Lack Of Immunosuppression Research Articles

Cutaneous squamous cell carcinoma metastatic to the axilla and groin: Outcomes and prognostic factors.

This study examined the clinical outcomes and prognostic factors of patients with metastatic cutaneous SCC metastatic to the axilla and groin when managed with curative-intent lymphadenectomy and received (neo)adjuvant treatment. We conducted a single institution retrospective review. Patients who had nodal disease without distant spread were 18 years or older with no non-cutaneous primary identified. From January 2000 to July 2015, 78 patients were treated for axilla (64, 82%) or inguinal (14, 18%) involvement with cSCC. The median age was 75.5 years (range: 29-95), and 8 patients (11%) were immunosuppressed. The median size of the largest node was 45 mm (range: 8-135), and extracapsular extension was found in 63 (81%) cases. A majority of patients were treated with surgery alone (21, 26.9%) and surgery with adjuvant radiation therapy (54, 69%). The 2-year OS and PFS were 50% (95% CI: 40%-63%) and 43% (95% CI: 33%-56%), and 5-year OS and PFS were 33% (95% CI:23%-47%) and 32% (95% CI:22%-46%) respectively in the entire cohort. On univariable analysis, factors associated with longer OS were as follows: younger age (HR 1.1, 95% CI: 0.9-1.3 P = 0.021), improved performance status (HR 1.5, 95% CI:1.0-2.3 P = 0.026), lack of immunosuppression (HR 3.3, 95% CI: 1.5-7.3 P = 0.001), lower lymph node ratio (HR 1.2, 95% CI:1.0-1.3 P = 0.007), lower number of positive nodes (HR 1.1, 95% CI:1.0-1.2 P = 0.004) and the use of radiation therapy (HR 0.5, 95% CI:0.3-0.9 P = 0.012). Metastasis to the axilla and groin with cSCC has poor outcomes with standard treatment. The addition of immunotherapy warrants investigation.

A case of Capnocytophaga canimorsus endocarditis in a non-immunosuppressed host: the value of 16S PCR for diagnosis

Capnocytophaga canimorsus is a rare cause of endocarditis and is particularly unusual in non-immunosuppressed hosts. It is associated with animal bites, particularly those from dogs. This case describes a healthy 59-year-old woman, with no identifiable risk factors or dog bite history, who presented with fever of unknown origin. Echocardiography demonstrated an aortic valve mass and root abscess, in keeping with endocarditis, requiring urgent valve replacement surgery. Eight sets of blood cultures were drawn in total; after prolonged incubation, one set grew C. canimorusus. There was initial uncertainty over this being the causative organism, given the lack of immunosuppression or dog bite history, but 16S PCR of the valve identified the same organism, permitting targeted treatment. This case highlights the value of valve 16S PCR as a diagnostic tool in endocarditis.

Program of transplant organization to coordinate the development of organ donation in Kazakhstan

Introduction: In recent years organ transplantation has become a well-established procedure for management of renal, liver, cardiac, and respiratory failure. In spite of that, a shortage of organs still remains a serious problem to the full development of these therapeutic approaches in Kazakhstan. Method: The first kidney transplantation was performed in Kazakhstan in 1979, approximately 40 years ago. The operation itself was technically successful, but the lack of immunosuppression caused graft rejection, and the patient died after a few days. Result: Due to government policy, an organized organ transplant program started more than 4 years ago and the program was supported by the Ministry of Health. During this period a well-designed program of transplant organization has been established. In Kazakhstan, each potential donor hospital has a transplant coordinator who is responsible for the whole process of organ procurement. Eleven transplant centers work currently in Kazakhstan, and 557 transplantations have been performed up to the middle of the year 2015. We found that renal, liver and cardiac transplants increased since coordination program started. Conclusion: We conclude that this program was successful in Kazakhstan and organ donation, procurement, and transplantation would become commonplace events to solve the problem of the organ donor shortage.

50-year history of kidney transplantation in Hungary

The first Hungarian kidney transplantation was performed by András Németh in Szeged in 1962, approximately 50 years ago. A preliminary agreement with Eurotransplant was signed in 2011, and special patient groups gained benefit from this cooperation in 2012, wnich lead to a full membership to Eurotransplant. This event inspired the authors to review the history of Hungarian kidney transplantation of the past 50 years, from the first operation to recent via the specific cornerstones of the transplant program. The donor of the first Hungarian kidney transplantation was the brother of the recipient. The operation itself was technically successful, but the lack of immunosuppression caused graft rejection, and the patient died after 79 days. His brother, the donor, is still healthy, after 50 years, and he encourages everybody to donate organs. Organized kidney transplant program started more than 10 years later, such as 1973, in Budapest. The program was supported by the Ministry of Health. New centers joined the program later, Szeged in 1979, Debrecen in 1991 and Pécs in 1993. These four transplant centers work currently in Hungary, and 6611 kidney transplantation has been performed up to the end of year 2012.

Toxicology study of repeat intracerebral administration of a measles virus derivative producing carcinoembryonic antigen in rhesus macaques in support of a phase I/II clinical trial for patients with recurrent gliomas.

Gliomas have a dismal prognosis, with the median survival of patients with the most common histology, glioblastoma multiforme, being only 12-15 months. Development of novel therapeutic agents is urgently needed. We have previously demonstrated that oncolytic measles virus strains derived from the Edmonston vaccine lineage have significant antitumor activity against gliomas [Phuong, L.K., Allen, C., Peng, K.W., Giannini, C., Greiner, S., Teneyck, C.J., Mishra, P.K., Macura, S.I., Russell, S.J., Galanis, E.C. (2003). Cancer. Res. 63, 2462-2469]. MV-CEA is an Edmonston vaccine lineage measles virus strain engineered to express the marker peptide carcinoembryonic antigen (CEA): CEA levels can serve as a correlate of viral gene expression. In support of a phase I clinical trial of intratumoral and resection cavity administration of MV-CEA to patients with recurrent gliomas, we assessed the neurotoxicity of MV-CEA in adult immune male rhesus macaques (Macaca mulatta). The animals ' immune status and administration schedule mimicked the trial population and proposed administration schema. Macaca mulatta represents the prototype animal species for assessment of measles neurotoxicity. The animals were stereotactically administered either vehicle (n = 1) or MV-CEA at 2 x 10(5)or 2 x 10(6) TCID(50) (each, n = 2) in the right frontal lobe in two injections on days 1 and 5. Macaques were closely monitored clinically for neurotoxicity. Body weight, temperature, complete blood count, CEA, clinical chemistries, coagulation, complement levels, immunoglobulin, measles antibody titers, viremia, and shedding (buccal swabs) were tested at multiple time points. Furthermore, cisterna magna spinal taps were performed on day 9 and 1 year after the first viral dose administration, and samples were analyzed for protein, glucose, cell differential, and presence of MV-CEA. Magnetic resonance imaging (MRI) was performed between 4 and 5 months after article administration to assess for subclinical neurotoxicity. To date, 36+ months from study initiation there has been no clinical or biochemical evidence of toxicity, including lack of neurological symptoms, fever, or other systemic symptoms and lack of immunosuppression. Quantitative RT-PCR analysis of blood, buccal swabs, and cerebrospinal fluid (CSF) was negative for MV-CEA at all time points, with the exception of viral genome deletion in the blood of one asymptomatic animal at the 2 x 10(6) TCID(50) dose level on day 85. Vero cell overlays of CSF cells and supernatant were negative for viral recovery. There was no detection of CEA in serum or CSF at any time point. MRI scans were negative for imaging abnormalities and showed no evidence of encephalitis. Our results support the safety of CNS administration of MV-CEA in glioma patients. A clinical trial of intratumoral and resection cavity administration of MV-CEA in patients with recurrent glioblastoma multiforme is currently ongoing.

297. Safety of Repeat Intracerebral Administration of MV-CEA in Rhesus Macaques in Support of a Phase I/II Clinical Trial for Patients with Recurrent Gliomas

Novel therapies for patients with recurrent gliomas are urgently needed, given their dismal prognosis,. Oncolytic measles virus strains derived from the Edmonston vaccine lineage are an attractive option for glioma therapy, because of their significant antitumor effect (Phuong et al, 2003). MV-CEA is an Edmonston lineage measles virus strain engineered to express the marker protein carcinoembryonic antigen (CEA), the levels of which can be monitored by a simple blood test and serve as a correlate of viral gene expression. In support of a clinical trial administering MV-CEA intracerebrally to patients with recurrent gliomas, we assessed the neurotoxicity of MV-CEA in five adult male rhesus macaques (Macaca mulatta).The animals were stereotactically administered either vehicle (n=1), 2|[times]|105 (n=2), or 2|[times]|106 (n=2) TCID50 MV-CEA in the right frontal lobe in two injections five days apart. Macaques were intensely monitored through clinical observations for neurotoxic effects, body weights, temperatures, CBC, CEA, clinical chemistries, coagulation, complement levels, immunoglobulin, measles antibody titers, viremia, and shedding (buccal swabs). Additionally, cisterna magna spinal taps were performed on day 9 post first article administration, and samples were analyzed for protein, glucose, cell differential, and presence of MV-CEA. After the first 3 month close follow-up period, the macaques entered a long-term observational period for an additional 9 months. MRIs were performed between 4 and 5 months post administration to assess for subclinical neurotoxicity. At the time of this abstract submission, and with a median follow up of 11 months, macaques have been remarkably tolerant of the treatment. There was no clinical or biochemical evidence of toxicity, including lack of neurological symptoms, fever, or other systemic symptoms and lack of immunosuppression. QRT- PCR analysis of blood, buccal swabs, or CSF was negative for MV- CEA at all time points. Vero cell overlays of CSF cells and supernatant have been negative for measles-related pathology. There was no CEA detection in serum or CSF at any time point. MRIs were negative for imaging abnormalities and showed no signs of encephalitis. Conclusions: Our results support the safety of CNS administration of MV-CEA. A clinical trial in patients with recurrent gliomas is planned to be activated later this year.

Factors associated with liver biopsy performance in HCV-HIV coinfected injecting drug users with HCV viremia: results from a five-year longitudinal assessment.

The last international consensus conference about hepatitis C virus (HCV) treatment emphasized the importance of treatment for persons coinfected with HCV and human immunodeficiency virus (HIV). As liver biopsy precedes treatment, we aimed to identify factors associated with the performance of liver biopsy among HIV-HCV coinfected drug users during a 5-year follow-up to study their access to HCV treatment. Of the 296 patients followed in the HIV hospital departments of Nice and Marseilles and with retrievable records about HCV diagnosis and care, 166 were eligible for analysis having had detectable HCV RNA at least once during the study period. Overall, 45.2% of patients underwent liver biopsy during follow-up. Using proportional hazard models, predictors of having had a liver biopsy were high social support, complete abstinence from drug injection, and lack of immunosuppression as well as male gender, no history of multiple incarcerations, more recent onset of drug use, and an increase of liver enzyme levels. These results suggest that specific efforts should be devoted to HIV-HCV coinfected drug users to assist with stabilizing these patients to optimize their access to HCV care whenever possible.

Antagonism of N-methyl-D-aspartate receptors reduces the vulnerability of the immune system to stress after chronic morphine.

It has been shown that morphine-tolerant animals have an altered immunological sensitivity to stress. Although the glutamatergic system has been implicated in the neuroadaptive process underlying this tolerant state, its potential role in development of the altered immunological sensitivity consequent to chronic morphine treatment is not known. To determine this, a morphine-tolerant state was induced by 10-day administration of an escalating dose of morphine from 10 to 40 mg/kg (s.c., b.i.d.), and lymphocyte proliferative response to a T-cell mitogen was measured. Morphine challenge (10 mg/kg s.c.) after days of treatment was gradually less immunosuppressive, and this tolerance progression was delayed by concurrent administration of the N-methyl-D-aspartate (NMDA) receptor antagonist (-)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801) (0.1 mg/kg s.c.) with chronic morphine. The effect was independent of glucocorticoid level changes and was not a result of an acute interaction of the drugs or the prolonged presence of the antagonist alone. Subsequent to chronic treatment, animals were subjected to opioid withdrawal and water stress. Both stressors induced 50% immunosuppression in morphine-tolerant animals compared with saline-treated controls. Increased immunological sensitivity to these stressors was attenuated when MK-801 was administered with chronic morphine as demonstrated by an accelerated recovery rate and lack of immunosuppression from opioid withdrawal and water stress, respectively. Together, these findings provide the first evidence that the neuroadapted state of the immune response after chronic morphine can be modified by NMDA receptor antagonism, as illustrated by a temporal deceleration of the development of immunological tolerance during chronic treatment that is associated with an attenuation of the immunological vulnerability of morphine-tolerant animals to stress.

Anti HIV-1 activity of a hydrophilic cyclosporin derivative with improved binding affinity to cyclophilin A

Due to its conformation, the hydrophilic compound [(D)MeSer-3, (4-OH)MeLeu-4] cyclosporin, 3, shows high affinity for cyclophilin A. This property, together with its lack of immunosuppression, confers 3 with very interesting anti HIV-1 activity.

Lack of immunosuppression by ketoconazole and itraconazole

The antifungal drugs ketoconazole and itraconazole were evaluated for their effects in the following test systems: in vitro, phytohaemagglutinin (PHA)-induced proliferation of human peripheral blood mononuclear cells and IL-2-driven proliferation of CTLL-2 cells; in vivo, antibody response to sheep red blood cells (SRBC) and delayed-type hypersensitivity (DTH) reaction to oxazolone. At a concentration of 10 μM, ketoconazole moderately and itraconazole strongly inhibited thymidine (Thd) incorporation in human peripheral blood mononuclear cells cultured in medium supplemented with 5% human serum. Increasing the serum concentration from 5 to 20% almost completely reversed these inhibitory effects. Also, cell viability, found to be less than 15% in cultures containing 10 μM itraconazole was restored by increasing the serum concentrations in the culture medium. Similar observations were made in experiments using IL-2-stimulated CTLL-2 cells: the growth inhibition in the presense of 10 μM ketoconazole or 1 μM itraconazole could be counteracted by increased serum supplementation. In vivo, subchronic intraperitoneal dosing with 40 mg/kg ketoconazole or itraconazole to mice had no effect on the antibody response to SRBC as measured by the number of splenic IgM and IgG plaque-forming cells and did not significantly affect the DTH response to oxozalone. These data indicate that neither ketoconazole nor itraconazole exert immunosuppressive properties in vivo. Their in vitro inhibitory effects on PHA-induced lymphocyte proliferation and IL-2-dependent CTLL-2 growth are reversed by the serum supplementation to the culture medium and these activities should therefore be considered as in vitro artefacts.