Prolonged Survival (prolonged + survival)

Distribution by Scientific Domains
Distribution within Medical Sciences

Selected Abstracts

Purified Eicosapentaenoic Acid Induces Prolonged Survival of Cardiac Allografts and Generates Regulatory T Cells

D. Iwami
Fish oil, which is rich in eicosapentaenoic acid (EPA), has been found to have immunomodulatory effects. We examined whether administration of purified EPA affected survival of fully mismatched murine cardiac allografts. Hearts from C57BL/10 (H-2b) mice were transplanted into CBA (H-2k) recipients treated with one intraperitoneal dose of purified EPA the day of transplantation. Untreated CBA recipients and recipients given 0.1 g/kg of EPA rejected C57BL/10 hearts (median survival time [MST], 8 and 13 days, respectively). With a 1.0 g/kg dose of EPA, graft survival was markedly prolonged (MST >100 days). To determine whether regulatory cells were generated, naÔve mice (secondary recipients) underwent adoptive transfer of splenocytes from EPA-treated primary recipients and cardiac allograft transplantation. Adoptive transfer of whole, CD4+ and CD4+CD25+ splenocytes from EPA-treated recipients induced indefinite survival in secondary recipients. Flow cytometry showed that the CD4+CD25+ cells were Foxp3+. In reverse transcriptase-polymerase chain reaction (RT-PCR) studies, the expression of peroxisome proliferator-activated receptor , (PPAR,) mRNA was upregulated by EPA treatment. A PPAR, antagonist abrogated the prolongation of graft survival induced by EPA treatment (MST, 13 days). Thus, in our model, purified EPA induced prolonged survival of fully mismatched cardiac allografts and generated regulatory T cells dependent on PPAR, activation. [source]

Prolonged Survival of Allogeneic Islets in Cynomolgus Monkeys After Short-Term Anti-CD154-Based Therapy: Nonimmunologic Graft Failure?

M. Koulmanda
Conventional drug therapy and several anti-CD154 mAb-based regimens were tested in the nonhuman primate (NHP) islet allograft model and found to be inadequate because islets were lost to rejection. Short-term therapy with an optimized donor-specific transfusion (DST) + rapamycin (RPM) + anti-CD154 mAb regimen enables immunosuppression drug-free islet allograft function for months following cessation of therapy in the NHP islet allograft model. After a substantial period of drug-free graft function, these allografts slowly and progressively lost function. Pathologic studies failed to identify islet allograft rejection as a destructive islet invasive lymphocytic infiltration of the allograft was not detected. To evaluate the mechanism, immunologic versus nonimmunologic, of the late islet allograft loss in hosts receiving the optimized therapeutic regimen, we performed experiments with islet autografts and studied islet function in NHPs with partial pancreatectomy. The results in both experiments utilizing autologous islet allografts and partially pancreatectomized hosts reinforce the view that the presence of a marginal islet mass leads to slowly progressive nonimmunological islet loss. Long-term clinically successful islet cell transplantation cannot be realized in the absence of parallel improvements in tolerizing regimens and in the preparation of adequate numbers of islets. [source]

Prolonged survival after the diagnosis of metastatic hepatic epitheliod haemangioendothelioma

Clinical-scientific Note
No abstract is available for this article. [source]

Third look surgery and beyond for appendiceal malignancy with peritoneal dissemination

Faheez Mohamed MBChB, MRCS
Abstract Background and Objectives Second look surgery has been previously studied in patients with recurrent peritoneal dissemination from appendiceal malignancy. However, selection criteria for third, fourth, and subsequent reoperations are not available. Methods Five hundred and one patients with epithelial peritoneal surface malignancy of appendiceal origin underwent treatment with cytoreductive surgery and intraperitoneal chemotherapy during an 18-year period. Forty-five of these patients (8.9%) underwent three or more operative interventions. A critical statistical analysis of the impact of selected clinical features on survival was performed from a prospective database. Results Overall 5-year survival of these 45 patients was 70%. Five- and ten-year survival rates for patients with three interventions were 60 and 48%, for four interventions were 78 and 36%, and for five or more interventions were 100 and 80%. Sites of recurrent disease, histopathologic type of tumor, and lymph node status had no impact on survival. A complete second and third cytoreduction was associated with an improved 5-year survival rate. Conclusions Prolonged survival in patients with three or more reoperations was significantly associated with a complete cytoreduction. However, after four or more interventions, the effects of tumor biology may predominate. Although 5-year survival is likely with multiple reoperations, prolonged follow-up shows that cancer cure is a rare event. J. Surg. Oncol. 2003;83:5,13. © 2003 Wiley-Liss, Inc. [source]

Prognostic value of laparoscopic ultrasound in patients with gastro-esophageal cancer

M. E. Flett
Forty-four patients with gastro-esophageal tumors regarded as resectable by conventional staging underwent laparoscopic ultrasonography (LUS). Following LUS, seven were found to be irresectable and were managed by palliative therapies. Thirty-seven patients proceeded to surgical exploration and 36 were resected (R0 80%, R1 11%, and R2 9%). All patients were reviewed until death or for a minimum of 24 months. Patients undergoing resection had a 62% 1-year survival (median 17 months; confidence intervals, CI 6,28). LUS defined nodal status indicated a trend toward prolonged survival in the node-negative group, median 22 months (CI 5,39), compared with 13 months (CI 6,20) in the node-positive group. Disease-free survival was greater in LUS node-negative patients at 29 months (CI 23,35) compared with node-positive patients at 13 months (CI 5,21) P=0.0083. LUS staging allows prediction of the likelihood of recurrence of gastro-esophageal malignancies. This may prove useful for the appropriate allocation of patients to primary and adjuvant therapies. [source]

Human immunodeficiency virus-associated progressive multifocal leucoencephalopathy: epidemiology and predictive factors for prolonged survival

A. K. Drake
We performed a retrospective review of cases of human immunodeficiency virus-associated progressive multifocal leucoencephalopathy in four hospitals (three in Australia and one in Hong Kong) between 1987 and 2003 in order to describe the local experience with this disease and to evaluate parameters impacting upon survival. Eighty-seven cases were identified and demographic details, baseline parameters and treatment methods and response were described. Survival was substantially increased in the post-highly active antiretroviral therapy (HAART) era with a median survival increase from 14 to 64 weeks. On multivariate analysis, variables associated with prolonged survival included a CD4 count of >100 cells/,l at diagnosis and the use of HAART post-diagnosis, with no significant additional advantage from the use of neuroactive antiretrovirals. [source]

Idiopathic myelofibrosis: pathogenesis to treatment

John T Reilly
Abstract Idiopathic myelofibrosis (IMF) is the least common of the chronic myeloproliferative disorders and carries the worst prognosis with a median survival of 4 years. It is a clonal haematopoietic stem-cell disorder and, although the pathogenesis remains unclear, approximately 50% of cases are known to possess an activating JAK2 V617F mutation. In contrast, the characteristic stromal proliferation is a reactive, or secondary, event that results from the aberrant release of a variety of growth factors from megakaryocytes and monocytes. Treatment for most cases is supportive, although androgens, recombinant erythropoietin, steroids and thalidomide are effective modalities for the amelioration of anaemia. Myelosuppression, splenectomy and irradiation are valuable therapeutic modalities for specific clinical situations. Prognostic scores are available to aid the identification of cases for whom bone marrow transplantation should be considered. Recently, the use of reduced intensity conditioning has resulted in prolonged survival and lower transplant-related mortality. This review summarises the recent advances in the disease's pathogenesis and discusses the role of the various therapeutic options. Copyright © 2006 John Wiley & Sons, Ltd. [source]

Nonoperative therapies for combined modality treatment of hepatocellular cancer: expert consensus statement

HPB, Issue 5 2010
Roderich E. Schwarz
Abstract Although surgical resection and liver transplantation are the only treatment modalities that enable prolonged survival in patients with hepatocellular carcinoma (HCC), the majority of HCC patients presents with advanced disease and do not undergo resective or ablative therapy. Transarterial chemoembolization (TACE) is indicated in intermediate/advanced stage unresectable HCC even in the setting of portal vein involvement (excluding main portal vein). Sorafenib has been shown to improve survival of patients with advanced HCC in two controlled randomized trials. Yttrium 90 is a safe microembolization treatment that can be used as an alternative to TACE in patients with advanced liver only disease or in case of portal vein thrombosis. External beam radiation can be helpful to provide local control in selected unresectable HCC. These different treatment modalities may be combined in the treatment strategy of HCC and also used as a bridge to resection or liver transplantation. Patients should undergo formal multidisciplinary evaluation prior to initiating any such treatment in order to individualize the best available options. [source]

Surgical treatment of liver metastases from pancreatic cancer

HPB, Issue 2 2006
Hidehisa Yamada PhD
Abstract Pancreatic cancer is a disease with a poor prognosis. Most patients are diagnosed at an advanced and unresectable stage. Even if the primary cancer is radically removed, postoperative recurrence frequently occurs. Generally, metastatic liver tumors from pancreatic cancer are not indicated for surgical treatment. Here we evaluate the results of performing hepatectomy for liver metastases of pancreatic cancer. In our institute, six patients with liver metastases from pancreatic cancer were treated by partial hepatectomy. Overall 1-, 3- and 5-year survival rates of six patients after hepatectomy were 66.7%, 33.3% and 16.7%, respectively, and one patient was alive for 65.4 months. Performing a hepatectomy for liver metastases of pancreatic cancer, when combined with a pancreas resection, was recently considered to be a safe operation, and one that might offer prolonged survival for highly selected patients with curative resection of liver metastases. In the future, it will be necessary to develop new multi-modality therapies to improve the prognosis of pancreatic cancer. [source]

Evidence for an age-related influence of microsatellite instability on colorectal cancer survival

Susan M. Farrington
Abstract It is well established that microsatellite instability (MSI), the hallmark of defective DNA mismatch repair (MMR), is associated with prolonged survival in colorectal cancer compared with tumours that are microsatellite stable (MSS). MSI in sporadic colorectal tumours is primarily due to epigenetic silencing of MLH1. However, there are no prospective population-based studies of survival in patients with germline MMR gene mutations who develop cancer. Although MSI is almost universal in tumours from HNPCC family members, there is a potential confounding effect of ascertainment and other biases that could explain the apparent survival benefit in HNPCC families. Resolving whether germline MMR gene mutations impact on survival is important because it potentially undermines the rationale for surveillance of mutation carriers. Here, we report an investigation of the influence of MSI on survival in cohorts of cancer patients (aged < 30 years at diagnosis, n = 118; non-age-selected, n = 181) in the context of clinicopathologic variables. There was a substantial age-related influence of tumour MSI status on survival. In young patients with tumour MSI, 65% of patients with MSI tumours had germline MSH2 or MLH1 mutations. Clinicopathologic variables and tumour MSI of the cohort were studied with respect to survival and compared with control groups. Young patients had excess MSI tumours (p < 0.000001), mucinous tumours (p < 0.01), advanced disease (p , 0.001) and poorer 5-year survival compared with older cases. Cox proportional hazard analysis identified Dukes' stage, age at diagnosis and calendar year of treatment as independent predictors of survival. There was no detectable association between tumour MSI and survival in young patients, although we confirmed previous observations that MSI is associated with better prognosis in later onset cohorts. These findings underscore the rationale for surveillance and early identification of tumours in MMR gene carriers as well as refining understanding of the influence of MSI on cancer progression. © 2002 Wiley-Liss, Inc. [source]

Creation of psoriatic plaques: the ultimate tumor suppressor pathway.

A new model for an ancient T-cell-mediated skin disease.
From an oncological and immunological perspective, the T-cell-mediated induction of psoriatic plaques should be prone to malignant transformation as the phenotype of psoriatic plaques includes: chronic inflammation, epidermal hyperplasia, prolonged survival and elevated telomerase levels in lesional keratinocytes, as well as angiogenesis, exposure to carcinogens and immunosuppressants. However, conversion of a psoriatic plaque to squamous cell carcinoma is exceedingly rare. This paper explores the possible molecular mechanism for the tumor suppressor pathway in psoriatic lesions, with an emphasis on a putative senescence-switch involving p16. [source]

Therapeutic benefits of intrathecal protein therapy in a mouse model of amyotrophic lateral sclerosis

Yasuyuki Ohta
Abstract When fused with the protein transduction domain (PTD) derived from the human immunodeficiency virus TAT protein, proteins can cross the blood,brain barrier and cell membrane and transfer into several tissues, including the brain, making protein therapy feasible for various neurological disorders. We have constructed a powerful antiapoptotic modified Bcl-XL protein (originally constructed from Bcl-XL) fused with PTD derived from TAT (TAT-modified Bcl-XL), and, to examine its clinical effectiveness in a mouse model of familial amyotrophic lateral sclerosis (ALS), transgenic mice expressing human Cu/Zn superoxide dismutase (SOD1) bearing a G93A mutation were treated by intrathecal infusion of TAT-modified Bcl-XL. We demonstrate that intrathecally infused TAT-fused protein was effectively transferred into spinal cord neurons, including motor neurons, and that intrathecal infusion of TAT-modified Bcl-XL delayed disease onset, prolonged survival, and improved motor performance. Histological studies show an attenuation of motor neuron loss and a decrease in the number of cleaved caspase 9-, cleaved caspase 3-, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive cells in the lumbar cords of TAT-modified Bcl-XL -treated G93A mice. Our results indicate that intrathecal protein therapy using a TAT-fused protein is an effective clinical tool for the treatment of ALS. © 2008 Wiley-Liss, Inc. [source]

Intractable recurrent cervical cancer with pelvic bone involvement successfully treated with external hemipelvectomy

Junzo Hamanishi
Abstract The indication of external hemipelvectomy for lateral recurrent cervical cancer involving the pelvic bone is controversial. We report the second longest surviving patient of recurrent cervical cancer successfully treated by external hemipelvectomy. A 38-year-old woman who had undergone conization for stage Ia1 cervical cancer six years earlier had severe right inguinal pain. A large multicystic recurrent tumor was identified in the right obturator region. After chemotherapy and chemoradiation, the tumor regressed, but soon relapsed. The patient's symptoms flared and the tumor was enlarged involving the right iliac bone. We performed right external hemipelvectomy with amputation of the right lower extremity, right iliac wing and ischiopubic bone. There was no major complication after the operation and the patient was discharged on postoperative day 48. After 27 months of follow-up, she has no complaints and is without evidence of recurrence. In selected cases of intractable lateral recurrent cervical cancer with pelvic bone involvement, relief from tumor-related pain and a possibility of prolonged survival can be expected by external hemipelvectomy. [source]

Intratumoral cancer chemotherapy and immunotherapy: opportunities for nonsystemic preoperative drug delivery

Eugene P. Goldberg
The recent literature documents the growing interest in local intratumoral chemotherapy as well as systemic preoperative chemotherapy with evidence for improved outcomes using these therapeutic modalities. Nevertheless, with few exceptions, the conventional wisdom and standard of care for clinical and surgical oncology remains surgery followed by radiation and/or systemic chemotherapy, as deemed appropriate based on clinical findings. This, in spite of the fact that the toxicity of conventional systemic chemotherapy and immunotherapy affords limited effectiveness and frequently compromises the quality of life for patients. Indeed, with systemic chemotherapy, the oncologist (and the patient) often walks a fine line between attempting tumour remission with prolonged survival and damaging the patient's vital functions to the point of death. In this context, it has probably been obvious for more than 100 years, due in part to the pioneering work of Ehrlich (1878), that targeted or localized drug delivery should be a major goal of chemotherapy. However, there is still only limited clinical use of nonsystemic intratumoral chemotherapy for even those high mortality cancers which are characterized by well defined primary lesions i.e. breast, colorectal, lung, prostate, and skin. There has been a proliferation of intratumoral chemotherapy and immunotherapy research during the past two to three years. It is therefore the objective of this review to focus much more attention upon intratumoral therapeutic concepts which could limit adverse systemic events and which might combine clinically feasible methods for localized preoperative chemotherapy and/or immunotherapy with surgery. Since our review of intratumoral chemo-immunotherapy almost 20 years ago (McLaughlin & Goldberg 1983), there have been few comprehensive reviews of this field; only one of broad scope (Brincker 1993), three devoted specifically to gliomas (Tomita 1991; Walter et al. 1995; Haroun & Brem 2000), one on hepatomas (Venook 2000), one concerning veterinary applications (Theon 1998), and one older review of dermatological applications (Goette 1981). However, none have shed light on practical opportunities for combining intratumoral therapy with subsequent surgical resection. Given the state-of-the-art in clinical and surgical oncology, and the advances that have been made in intratumoral drug delivery, minimally invasive tumour access i.e. fine needle biopsy, new drugs and drug delivery systems, and preoperative chemotherapy, it is timely to present a review of studies which may suggest future opportunities for safer, more effective, and clinically practical non-systemic therapy. [source]

Prolonged disease-free survival after orthotopic liver transplantation plus adjuvant chemoirradiation for cholangiocarcinoma

Ilja De Vreede
Orthotopic liver transplantation (OLT) alone for unresectable cholangiocarcinoma is often associated with early disease relapse and limited survival. Because of these discouraging results, most programs have abandoned OLT for cholangiocarcinoma. However, a small percentage of patients have achieved prolonged survival after OLT, suggesting that adjuvant approaches could perhaps improve the survival outcome. Based on these concepts, a protocol was developed at the Mayo Clinic using preoperative irradiation and chemotherapy for patients with cholangiocarcinoma. We report our initial results with this pilot experience. Patients with unresectable cholangiocarcinoma above the cystic duct without intrahepatic or extrahepatic metastases were eligible. Patients initially received external-beam irradiation plus bolus fluorouracil (5-FU), followed by brachytherapy with iridium and concomitant protracted venous infusion of 5-FU. 5-FU was then administered continuously through an ambulatory infusion pump until OLT. After irradiation, patients underwent an exploratory laparotomy to exclude metastatic disease. To date, 19 patients have been enrolled onto the study and have been treated with irradiation. Eight patients did not go on to OLT because of the presence of metastasis at the time of exploratory laparotomy (n = 6), subsequent development of malignant ascites (n = 1), or death from intrahepatic biliary sepsis (n = 1). Eleven patients completed the protocol with successful OLT. Except for 1 patient, all had early-stage disease (stages I and II) in the explanted liver. All patients who underwent OLT are alive, 3 patients are at risk at 12 months or less, and the remaining 8 patients have a median follow-up of 44 months (range, 17 to 83 months; 7 of 9 patients > 36 months). Only 1 patient developed tumor relapse. OLT in combination with preoperative irradiation and chemotherapy is associated with prolonged disease-free and overall survival in highly selected patients with early-stage cholangiocarcinoma. [source]

The immunology of parasite infections in immunocompromised hosts

SUMMARY Immune compromise can modify the severity and manifestation of some parasitic infections. More widespread use of newer immnosuppressive therapies, the growing population of individuals with immunocompromised states as well as the prolonged survival of these patients have altered the pattern of parasitic infection. This review article discusses the burden and immunology of parasitic infections in patients who are immunocompromised secondary to congenital immunodeficiency, malnutrition, malignancy, and immunosuppressive medications. This review does not address the literature on parasitic infections in the setting of HIV-1 infection. [source]

Idiotype-pulsed antigen presenting cells following autologous transplantation for multiple myeloma may be associated with prolonged survival,

Martha Q. Lacy
Vaccines are attractive as consolidation therapy after autologous stem cell transplantation (ASCT) for multiple myeloma (MM). We report the results of a phase II trial of the immunotherapeutic, APC8020 (Mylovenge‘), given after ASCT for MM. We compared the results with that of other patients with MM who underwent ASCT at Mayo Clinic during the same time period. Twenty-seven patients were enrolled on the trial between July, 1998 and June, 2001, and the outcomes were compared to that of 124 consecutive patients transplanted during the same period, but not enrolled on the trial. The median (range) follow-up for patients still alive from the vaccine trial is 6.5 (2.9,8 years), and 7.1 (6,8 years) in the control group. The median age was 57.4 range (36.1,71.3) in the DB group and 56.4 (range, 30,69) in the trial group. Known prognostic factors including PCLI, B2M, and CRP were comparable between the groups. The median overall survival for the trial patients was 5.3 years (95% CI: 4.0 years,N/A) compared to 3.4 years (95% CI: 2.7,4.6 years) for the DB group (P = 0.02). The median time to progression and progression-free survival for the trial group was similar to the DB group. Although not a controlled trial, the vaccines given after ASCT appear to be associated with improved overall survival compared to historical controls. This approach warrants further investigation to confirm this and define the role of vaccine therapy in myeloma. Am. J. Hematol. 2009. © 2009 Wiley-Liss, Inc. [source]

Relapsed or refractory nongastric marginal zone B-cell lymphoma: Multicenter retrospective analysis of 92 cases,

Sung Yong Oh
Over its long survival duration, marginal zone B-cell lymphoma (MZL) routinely involves frequent relapses. In this study, we conducted a retrospective analysis to identify the clinical features and outcomes of relapsed or refractory MZL. From 1995 to 2008, a total of 92 patients with relapsed MZL were retrospectively analyzed. The median age of our subjects was 53.5 years (range: 23,82 years). The most common primary sites of involvement were the orbit and ocular adnexa (28.3%) followed by the lymph node and lymphatic organs (23.9%), and multiple mucosa-associated lymphoid tissue (MALT) sites (13.0%). The median time to relapse from initial diagnosis was 25.5 months. Of the 53 patients with Stage I or II at diagnosis, 42 patients (79.2%) evidenced locoregional recurrence. Among these locoregional relapsed patients, 27 patients achieved CR (54.1%) or PR (18.9%). In addition to the 39 patients initially in advanced Stage III or IV, a total of 50 patients were in advanced stage at relapse. Among those patients with advanced stage at relapse, 44 patients were treated. The overall response rate was 54.5% (24 patients), with 18 CRs and 6 PRs. The median time to progression (TTP) was 34.1 months (95% CI: 11.3,56.9 months) and the estimated 5-year overall survival (OS) was 84.3%. The majority of them was controlled well with salvage treatment, and could achieve prolonged survival. However, patients' refractory to initial therapy and advanced relapse evidenced shorter TTP and OS. Thus, we need to consider more aggressive treatment in cases of refractory MZL or advanced relapsed MZL. Am. J. Hematol., 2009. © 2009 Wiley-Liss, Inc. [source]

New challenges in the management of prolonged survivors of pediatric neuromuscular diseases: A pulmonologist's perspective

David J. Birnkrant MD
Abstract Many patients with pediatric neuromuscular diseases (NMDs) are now achieving prolonged survival through advances in management of the cardiopulmonary complications of their illnesses. Because respiratory complications are among the main causes of mortality and morbidity in these diseases, pulmonologists are in a unique position to observe and describe the largely unanticipated medical, social, and ethical problems generated when patients with progressive NMDs achieve prolonged survival. For example, prolonged survivors of pediatric NMDs are now experiencing previously rare or unknown medical complications, an unprecedented severity of burden of disease and the potential for prolonged impairment of quality of life. As the patients age, their families must cope with a high level of burden of care. Society's acceptance of the eligibility of these patients to utilize critical care resources, and issues related to the transition of prolonged survivors from pediatric to adult medical providers and venues have resulted in complex practical and ethical issues. In this article, the author, a pediatric pulmonologist closely involved in the care of patients with NMDs, will identify and discuss some of the major medical, social, and ethical implications of prolonged survival among these patients, with an emphasis on Duchenne muscular dystrophy (DMD), the most common of the pediatric NMDs. Pediatr Pulmonol. 2006; 41:1113,1117. © 2006 Wiley-Liss, Inc. [source]

Leiomyosarcoma of the main bronchus in a girl: A long-time survivor with multiple lung metastases

Fumihiro Takeda MD
Abstract Primary leiomyosarcoma of the respiratory tract is a very rare malignancy, especially in childhood, with only 15 cases in patients under 16 years old having been reported. In the present case, the survival period from the onset of symptoms has been over 7 years, despite incomplete resection. Based on the 15 published cases, the prognosis is poorer when the tumor is unresected or incompletely resected, but under favorable circumstances, prolonged survival is possible. Pediatr Pulmonol. 2004; 37:368,374. © 2004 Wiely-Liss, Inc. [source]

Brain engraftment and therapeutic potential of stem/progenitor cells derived from mouse skin

Patrizia Tunici
Abstract Skin stem/progenitor cells (SKPs) derive from the dermis and in culture can generate mesodermal and neural progenies. To investigate their potential for the treatment of brain diseases, we first injected SKPs into the brain of syngeneic mice. Brain histology indicated that most SKPs remained undifferentiated and clustered at the injection site, while, in vitro, 17% of SKPs expressed neural markers, as assessed by flow cytometry. After labeling with magnetodendrimers, murine and human SKPs were detected by magnetic resonance imaging even 5 months after brain injection. To evaluate their therapeutic potential on malignant gliomas, IL-4 SKPs (i.e. SKPs transduced by a lentiviral vector carrying the cDNA of the anti-glioma cytokine interleukin-4) were injected into GL261 experimental gliomas. IL-4-SKPs prolonged significantly the survival of tumor-bearing mice: furthermore, GL261 gliomas attracted SKPs originally injected into the contralateral hemisphere. Thus, prolonged survival, capacity for transgene expression, and lack of uncontrolled proliferation suggest that SKPs warrant further consideration as therapeutic tools for brain tumors and, possibly, other neurological disorders. Copyright © 2006 John Wiley & Sons, Ltd. [source]

Impact of Thrombocytopenia on Survival of Baboons with Genetically Modified Pig Liver Transplants: Clinical Relevance

B. Ekser
A lack of deceased human donor livers leads to a significant mortality in patients with acute-on-chronic or acute (fulminant) liver failure or with primary nonfunction of an allograft. Genetically engineered pigs could provide livers that might bridge the patient to allotransplantation. Orthotopic liver transplantation in baboons using livers from ,1,3-galactosyltransferase gene-knockout (GTKO) pigs (n = 2) or from GTKO pigs transgenic for CD46 (n = 8) were carried out with a clinically acceptable immunosuppressive regimen. Six of 10 baboons survived for 4,7 days. In all cases, liver function was adequate, as evidenced by tests of detoxification, protein synthesis, complement activity and coagulation parameters. The major problem that prevented more prolonged survival beyond 7 days was a profound thrombocytopenia that developed within 1 h after reperfusion, ultimately resulting in spontaneous hemorrhage at various sites. We postulate that this is associated with the expression of tissue factor on platelets after contact with pig endothelium, resulting in platelet and platelet-peripheral blood mononuclear cell(s) aggregation and deposition of aggregates in the liver graft, though we were unable to confirm this conclusively. If this problem can be resolved, we would anticipate that a pig liver could provide a period during which a patient in liver failure could be successfully bridged to allotransplantation. [source]

Purified Eicosapentaenoic Acid Induces Prolonged Survival of Cardiac Allografts and Generates Regulatory T Cells

D. Iwami
Fish oil, which is rich in eicosapentaenoic acid (EPA), has been found to have immunomodulatory effects. We examined whether administration of purified EPA affected survival of fully mismatched murine cardiac allografts. Hearts from C57BL/10 (H-2b) mice were transplanted into CBA (H-2k) recipients treated with one intraperitoneal dose of purified EPA the day of transplantation. Untreated CBA recipients and recipients given 0.1 g/kg of EPA rejected C57BL/10 hearts (median survival time [MST], 8 and 13 days, respectively). With a 1.0 g/kg dose of EPA, graft survival was markedly prolonged (MST >100 days). To determine whether regulatory cells were generated, naÔve mice (secondary recipients) underwent adoptive transfer of splenocytes from EPA-treated primary recipients and cardiac allograft transplantation. Adoptive transfer of whole, CD4+ and CD4+CD25+ splenocytes from EPA-treated recipients induced indefinite survival in secondary recipients. Flow cytometry showed that the CD4+CD25+ cells were Foxp3+. In reverse transcriptase-polymerase chain reaction (RT-PCR) studies, the expression of peroxisome proliferator-activated receptor , (PPAR,) mRNA was upregulated by EPA treatment. A PPAR, antagonist abrogated the prolongation of graft survival induced by EPA treatment (MST, 13 days). Thus, in our model, purified EPA induced prolonged survival of fully mismatched cardiac allografts and generated regulatory T cells dependent on PPAR, activation. [source]

Renal and Cardiac Endothelial Heterogeneity Impact Acute Vascular Rejection in Pig-to-Baboon Xenotransplantation

C. Knosalla
Xenograft outcomes are dictated by xenoantigen expression, for example, Gal ,1, 3Gal (Gal), but might also depend on differing vascular responses. We investigated whether differential vascular gene expression in kidney and cardiac xenografts correlate with development of thrombotic microangiopathy (TM) and consumptive coagulation (CC). Immunosuppressed baboons underwent miniswine or hDAF pig kidney (n = 6) or heart (n = 7), or Gal-transferase gene-knockout (GalT-KO) (thymo)kidney transplantation (n = 14). Porcine cDNA miniarrays determined donor proinflammatory, apoptosis-related and vascular coagulant/fibrinolytic gene expression at defined time points; validated by mRNA, protein levels and immunopathology. hDAF-transgenic and GalT-KO xenografts, (particularly thymokidneys) exhibited prolonged survival. CC was seen with Gal-expressing porcine kidneys (3 of 6), only 1 of 7 baboons postcardiac xenotransplantation and was infrequent following GalT-KO grafts (1 of 14). Protective-type genes (heme oxygenase-I, superoxide dismutases and CD39) together with von Willebrand factor and P-selectin were upregulated in all renal grafts. Transcriptional responses in Gal-expressing xenografts were comparable to those seen in the infrequent GalT-KO rejection. In cardiac xenografts, fibrin deposition was associated with increased plasminogen activator inhibitor-1 expression establishing that gene expression profiles in renal and cardiac xenografts differ in a quantitative manner. These findings suggest that therapeutic targets may differ for renal and cardiac xenotransplants. [source]


A. H. Imisairi
Objective This paper reviews the diagnostic, therapeutic strategies and outcomes of ADCC in 3 Institutions between Newcastle and Sheffield in United Kingdom and Putrajaya, Malaysia. Patients and Methods A 10-year retrospective analysis of proven cases of ADCC was collected from January 1997 to December 2006. The patients' demographic data, clinical manifestation, site and size of the tumour were analysed. The record of metastasis, and therapeutic modality and outcomes were evaluated. Results A total of 22 cases of ADCC were documented in United Kingdom with 11 cases in each respective center. 16 cases were reviewed from Putrajaya. There was no gender preponderance and age significance. Cushing's Syndrome was the most common clinical manifestation (36.4%) in United Kingdom and (37.5%) in Putrajaya. The mean size of the ADCC was 9.3 cm (5,15 cm) in Newcastle and 9.8 cm (6,15 cm) in Sheffield as compared to 15.7 cm (5,25 cm) in Putrajaya. There were 12(75%) of patients in Putrajaya were diagnosed with Stage IV disease upon presentation whilst only 3(27.3%) and 5(45.4%) patients had metastasis noted in Newcastle and Sheffield respectively. Of note, 7(63.3%) patients in Sheffield were offered radical adrenalectomy. Our data revealed that the 2 years survival of patients who had radical approach in Sheffield has the highest rate of survival of 8(72.7%) as compared to 5(45.4%) in Newcastle and 2(12.5%) in Putrajaya. Conclusions Surgical removal remains the only form of curative therapy and hope of prolonged survival. The poorer prognosis of patients in Putrajaya may be attributed to the advanced stage of the disease. [source]

Position paper on the therapeutic use of rituximab in CD20-positive diffuse large B-cell non-Hodgkin's lymphoma

Ruth Pettengell
Summary. The available data on rituximab in combination with chemotherapy confirm that the addition of an independently active biological agent to full-dose standard chemotherapy results in higher rates of complete response, lower rates of relapse, prolonged survival, little additional toxicity and no compromise of the dose intensity of standard chemotherapy regardless of age and risk group. Given the strength of these data, the British Committee for Standards in Haematology believes that rituximab should be available for prescription by UK haematologists and oncologists according to its licensed indication in patients with diffuse large B-cell lymphoma until further data are available to confirm or refute these results. We consider that the use of rituximab with chemotherapy in aggressive lymphoma is cost-effective and that failure to support its introduction will be strongly in conflict with professional and patient opinion. [source]

An intraductal papillary component is associated with prolonged survival after hepatic resection for intrahepatic cholangiocarcinoma,

Y. Tajima
Background: The outcome after surgery for intrahepatic cholangiocarcinoma (ICC) is dismal and data on long-term survival are not available. This study evaluated prognostic indicators and characteristic features of long-term survivors after hepatic resection for ICC. Methods: Thirty-one patients who had undergone hepatic resection for ICC were studied. Univariate and multivariate survival analyses of clinicopathological data included an intraductal papillary carcinoma component (IDPCC) in the tumour, which was defined as the histological demonstration of cancer cells growing in a papillary fashion into the lumen of the large bile duct. Results: The overall cumulative survival rate after hepatic resection for ICC was 51∑2 per cent at 1 year and 24∑5 per cent at 5 years, with a mean(s.d.) survival time of 11(4) months. The presence of IDPCC (P = 0∑003), curative resection (P = 0∑009) and the absence of perineural invasion (P = 0∑040) were identified as favourable independent prognostic factors in multivariate analysis. Eight patients with IDPCC had a 5-year survival rate of 87∑5 per cent and a mean(s.d.) survival time of 69(13) months. All seven patients who survived for more than 5 years after surgery had IDPCC, regardless of the gross appearance of the tumour. Conclusion: An IDPCC in the tumour resulted in long-term survival after hepatic resection for ICC. Copyright © 2003 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd. [source]

Potent antitumor effect elicited by superantigen-linked tumor cells transduced with heat shock protein 70 gene

CANCER SCIENCE, Issue 2 2004
Changxin Huang
Heat shock proteins (HSP) induce antitumor-specific immunity via a unique mechanism, but HSP alone fails to produce a satisfactory antitumor efficacy. We considered that the potent immune-activation of superantigen (SAg) might assist HSP to elicit a strong tumor-antigen-specific immunity. We initially prepared B16 melanoma cells linked to SAg SEA via a fusion protein with a trans-membrane sequence (TM), and demonstrated that SEA thus anchored on the tumor cell surface could elicit strong antitumor immunity. We then prepared cells transduced with an inducible heat shock protein 70 (HSP70) gene, and bearing SEA-TM fusion protein on the cell surface, and used these cells as a dual-modified vaccine. In this study, either in a therapeutic setting or in a pre-immune model, the SEA-anchored vaccine or the HSP70 gene-modified vaccine induced marked tumor suppression, prolonged survival, augmented lymphocyte proliferation and higher NK and CTL activity in C57BL/6 mice compared with their controls (P<0.01), though they were less effective than the dual-modified vaccine. Among these vaccines, the dual-modified vaccine showed the best therapeutic efficacy in B16 melanoma-bearing mice and gave the greatest protection against wild-type B16 melanoma challenge. The results indicated that the dual-modified vaccine could induce a potent tumor-antigen-specific immune response in addition to an increase of non-specific immunity. This study offers a novel approach to bridging specific and non-specific immunity for cancer therapy. [source]