trilobectomy. Transfection of keratinocyte growth factor-FLAG expression vector resulted in further significant enhancement of proliferating cell nuclear antigen at day 4 after trilobectomy; however, the transfection of FLAG expression vector did not alter the enhancement of proliferating cell nuclear antigen. Exogenous expression of keratinocyte growth factor in the remaining lung by means of electroporation significantly augmented epithelial proliferation and decreased the average airspace distance (mean linear intercept). CONCLUSION: Our results implicate keratinocyte growth factor in the induction of alveolar epithelial cell proliferation for compensatory lung growth and indicate that overexpression of keratinocyte growth factor in the remaining lung by means of electroporation significantly augmented lung epithelial proliferation

A rare case of segmental ulcerative colitis

Background: Ulcerative colitis (UC) typically develops in the rectum and progresses proximally. Segmental UC is a rare condition that is often difficult to diagnose. We present a case of segmental UC mimicking colon cancer that developed in the transverse colon. Case presentation: An 83-year-old woman with abdominal pain visited our hospital. Total colonoscopy revealed a granular mass with stenosis in the transverse colon. Biopsy specimen showed infiltration of inflammatory cells. No mucosal inflammation was evident on the anal side of the colon and rectum. Abdominal computed tomography showed enhanced mural thicknening in the transverse colon. Enlarged regional lymph nodes were apparent. Although no malignancy was evident, cancerlike stenosis and swollen lymph nodes were identified, so colectomy with regional lymph node resection was performed. The resected specimen showed near-circumferential thicknening. Aggregated small polypoid lesions and a mucosal bridge were also revealed. Histological findings showed a wide range of crypt abscess. No cellular atypia was found. We finally diagnosed segmental UC. The patient was subsequently followed closely without treatment, and abdominal distension developed one and a half years later. Total colonoscopy showed mucosal redness and erosion in the residual transverse colon. Pharmacotherapy immediately improved symptoms. As of 10 years postoperatively, she has experienced no further recurrence. Conclusion: We encountered a rare case of segmental UC in the transverse colon. UC does not always develop from the rectum and progress towards the oral side. Early definitive diagnosis can achieve good results for treatment and the clinical course

A rare case of segmental ulcerative colitis

Background: Ulcerative colitis (UC) typically develops in the rectum and progresses proximally. Segmental UC is a rare conditionthat is often difficult to diagnose. We present a case of segmental UC mimicking colon cancer that developed in the transverse colon.Case presentation: An 83-year-old woman with abdominal pain visited our hospital. Total colonoscopy revealed a granular mass with stenosis in the transverse colon. Biopsy specimen showed infiltration of inflammatory cells. No mucosal inflammation was evident on the anal side of the colon and rectum. Abdominal computed tomography showed enhanced mural thicknening in the transverse colon. Enlarged regional lymph nodes were apparent. Although no malignancy was evident, cancerlikestenosis and swollen lymph nodes were identified, so colectomy with regional lymph node resection was performed. The resected specimen showed near-circumferential thicknening. Aggregated small polypoid lesions and a mucosal bridge were also revealed. Histological findings showed a wide range of crypt abscess. No cellular atypia was found. We finally diagnosed segmental UC. The patient was subsequently followed closely without treatment, and abdominal distension developed one and a half years later. Total colonoscopy showed mucosal redness and erosion in the residual transverse colon. Pharmacotherapy immediately improved symptoms. As of 10 years postoperatively, she has experienced no further recurrence. Conclusion: We encountered a rare case of segmental UC in the transverse colon. UC does not always develop from the rectum and progress towards the oral side. Early definitive diagnosis can achieve good results for treatment and the clinical course

Usefulness of FDG PET/CT derived parameters in prediction of histopathological finding during the surgery in patients with pancreatic adenocarcinoma

Purpose Pancreatic cancer is the 4th most common cause of cancer death in Japan and exhibits a 5-year overall survival rate of approximately 7%. The accurate diagnosis of pancreatic cancer is important for determining the optimal management strategy. Fludeoxyglucose-positron emission tomography (FDG PET) integrated with computed tomography (18F-FDG PET/ CT) has emerged as a powerful imaging tool for detecting and evaluating various cancers, and it is used for staging, detecting local recurrence and distant metastasis, measuring therapeutic effects,and predicting prognosis in pancreatic cancer patients. Lately, FDG PET/CT-derived parameters, such as standardized uptake values (SUV), the metabolic tumor volume (MTV), and total lesion glycolysis (TLG), have been suggested as prognostic factors for various types of cancer, including pancreatic cancer. However, there is no consensus regarding the best parameters for evaluating patient prognosis, operability, etc. The purpose of this study was to examine the differences between operable and non-operable pancreatic cancer using FDG PET/CT-derived parameters, and to investigate whether volumetric parameters (TLG and the MTV) are superior to SUV-based parameters for predicting infiltration status/determining operability. Materials and methods We conducted a retrospective study of the cases of 48 patients with clinically proven pancreatic adenocarcinoma, who underwent FDG PET/CT imaging before treatment. In the operable group, the surgical specimens were subjected to histopathological examinations, and the cases were separated into those exhibiting less and greater infiltration. SUVmax, SUVpeak, the tumor background ratio (TBR), TLG, and the MTV were compared between these groups as well as between the operable and non-operable groups.Results Venous infiltration showed significant associations with several metabolic parameters (SUVmax, SUVpeak, and the TBR). However, it did not display any significant associations with volumetric parameters, such as TLG or the MTV. None of the FDG PET/CT-derived parameters exhibited significant associations with lymphatic or neural infiltration. Significant differences in volumetric parameters, such as the MTV and TLG,were detected between the operable and non-operable subgroups. Conclusions Metabolic18F-FDG PET/CT-derived parameters,such as SUVmax, SUVpeak, and the TBR, are useful for predicting venous infiltration status in patients with operable pancreatic adenocarcinoma