Long-term results of concurrent chemoradiotherapy with daily-low-dose continuous infusion of 5-fluorouracil and cisplatin (LDFP) for Stage I-II esophageal carcinoma.

We investigated long-term treatment outcomes and the feasibility of chemoradiotherapy consisting of daily-low-dose 5-fluorouracil and cisplatin (LDFP) chemotherapy plus radiotherapy for Stage I-II squamous cell esophageal cancer. Treatment records from the 2000 through 2008 period were reviewed retrospectively. Fractionated radiotherapy was performed with a total dose of 60 Gy delivered in 2 Gy per fraction. LDFP chemotherapy, as continuous infusion of 200 mg/m2 5-fluorouracil combined with one hour infusion of 4 mg/m2 cisplatin, was administered on the same days as radiotherapy. Survival was calculated by the Kaplan-Meier method. Survival, responses, failure patterns, and toxicities were evaluated. Seventy-six (47 stage I and 29 stage II) patients were analyzed with a median follow-up of 93.6 months. The 8-year overall survival (OS), progression-free survival (PFS) and cause-specific survival (CSS) rates were 63.4%, 49.8%, and 76.7%, respectively. The 8-year OS, PFS, and CSS for stage I and stage II patients were 71.0%/56.1%/82.9% and 45.2%/40.2%/66.6%, respectively. Sixty-eight patients (89.5%) completed the treatment regimen. A complete response (CR) was achieved in 68 patients (89.5%). Twenty-five patients (36.8%) experienced recurrence after CR. The failure patterns were (overlap included): local failure (n = 12), nodal metastasis (n = 12), distant metastasis (n = 3), details unknown (n = 2). Salvage therapy was performed for local failure; endoscopic therapy (n = 7) or surgery (n = 2). Six patients remain alive without relapse after salvage endoscopic therapy. Major Grade 3 or higher acute adverse events were leukopenia (22%), anorexia (17%), and esophagitis (11%). Major late toxicities (Grade 3 or 4) involved pericardial effusion (12%), pleural effusion (4%), and esophageal stenosis (3%). Chemoradiotherapy with LDFP provided favorable long-term survival with acceptable toxicity for Stage I-II squamous cell esophageal cancer. The tumor response was excellent, but close endoscopic follow-up is essential for detecting and treating local recurrence.

High-resolution intravital imaging for monitoring the transplanted islets in mice.

Intravital imaging techniques will be a valuable tool to monitor the post-transplantation dynamics of the cells/tissues in regenerative medicine research. Among the conventional live imaging techniques, the cranial window model has various advantages regarding resolution, longevity, and easy manipulability. We describe the use of the cranial window model to visualize the post-transplantation processes of primary pancreatic islets in the living mouse. Macroscopic or microscopic analyses were performed to evaluate the post-transplantation dynamics of primary murine islets, including the revascularization process inside the cranium. Consistent with earlier literature on clinical outcomes of islet transplantation, marked loss of transplanted islets was observed within 7 days. Intravital confocal microscope analysis revealed that functional revascularization seldom occurred in the central regions of the transplants. Our results suggest that the cranial window model offers an ideal platform for understanding cellular dynamics, through the possibility of long-term imaging studies over time scales. This platform is possibly applied not only for transplant studies of pancreatic islets, but also for other endodermal cell/tissue types in vivo.

Incidence, diagnosis and pathophysiology of amniotic fluid embolism.

Amniotic fluid embolism (AFE) is a rare clinical entity, sometimes fatal. A review was conducted to describe the frequency, diagnosis and pathophysiology of AFE. The reported incidences ranged from 1.9 cases per 100,000 maternities (UK) to 6.1 per 100,000 maternities (Australia), which can vary considerably, depending on the period, region of study and the definition. Although the development of amniotic fluid-specific markers would have an impact on early diagnosis, definition of AFE based on these markers is not widely accepted. To date, immunological mechanisms, amniotic fluid-dependent anaphylactic reaction and complement activation, have been proposed as potential pathogenetic and pathophysiological mechanisms. Immune cell activation induced through complement activation may be associated with the mechanism that immediately initiates maternal death, only in susceptible individuals. This review will focus on advances in the field of AFE biology and discuss the prevalence, diagnosis and pathophysiology of AFE.

The association between neutropenia and prognosis in stage III colorectal cancer patients receiving adjuvant chemotherapy.

Neutropenia during chemotherapy has been reported to be a predictor of better survival in patients with several types of cancer, although there are no reports on stage III colorectal cancer (CRC). The purpose of this study was to examine the association between neutropenia and prognosis in stage III CRC patients receiving adjuvant chemotherapy consisting of oral uracil and tegafur (UFT) plus leucovorin (LV). We retrospectively analysed 123 patients with stage III CRC who received UFT/LV as adjuvant chemotherapy. The end-point was disease-free survival (DFS). Survival curves of the two categories (neutropenia absent vs. present) were estimated using the Kaplan-Meier method and compared by the log-rank test. We estimated the hazard ratio (HR) for DFS according to neutropenia after adjustment for covariates by multivariate analyses using Cox's regression analysis. A total of 33 (26.8%) patients experienced neutropenia. Patients without neutropenia showed a significantly lower DFS than those with neutropenia (3-year DFS 57.3% vs. 81.2%, P = 0.0213). By multivariate analysis, neutropenia and histological type were independent prognostic factors, with HR of 0.410 (neutropenia absent vs. present, P = 0.045) and 4.793 (well to moderately differentiated vs. poorly differentiated, P = 0.004) respectively. We demonstrated that neutropenia occurring during adjuvant chemotherapy consisting of UFT/LV may be a prognostic factor of recurrence in stage III CRC patients.

Generation of functional human vascular network.

BACKGROUND: One of the major obstacles in regenerating thick, complex tissues such as the liver is their need for vascularization, which is essential to maintain cell viability during tissue growth and to induce structural organization. Herein, we have described a method to engineer a functional human vascular network. METHODS: Enhanced green fluorescence protein-labeled human umbilical vein endothelial cells (GFP-HUVECs) were cocultivated with kusabira orange-labeled human mesenchymal stem cells (KO-hMSCs) inside a collagen/fibronectin matrix. Premature vascular network formation was visualized by fluorescence microscopy imaging. Furthermore, constructs prevascularized in vitro were implanted into a transparency window in immunodeficient mice. RESULTS: Following several days of cultivation, GFP-HUVECs formed vessel-like structures that were stabilized by pericytes differentiated from KO-hMSCs. After implantation in vivo, the patency of human vascular structures was proved by rhodamine dextran infusion. These functional vascular structures remained for over 2 months. DISCUSSION: Vascularization is the key challenge to organ generation. We successfully generated human vascular networks inside a matrix. Integration of parenchymal cells using our engineering technique should facilitate future efforts to reconstitute vascularized human organ systems in vitro.

CT evaluations of focal liver reactions following stereotactic body radiotherapy for small hepatocellular carcinoma with cirrhosis: relationship between imaging appearance and baseline liver function.

This study aimed to assess the imaging appearances of focal liver reactions following stereotactic body radiotherapy (SBRT) for small hepatocellular carcinoma (HCC) and to examine relationships between imaging appearance and baseline liver function. We retrospectively studied 50 lesions in 47 patients treated with SBRT (30-40 Gy in 5 fractions) for HCC, who were followed up for more than 6 months. After SBRT, all patients underwent regular follow-ups with blood tests and dynamic CT scans. At a median follow-up of 18.1 months (range 6.2-43.7 months), all lesions but one were controlled. 3 density patterns describing focal normal liver reactions around HCC tumours were identified in pre-contrast, arterial and portal-venous phase scans: iso/iso/iso in 4 patients (Type A), low/iso/iso in 8 patients (Type B) and low/iso (or high)/high in 38 patients (Type C). Imaging changes in the normal liver surrounding the treated HCC began at a median of 3 months after SBRT, peaked at a median of 6 months and disappeared 9 months later. Liver function, as assessed by the Child-Pugh classification, was the only factor that differed significantly between reactions to treatment showing "non-enhanced" (Type A and B) and "enhanced" (Type C) appearances in CT. Hence, liver tissue with preserved function is more likely to be well enhanced in the delayed phase of a dynamic contrast-enhanced CT scan. The CT appearances of normal liver seen in reaction to the treatment of an HCC by SBRT were therefore related to background liver function and should not be misread as recurrence of HCC.

[Aortic dissection and annulo-aortic ectasia complicating systemic lupus erythematousus; report of a case].

A 31-year-old man with systemic lupus erythematosus had received long term steroid therapy. He had no compliant, but magnetic resonance imaging showed aortic dissection and annulo-aortic ectasia. Echocardiogram showed severe aortic regurgitation. Therefore aortic root replacement was performed. A histological study of the aortic wall demonstrated myxomatous degeneration in the media. He recovered uneventfully, except for receiving continious hemodia filtration during 4 days after the operation

[Infective endocarditis with the fistula from sinus Valsalva to right atrium and ventricle; report of a case].

A 77-year-old man complained general fatigue and fever. Preoperative echocardiography revealed vegetation of aortic valve, abnormal shunt flow from the sinus of Valsalva was detected in the right atrium and ventricle without perivalvular abscess cavity or aneurysm of the sinus of Valsalva. He diagnosed aortic valve endocarditis with aorto-right atrium and ventricle fistula. He received aortic valve replacement and patch closure at the sinus of Valsalva using the pericardium. Residural aortic-right atrium and ventricle shunt was not detected after the operation, the post operative course was uneventful without congestive heart failure nor signs of infection.

[Large coronary aneurysm after coronary intervention for acute myocardial infarction; report of a case].

A 59-year-old man was admitted to our hospital because of angina pectoris and a large right coronary aneurysm. Two years previously, he underwent percutaneous coronary balloon angioplasty for a stenotic lesion in right coronary artery (RCA) #3. Angiography and computed tomography showed a large right coronary aneurysm. On-pump coronary artery bypass grafting (CABG), ligation of RCA proximal and distal to the aneurysm, resection of the aneurysm was performed successfully. Postoperative course was uneventful with satisfactory angiographic results.

[Perforation due to new myocardial infarction long time; report of a case].

A 65-year-old man was admitted to the hospital because of effort chest pain, 8 years after he received coronary artery bypass grafting [CABG: left internal thoracic artery (LITA) to left anterior descending artery (LAD), saphenous vein graft (SVG) to first diagonal branch (D1) and SVG to postero-lateral branch (PL)]. Emergent coronary angiography revealed right coronary artery occlusion with well patent bypass grafts. Percutaneus coronary intervention (PCI) was performed successfully, but 9 hours later, ventricular septal perforation (VSP) was occurred. Swan-Ganz catheter revealed that pulmonary to systemic blood flow ratio (Qp/Qs) was 2.6. In spite of intensive medical care, his hemodynamics was gradually exacerbated. Subsequent intracavitary repair with equine pericardial patch, sutured using interrupted mattress sutures with felt pledgets, was performed. He had an uneventful recovery thereafter, extubated and weaned from an intra-aortic balloon pumping at the 1st day. He was discharged from hospital on the 27th postoperative day.

[Endovascular stent-grafting for mycotic thoracic aortic aneurysm].

We report 3 cases of endovascular stent-grafting (ESG) for mycotic thoracic aortic aneurysm. The case 1 was a rupture of pseudoaneurysm of the descending aorta caused by mediastinitis due to perforation of esophageal ulcer. The patient underwent emergent ESG for temporary control of the rupture. He underwent esophagus reconstruction 5 month after ESG. The case 2 was admitted due to inflammatory reaction. She was diagnosed with mycotic descending aortic aneurysm and underwent elective ESG because of her old age. Her postoperative course was uneventful and no infection recurred. The case 3 underwent ESG for a ruptured mycotic descending aortic aneurysm. But 113 days after ESG, he underwent ESG again for a ruptured endoleak of the stentgraft. His blood culture demonstrated methillin-resistant Staphylococcus aureus (MRSA). He died of rupture to bronchus and esophagus at 18th day after ESG. We believe that ESG is useful in high risk patients for temporary management of the rupture.

[Successful consecutive seven time's surgical repair of Marfan syndrome].

We report a patient with Marfan syndrome who received successful 7 consecutive operations during 11 years. She underwent descending aortic replacement for chronic type B dissection at the age of 24. Mitral valve replacement (MVR) was performed for mitral regurgitation (MR) at the age of 30, and abdominal aortic replacement was done for persistent dissection at the age of 31, aortic root and arch replacement was done at the age of 34. The 9 months later, she received re-MVR for dysfunction of bioprosthesis and tricuspid valve anuloplasty (TAP) for tricuspid regurgitation (TR). But severe paravalvuler leakage of mitral valve necessitated direct closure of detachment. Thoracoabdominal replacement was performed for rupture of persistent dissection at the age of 35. She was discharged on the 54th day after the 7th surgery.

[Left atrial myxoma combined with coronary artery bypass grafting].

We experienced 2 cases of surgical treatment for left atrial myxoma combined with coronary artery bypass grafting (CABG) using only in situ arterial grafts. A 58-year-old man who had undergone CABG [left internal thoracic artery (LITA)-right coronary artery (RCA) and saphenous vein graft (SVG)-left anterior descending artery (LAD)] 14 years before was admitted to our hospital, complaining of anterior chest pain. Coronary arteriography demonstrated total occlusion of the LAD and RCA, as well as the stenosis of high lateral branch (HL) and SVG. Left atrial myxoma was incidentally detected by echocardiography. Myxoma was resected at first, and then the right internal thoracic artery (RITA) was anastomosed to the LAD. The postoperative course was uneventful. A 69-year-old woman was admitted to another hospital, complaining of chest pain and dyspnea. Coronary arteriography revealed stenosis of LAD, left circumflex artery (LCx) and HL, as well as left main trunk (LMT). Left atrial myxoma was incidentally detected by echocardiography. Myxoma was resected at first, and then CABG [LITA-HL, gastroepiploic artery (GEA)-RCA and RITA-LAD] was carried out. The postoperative course was uneventful. The priority between CABG and the surgical treatment for cardiac myxoma remains controversial from the point of view of myocardial protection and prevention of systemic embolism of myxomal fragment.

MUC 1 core protein as a marker of gallbladder malignancy.

AIM: The significance of MUC 1 expression in the gallbladder tissues in relation to cancer and non-cancer disease is not well understood. The aim of this study was to clarify the significance of MUC 1 expression. MATERIALS AND METHODS: A monoclonal antibody (CA 15--3; DF 3) was applied to stain MUC 1 core protein in surgical specimens. RESULTS: MUC 1 expression is significantly higher (p<0.0001) in gallbladder cancer (69/88) compare to non-cancerous tissue, while, very trace in normal and inflammatory tissues. The expression rate was significantly lower (p<0.0001) when the cancer did not penetrate the mucosal layer than when cancers did penetrate this layer. The MUC 1 expression rate was (4/14) in T1 tumours, (11/14) in T4, (40/45) in T3, and (14/15) in T2, respectively. Every cell of normal and inflammatory mucosa, and T1 cancers had the polarized pattern. The depolarized pattern was dominant in cancer cells from the advanced tumours of T2, T3 and T4. That is, (45/74) of cancer cells from the mucosal layer and (58/74) of penetrating cancer cells in submucosal layer had the depolarized pattern. There was no significant correlation of MUC 1 expression rate and staining pattern with cancer differentiation and microscopic venous invasion. On the other hand, lymphatic vessel invasion was significantly correlated with the staining pattern but not with expression rate. CONCLUSION: MUC 1 core protein expression rate and pattern are suggesting that MUC 1 core protein would be a marker of malignant transformation of gallbladder epithelium and its depolarized expression would also be a marker of invasion of gallbladder cancer.

Augmentation of antitumor immune responses after adoptive transfer of bone marrow derived from donors immunized with tumor lysate-pulsed dendritic cells.

We demonstrated previously that tumor lysate-pulsed dendritic cells (TP-DC) could mediate a specific and long-lasting antitumor immune response against a weakly immunogenic breast tumor during early lymphoid reconstitution. The purpose of this study was to examine the potential therapeutic efficacy of bone marrow transplants from TP-DC-vaccinated donors. In 2 aggressive metastatic models, bone marrow transplantation with donor bone marrow cells from TP-DC-immunized mice mediated a tumor-specific immune response in the recipient, and this caused regressions of preexisting tumor metastases. After vaccination with TP-DC, donors harbored increased numbers of both activated CD4+ and CD8+ T-cell populations in the bone marrow. Adoptive transfer of T cells purified from the bone marrow of TP-DC-vaccinated mice led to a reduction in preestablished lung metastases, whereas depletion of T cells from bone marrow abolished this effect. By using T cells derived from the bone marrow of TP-DC-vaccinated major histocompatibility complex class I and class II knockout mice, the effector cells required for the observed antitumor effect were determined to be major histocompatibility complex class I-restricted CD8+ T cells. Additionally, the tumor burden in TP-DC-immunized transplant recipients could be reduced further by repetitive TP-DC immunizations after bone marrow transplantation. Collectively, these results demonstrate an important therapeutic role of bone marrow from TP-DC-immunized donors and raise the potential for this approach in patients with advanced cancer.

Progress in pursuit of therapeutic A2A antagonists: the adenosine A2A receptor selective antagonist KW6002: research and development toward a novel nondopaminergic therapy for Parkinson's disease.

Research and development of the adenosine A2A receptor selective antagonist KW6002 have focused on developing a novel nondopaminergic therapy for Parkinson's disease (PD). Salient pharmacologic features of KW6002 were investigated in several animal models of PD. In rodent and primate models, KW6002 provides symptomatic relief from parkinsonian motor deficits without provoking dyskinesia or exacerbating existing dyskinesias. The major target neurons of the A2A receptor antagonist were identified as GABAergic striatopallidal medium spiny neurons. A possible mechanism of A2A receptor antagonist action in PD has been proposed based on the involvement of striatal and pallidal presynaptic A2A receptors in the "dual" modulation of GABAergic synaptic transmission. Experiments with dopamine D2 receptor knockout mice showed that A2A receptors can function and anti-PD activities of A2A antagonists can occur independent of the dopaminergic system. Clinical studies of KW6002 in patients with advanced PD with L-dopa-related motor complications yielded promising results with regard to motor symptom relief without motor side effects. The development of KW6002 represents the first time that a concept gleaned from A2A biologic research has been applied successfully to "proof of concept" clinical studies. The selective A2A antagonist should provide a novel nondopaminergic approach to PD therapy.

Synthesis and antiherpesvirus activities of 5-alkyl-2-thiopyrimidine nucleoside analogues.

Twenty 5-alkyl-2-thiopyrimidine nucleosides were newly synthesized and examined for antiviral activities against herpes simplex virus (HSV), varicella-zoster virus (VZV) and human cytomegalovirus (HCMV). In this study, 2'-deoxy-5-alkyl-2-thiocytidine analogues had lower 50% effective concentration (EC50) values against HSV-1, and 2'-deoxy-5-alkyl-2-thiouridine analogues showed lower EC50 against VZV than their congeners of arabinoside form. Among the compounds examined, 2'-deoxy-5-ethyl and 5-propyl-2-thiocytidine (TN-53 and TN-54) were most potent and selective anti-HSV compounds. Their EC50s were 0.04 and 0.15 microM, and selectivity indexes were more than 7,215 and 1,849, respectively. On the other hand, 2'-deoxy-5-propyl-2-thiouridine (TN-51), 5-bromovinyl-2-thiouracil arabinoside (TN-65) and 5-styryl-2-thiouracil arabinoside (TN-67) were most potent and selective anti-VZV compounds. Their EC50s were 3.1, 3.8 and 2.6 pM for CaQu strain of VZV, respectively, and 2.1 to 3.0 times lower than that of acyclovir. All 2-thiopyrimidine nucleoside analogues did not show antiviral activities against thymidine kinase (TK) negative strains of HSV-1 and VZV. Only three 2-thiocytosine arabinoside compounds showed marginal anti-CMV activities (EC50s were 57-159 pM). All of the five alkyl-2-thio-pyrimidine nucleoside analogues examined were not cytotoxic to human lymphoblastoid cells (RPM18226) and human embryonic fibroblast cells (MRC-5) at 240 microM (100 microg/ml) or more. Regarding the structure-activity relationship of 5-alkyl-2-thiopyrimidine nucleoside analogues, the following remarks will be noted. Elongation of 5-alkyl chain (methyl to ethyl) of 2-thiocytosine in both deoxyribosyl and arabinosyl nucleosides increased anti-HSV-1 activity but not anti-VZV activity. Furthermore, elongation of the same chain (ethyl to propyl) of 2-thiodeoxyuridine increased anti-VZV activity whereas it did not in the case of 2-thiouracil arabinosides.

Transition and improvement in surgical treatment for rectal cancer during the last 21 years in our department.

The subject of this study was to examine the net effect of numerous changes in basic strategies, personnel and devices, upon the clinical courses and outcomes of rectal cancer patients. A total of 151 rectal cancer patients who underwent low anterior resection were divided into 4 groups (period 1 to 4) based upon the time period of the operation. They were compared among groups based upon the following parameters: blood loss, operation time, incidence of leakage and urinary dysfunction, incidence of ileus, duration of naso-gastric tube insertion, timing of initial oral feeding and survival. The blood loss during the operations, urinary dysfunction and duration of naso-gastric tube insertion tended to decrease in every period. Timing of initial oral feeding became faster. The operation times, incidence of leakage and ileus were nearly the same in each period. The 5-year survival rates on Dukes' C cases were 100% in period 4, 82.4% in period 3 and 50% in period 2. Survival rates became better. Our net outcome for rectal cancer treatment was satisfactory, because the survival rates became better under function preserving strategies.

Pim-1 translocates sorting nexin 6/TRAF4-associated factor 2 from cytoplasm to nucleus.

Pim-1, an oncogene product of serine/threonine kinase, has been found to play roles in apoptosis induction/suppression, cell-cycle progression and transcriptional regulation by phosphorylating the target proteins involved in these processes. The target proteins phosphorylated by Pim-1, including p100, Cdc25A, PAP-1 and heterochromatin protein 1, have been identified. The precise functions of Pim-1, however, are still poorly understood. In this study, we identified tumor necrosis factor receptor-associated factor 4-associated factor 2/sorting nexin 6 (TFAF2/SNX6) as a Pim-1-binding protein, and we found that TFAF2/SNX6 was phosphorylated and translocated from the cytoplasm to nucleus by Pim-1. This translocation of the protein was not affected by Pim-1-dependent phosphorylation. Since sorting nexins, including TFAF2/SNX6, have been reported to be located in the cytoplasm or membrane by association with several receptors of tyrosine- or serine/threonine-kinase, this is the first report of TFAF2/SNX6 being located in the nucleus after binding to Pim-1.