Excellent results with high-dose mizoribine combined with cyclosporine, corticosteroid, and basiliximab in renal transplant recipients: multicenter study in Japan

We performed a multicenter study in Japan to assess the efficacy and safety of immunosuppressive therapy with high-dose mizoribine (MZR; 6 mg/kg) combined with basiliximab (Bas), cyclosporine (CyA), and a corticosteroid in 90 patients. MZR was adjusted to maintain a target trough level of 1 to 2 μg/mL. CyA was started at 7 mg/kg to maintain blood levels in the target therapeutic range of 200 ng/mL (trough [C0]), 1200 ng/mL (2-hour post-dose [C2]), and 6000 ng · h/mL (area under the curve_0-9). Bas (20 mg/body weight) was administered on the day of transplantation and on postoperative day 4. Rejection was diagnosed by episode and protocol biopsies. Cytomegalovirus (CMV) antigenemia (direct immunological staining of leukocytes using peroxidase-labeled monoclonal antibody [C7-HRP]) levels were measured every 2 weeks for 6 months. At 12 months, all patients and grafts were surviving except for one death from infection: the 1-year patient and graft survival rate was 98.9%. The acute rejection rate was 21.1%. The mean serum creatinine level at 1 year was 1.51 ± 0.61 mg/dL. The incidence of CMV disease was 0% with 28.9%, CMV antigenemia and 5.6%, ganoyclovir treatment. The incidence of BK virus disease was 2.2%. The mean serum uric acid level was 7.15 ± 1.79 mg/dL at 1 month and 7.06 ± 1.78 mg/dL at 3 months. We observed that a high-dose MZR regimen in combination with CyA, Bas, and corticosteroid was safe and effective to reduce the frequency of CMV and BK virus-related events in renal transplant recipients.     

Glycolysis inhibitors as a potential therapeutic option to treat aggressive neuroblastoma expressing GLUT1

Background/PurposeIncreased glycolysis is among the biochemical characteristics of cancerous tissue. The glucose transporter isoform 1 (GLUT1) gene encodes a key factor for glucose transport into cancerous tissue. However, the expression and functional significance of GLUT1 in neuroblastoma have not been fully characterized. Therefore, we investigated the association of GLUT1 expression with clinical outcomes in patients with neuroblastoma using immunohistochemical staining for GLUT1 in neuroblastoma tissues. We also assessed the efficacy of glycolysis inhibition as an anticancer treatment in neuroblastoma cell lines with altered expression of GLUT1.MethodsWe obtained total RNA from cancerous tissue by microdissection in 47 patients with neuroblastoma. GLUT1 expression levels were evaluated by quantitative real-time polymerase chain reaction. We analyzed the association of GLUT1 expression levels with clinical outcomes. We also examined changes in GLUT1 expression and proliferative responses in vitro using 4 neuroblastoma cell lines treated with a glycolysis inhibitor, 3-Bromopyruvate acid.ResultsElevated GLUT1 expression was associated with poor prognosis. Moreover, elevated GLUT1 expression independently predicted overall survival. Immunohistochemical analysis showed that GLUT1 expression tended to be localized to the centers of neuroblastoma cell nests. Our in vitro studies showed that 3-Bromopyruvate acid significantly suppressed the proliferation of neuroblastoma cells with high GLUT1 gene expression compared with those with low expression.ConclusionGlycolysis inhibitors are a potential therapeutic option for treating aggressive tumors expressing GLUT1.     

Survival and quality of life after minimally invasive esophagectomy: a single-surgeon experience

Background

Reports on quality of life (QOL) after minimally invasive esophagectomy (MIE) have been limited. This report compares perioperative outcomes, survival, and QOL after MIEs with open transthoracic esophagectomy (TTE) and open transhiatal esophagectomy (THE).

Methods

After institutional review board approval, retrospective review of a prospectively maintained database identified patients who underwent esophageal resection for esophageal cancer at Creighton University between August 2003 and August 2010. Patients with preoperative stage 4 disease, emergent procedures, laparoscopic transhiatal esophagectomies, or esophagojeujunostomies were excluded from the study. The study patients were categorized as having undergone open TTE, open THE, or MIE. Overall survival (OS) was the interval between diagnosis and death or follow-up assessment. Disease-free survival (DFS) was the interval between surgery and recurrence, death, or follow-up assessment. For the patients who survived at least 1?year after surgery, QOL was assessed using European Organization for Research and Treatment of Cancer (EORTC-QLQ, version 3.0) and esophageal module (EORTC-QLQ OES 18) questionnaires.

Results

The study criteria were satisfied by 104 patients. Lymph node harvest with MIE (median = 20) was similar to that with open TTEs (median = 19) and significantly higher (P?P?Conclusions MIEs offer a safe and viable alternative to open esophagectomies because they reduce the need and volume of intraoperative blood product transfusion and postoperative respiratory complications without compromising oncological clearance, survival, and QOL.     

Hepatectomy with portal vein resection for hilar cholangiocarcinoma: audit of 52 consecutive cases

OBJECTIVE: To better determine the role of portal vein resection and its effect on survival, as well as to appreciate the impact of portal vein invasion on prognosis in hilar cholangiocarcinoma. SUMMARY BACKGROUND DATA: Hepatectomy with portal vein resection is sometimes performed for locally advanced hilar cholangiocarcinoma. However, the significance of microscopic invasion of the portal vein has not been determined. METHODS: Medical records of 160 patients with hilar cholangiocarcinoma who underwent macroscopically curative hepatectomy with (n = 52) or without portal vein resection (n = 108) were reviewed. Invasion of the portal vein was assessed histologically on the surgical specimen, and results were correlated with clinicopathologic features and survival. RESULTS: Surgical mortality, including all hospital deaths, was similar in patients who did and did not undergo portal vein resection (9.6% vs. 9.3%), but the primary tumor was more advanced in patients who underwent portal vein resection. Histologically, no invasion was found in 16 (30.8%) of resected portal veins. However, dense fibrosis adjacent to the portal vein was common, and the mean distance between the leading edge of cancer cells and the adventitia of the portal vein was 437 +/- 431 mum. The prognosis was worse in patients with than without portal vein resection (5-year survival, 9.9% vs. 36.8%; P < 0.0001). The presence or absence of microscopic invasion of the resected portal vein did not influence survival (16.6 months in patients with microscopic invasion vs. 19.4 months in those without; P = 0.1506). Multivariate analysis identified histologic differentiation, lymph node metastasis, and macroscopic portal vein invasion as independent prognostic factors. CONCLUSIONS: Microscopic invasion of the portal vein may be misdiagnosed clinically in patients with hilar cholangiocarcinoma. However, the distance between tumor and adventitia is so narrow that curative resection without portal vein resection is unlikely to be possible. Gross portal vein invasion has a negative impact on survival, and hepatectomy with portal vein resection can offer long-term survival in some patients with advanced hilar cholangiocarcinoma.     

Internalization of antibodies by endothelial cells via fibronectin implicating a novel mechanism in lupus nephritis

BACKGROUND: One of the crucial events in lupus nephritis is the glomerular deposition of immunoglobulins (Igs), of which pathogenic properties have been proposed mostly to be either type IIor type III allergic reactions. Some of IgG3-producing hybridoma clones established from an MRL/MpTn-gld/gld (MRL/gld) lupus mouse generate wire loop-like lesions in glomeruli resembling lupus nephritis when injected into SCID mice. These clones are useful for analyzing the mechanisms of glomerular deposition of antibodies in lupus nephritis at the monoclonal level. METHODS: Glomerular lesions of SCID mice injected with the hybridoma clones, 17H8a or 1G3 as control were analyzed by light and electron microscopy. Interaction of the antibodies with human glomerular endothelial cells (HGECs) and human umbilical vein endothelial cells (HUVECs) in vitro was studied by fluorescence microscopy, electron microscopy, and flow cytometry. RESULTS: Both antibodies did not show any antigen specificity for mouse glomeruli. The glomerular lesions generated by 17H8a, but not by 1G3, contained electron-dense deposits not only in subendothelial regions but also in the cytoplasm of endothelial cells, suggesting internalization of the 17H8a antibodies by endothelial cells. In cell culture studies, internalization of only 17H8a antibodies by HGECs and HUVECs was observed, but the antibodies did not have antigen specificity for both types of endothelial cells. The internalization by HUVECs was mediated by actin polymerization, and it was inhibited by RGDS (Arg-Gly-Asp-Ser) tetrapeptide, antihuman fibronectin and antihuman integrin beta1 monoclonal antibodies. CONCLUSION: The interaction between particular antibodies and endothelial cell surface integrins via fibronectin may be involved in their subsequent internalization by endothelial cells leading to antibody deposition in glomeruli. This may be one of the mechanisms of glomerular injury in lupus nephritis.     

Brain death with calcium oxalate deposition in the kidney: clue to the diagnosis of ethylene glycol poisoning

A young man presented to the emergency department with mental status changes, severe metabolic acidosis, and oliguria. Acute ethylene glycol intoxication was diagnosed. The patient suffered clinical brain death three days after admission despite intensive care and continuous hemodiafiltration. The patient died one month after admission. Autopsy revealed acute tubular necrosis of the kidneys with significant calcium oxalate depositions. The brain was markedly softening and with chronic meningoencephalitis and dural sinus thrombosis. We considered that the amount and the persistence of the calcium oxalate deposition in the kidney may afford a best clue to the postmortem diagnosis of ethylene glycol poisoning even in the chronic stage.     

Clinicoanatomical studies on the dorsal subsegmental bile duct of the right anterior superior segment of the human liver

BACKGROUND: The dorsal subsegmental intrahepatic bile duct in the right anterior superior segment (B8c) sometimes joins the posterior sectorial duct. In such cases it can be misidentified as the right posterior superior segmental duct (B7). However, there are no published studies on the confluent pattern of B8c. MATERIALS AND METHODS: We studied B8c in the resected liver of 107 patients (65 with bile duct carcinoma and 42 with gallbladder carcinoma) who had undergone right hepatectomy or more extensive right-sided liver resection. RESULTS: B8c was identified in all cases. It joined the right posterior sectorial duct or B7 in 18 cases (16.8%). In 12 cases B8c joined independently the posterior sectorial duct or B7. In 6 cases B8c joined the posterior sectorial duct after making the common duct with the lateral subsegmental duct in the anterior superior or anterior inferior segment (B8b or B5c). CONCLUSIONS: B8c does not join the anterior sectorial bile duct in every sixth case.     

Hemodynamic and catecholamine responses during tracheal intubation using a lightwand device (Trachlight) in elderly patients with hypertension

Purpose.Tracheal intubation using a lightwand device (Trachlight) should minimize hemodynamic change by avoiding direct-vision laryngoscopy. We evaluated hemodynamic and catecholamine responses during tracheal intubation using a Trachlight in elderly patients with hypertension.Methods.Twenty-six hypertensive patients aged over 65 years undergoing orthopedic surgery were randomly divided into two groups, group L (n = 13) and group T (n = 13). Anesthesia was induced with fentanyl (2g·kg^–1) and propofol (1.5mg·kg^–1), and then muscle relaxation was obtained with vecuronium (0.15mg·kg^–1). The trachea was intubated with either a Macintosh laryngoscope (group L) or a Trachlight (group T). Hemodynamics, plasma catecholamine concentrations, and arterial blood gases were measured before the induction of anesthesia (T0), before tracheal intubation (T1), immediately after tracheal intubation (T2), and 3min after tracheal intubation (T3).Results.The intubation time was shorter in group T than in group L (12.6 ± 1.7 vs 23.5 ± 2.9s, mean ± SE; P 0.01). Compared with the preinduction (T0) value, systolic blood pressure (SBP) showed a significant decrease at T1 and T3 in group L and at T1, T2, and T3 in group T. The heart rate (HR) and plasma norepinephrine (NE) concentration showed no change in either group throughout the time course, whereas the plasma epinephrine (E) concentration showed a significant decrease at T2 and T3 in both groups. The mean values of the rate-pressure product (RPP: HR × SBP) were less than 15 000 after tracheal intubation in both groups. There was no significant difference in hemodynamic or catecholamine responses between groups at any point. No patient had ischemic ST-T changes in either group.Conclusion.A lightwand has no advantage over a laryngoscope in terms of hemodynamic and plasma catecholamine responses to tracheal intubation in elderly patients with hypertension, despite a shorter intubation time.     

Development of a therapeutic adenoviral vector for cholangiocarcinoma combining tumor-restricted gene expression and infectivity enhancement

Cholangiocarcinoma is an invasive malignancy that is most often unresectable upon diagnosis and unresponsive to chemotherapy and radiation. While adenoviral gene therapy has shown promise in treating many tumors, systemic toxicity and low tumor transduction efficiency have hampered its application in many gastrointestinal cancers. To overcome these difficulties, we have constructed an adenoviral vector utilizing a tumor-specific promoter (TSP) for selective transgene expression and a vector with an RGD-motif in the fiber-knob region for infectivity enhancement. In seeking a TSP for cholangiocarcinoma, Secretory Leukoprotease Inhibitor, Midkine, Gastrin Releasing Peptide, VEGF, Cox-2M, and Cox-2L promoters were configures in adenoviral vectors, and evaluated in cholangiocarcinoma cells lines (Oz and SkChA-1). Luciferase assays demonstrated that Cox-2 promoters (M and L) showed the highest promoter activity, with Cox-2M appearing slightly stronger than Cox-2L. Infectivity enhanced vectors with RGD-motif in the fiber-knob region were also constructed with the luciferase transgene driven by a CMV control and the Cox-2M and Cox-2L promoters. Subsequent luciferase assays comparing the unmodified vectors to the RGD-modified versions demonstrated higher levels of luciferase activity than the RGD-infected cells. This paradigm was then applied to a therapeutic HSV-TK/GCV model by constructing RGD-enhanced HSV-TK vectors driven by Cox-2M and Cox-2L promoters. In vitro cytocidal effect analysis confirmed that the RGD-modified, cox-2 (M and L) driven vectors showed a stronger cytocidal effect upon gancyclovir administration than the vectors with wild-type fiber. The Cox-2 promoter demonstrates a favorable selectivity profile for cholangiocarcinoma, and RGD-modification further enhances transduction efficiency. This combination has potential to overcome the obstacles to clinical application of adenoviral gene therapy in cholangiocarcinoma. Presented at the Forty-Third Annual Meeting of The Society for Surgery of The Alimentary Tract, San Francisco, California, May 19–22, 2002 (oral presentation).     

An evaluation of quality of life in patients who underwent orthotopic bladder replacement after cystectomy: comparison of ileal neobladder versus colon neobladder

OBJECTIVE: The objective of this study was to determine whether the quality of life (QOL) in patients who underwent orthotopic bladder replacement after radical cystectomy was affected by the intestinal segment used for the creation of a neobladder. MATERIALS AND METHODS: A total of 52 patients who underwent radical cystectomy for bladder cancer were included in this study; i.e., 24 patients with an ileal neobladder and 28 patients with a sigmoid neobladder. QOL was evaluated using the SF-36 health-related QOL survey and a questionnaire designed to evaluate the continent status. RESULTS: The mean follow-up periods for patients with an ileal and a sigmoid neobladder was 40.2 and 43.1 months, respectively. The SF-36 survey revealed that patients with colon neobladder had a significantly higher score for role-emotional functioning than those with ileal neobladder, while there was no significant difference in the remaining seven scores between patients with ileal and colon neobladders; however, general health and social functioning in patients with both types of neobladder appeared to be significantly lower than those in the general population in the United States. The results of the questionnaire analyzing the continent status were also similar between these two groups, including the desire to urinate, the incidence of both day- and nighttime urinary leakage, the frequency of pad exchange, and the concern of urine odor. CONCLUSIONS: Six of the eight scales concerning health-related QOL were favorable with both patients with ileal and colon neobladders, and the health-related QOL in orthotopic neobladder patients except for role-emotional functioning was not affected by the segment of the intestine used for neobladder construction. Moreover, no significant differences were observed in the QOL associated with continent status between these two groups. Therefore, patients with both types of orthotopic neobladder were generally satisfied with their health-related as well as disease-specific QOL.