Arenavirus Therapy in Combination with Checkpoint Blockade as an Effective Way for Better Tumour Clearance.

Viruses have been widely used to treat cancer for many years and they achieved tremendous success in clinical trials with outstanding results, which has led to the foundation of companies that develop recombinant viruses for a better tumor treatment. Even though there has been a great progress in the field of viral tumor immunotherapy, until now only one virus, the oncolytic virus talimogene laherparepvec (TVEC), a genetically modified herpes simplex virus type 1 (T-VEC), has been approved by the FDA for cancer treatment. Although oncolytic viruses showed progress in certain cancer types and patient populations but they have yet shown limited efficacy when it comes to solid tumors. Only recently it was demonstrated that the immune stimulatory aspect of oncolytic viruses can strongly contribute to their anti-tumoral activity. One specific example in this context are arenaviruses, which have been shown to be non-cytopathic in nature lead to the massive immune activation within the tumor resulting in strong anti-tumoral activity. This strong immune activation might be also linked to their noncytopathic features, as their immune stimulatory potential is not self-limiting as is the case for oncolytic viruses due to their fast eradication by anti-viral immune effects. Because of this strong immune activation, arenaviruses appear superior to oncolytic viruses when it comes to potent and long-lasting anti-tumor effects in a broad variety of tumor types. Currently one of the most promising therapeutics which has turned to be very much beneficial for the treatment of different cancer types is represented by antibodies targeting checkpoint inhibitors such as PD-1/PD-L-1. In this review, we will summarize anti-tumoral effects of arenaviruses, and will discuss their potential to be combined with checkpoint inhibitors for a more efficient tumor treatment, which further emphasizes that arenavirus therapy as a viroimmunotherapy can be an efficient tool for the better clearance of tumors.

Corrigendum to: Tranexamic acid use in a patient with sickle cell disease undergoing posterior scoliosis correction surgery: safely mitigating bleeding and vaso-occlusive crises.

[This corrects the article DOI: 10.1093/jscr/rjaa559.].

Tranexamic acid use in a patient with sickle cell disease undergoing posterior scoliosis correction surgery: safely mitigating bleeding and vaso-occlusive crises.

A 15-year-old female with 2-year post-menarchal adolescent idiopathic scoliosis and sickle cell disease (SCD) underwent posterior scoliosis correction surgery. SCD is associated with higher rates of surgical complications, and these patients require careful management to prevent vaso-occlusive sickle cell crises (VOSCC); scoliosis correction surgery can be associated with high morbidity and mortality, including significant blood loss. Multiple techniques were employed to successfully prevent VOSCC in this patient including a preoperative transfusion, meticulous haemostasis at osteotomy sites, not performing a costoplasty despite presence of a rib hump, maintenance of intraoperative mean arterial pressure below 70 mmHg, aggressive postoperative hydration and the use of intraoperative tranexamic acid (TXA). This is the first reported case of the use of TXA in a patient with SCD and scoliosis correction surgery. A satisfactory correction was achieved with a longer than average inpatient stay due to non-sickle cell pain and protracted wound ooze.

Arenavirus Induced CCL5 Expression Causes NK Cell-Mediated Melanoma Regression.

Immune activation within the tumor microenvironment is one promising approach to induce tumor regression. Certain viruses including oncolytic viruses such as the herpes simplex virus (HSV) and non-oncolytic viruses such as the lymphocytic choriomeningitis virus (LCMV) are potent tools to induce tumor-specific immune activation. However, not all tumor types respond to viro- and/or immunotherapy and mechanisms accounting for such differences remain to be defined. In our current investigation, we used the non-cytopathic LCMV in different human melanoma models and found that melanoma cell lines produced high levels of CCL5 in response to immunotherapy. In vivo, robust CCL5 production in LCMV infected Ma-Mel-86a tumor bearing mice led to recruitment of NK cells and fast tumor regression. Lack of NK cells or CCL5 abolished the anti-tumoral effects of immunotherapy. In conclusion, we identified CCL5 and NK cell-mediated cytotoxicity as new factors influencing melanoma regression during virotherapy.

Dead Cells Induce Innate Anergy via Mertk after Acute Viral Infection.

Infections can result in a temporarily restricted unresponsiveness of the innate immune response, thereby limiting pathogen control. Mechanisms of such unresponsiveness are well studied in lipopolysaccharide tolerance; however, whether mechanisms of tolerance limit innate immunity during virus infection remains unknown. Here, we find that infection with the highly cytopathic vesicular stomatitis virus (VSV) leads to innate anergy for several days. Innate anergy is associated with induction of apoptotic cells, which activates the Tyro3, Axl, and Mertk (TAM) receptor Mertk and induces high levels of interleukin-10 (IL-10) and transforming growth factor ß (TGF-ß). Lack of Mertk in Mertk-/- mice prevents induction of IL-10 and TGF-ß, resulting in abrogation of innate anergy. Innate anergy is associated with enhanced VSV replication and poor survival after infection. Mechanistically, Mertk signaling upregulates suppressor of cytokine signaling 1 (SOCS1) and SOCS3. Dexamethasone treatment upregulates Mertk and enhances innate anergy in a Mertk-dependent manner. In conclusion, we identify Mertk as one major regulator of innate tolerance during infection with VSV.

Integrin Alpha E (CD103) Limits Virus-Induced IFN-I Production in Conventional Dendritic Cells.

Early and strong production of IFN-I by dendritic cells is important to control vesicular stomatitis virus (VSV), however mechanisms which explain this cell-type specific innate immune activation remain to be defined. Here, using a genome wide association study (GWAS), we identified Integrin alpha-E (Itgae, CD103) as a new regulator of antiviral IFN-I production in a mouse model of vesicular stomatitis virus (VSV) infection. CD103 was specifically expressed by splenic conventional dendritic cells (cDCs) and limited IFN-I production in these cells during VSV infection. Mechanistically, CD103 suppressed AKT phosphorylation and mTOR activation in DCs. Deficiency in CD103 accelerated early IFN-I in cDCs and prevented death in VSV infected animals. In conclusion, CD103 participates in regulation of cDC specific IFN-I induction and thereby influences immune activation after VSV infection.

Tamoxifen Protects from Vesicular Stomatitis Virus Infection.

BACKGROUND: Tamoxifen (TAM) is an estrogen-receptor antagonist, widely used in the adjuvant treatment of early stage estrogen-sensitive breast cancer. Several studies have revealed new biological targets of TAM that mediate the estrogen receptor independent activities of the drug. Recently, the antiviral activity of TAM on replication of human immunodeficiency virus (HIV), hepatitis C virus (HCV) and Herpes simplex virus (HSV-1) in vitro was described. In the current study, we aimed to investigate the effect of TAM on infection with vesicular stomatitis virus (VSV). METHODS: Vero cells were treated with different concentrations of TAM for 24 h and then infected with VSV. Additionally, C57BL/6 mice were pretreated with 4 mg TAM, one day and three days before infection with VSV. Results: Treatment of Vero cells with TAM suppressed the viral replication of VSV in vitro and in vivo. The inhibitory effect of TAM on VSV replication correlated with an enhanced interferon-I response and stimulation of macrophages. Conclusions: TAM was identified as being capable to protect from VSV infection in vitro and in vivo. Consequently, this antiviral function (as an advantageous side-effect of TAM) might give rise to new clinical applications, such as treatment of resistant virus infections, or serve as an add-on to standard antiviral therapy.

Hydatid disease of the spine: a report on nine patients.

PURPOSE: The author presents this prospective study of nine cases of pathologically confirmed spinal hydatid disease. METHOD: Hydatid disease is a difficult diagnosis in non endemic areas but it should be considered in the differential diagnosis of spinal pathology in endemic areas. Spinal involvement is very unusual. There is nothing typical of spinal involvement. Nine patients presented with hydatid disease of the spine between September 2001 and October 2010. The patients were clinically evaluated as well as by the latest imaging modalities, haematological and serological tests. All had decompressive surgery with or without fixation and the diagnosis was confirmed by histopathological examination. All received albendazole and praziquantel for ten months. RESULTS: MRI was the best diagnostic test, CAT scan was also useful, eosinophilia was a constant finding, and ESR was above normal in five patients. All had decompression laminectomy and clearance; in addition, transpedicular fixation was done to three patients. After surgery one patient had complete recovery with no recurrence, seven patients showed recurrence over time and residual disease was observed, and one patient died within 24 hours of surgery. CONCLUSION: Diagnosis was easy from the start, but eradication was difficult, and recurrence rate was very high despite the use of chemotherapy.

Postoperative disc space infection after discectomy: a report on thirty-five patients.

PURPOSE: The focus of this study was to analyse the patient with disc space infection and the need for re-exploration. METHOD: Thirty-five patients were analysed within the period from April 1992 and May 2011. The diagnosis was confirmed by the cardinal clinical features, raised erythrocyte sedimentation rate [ESR], raised C-reactive protein and MRI findings. All received 500-mg intravenous amikacin and one gram ceftriaxone at the time of anaesthetic induction and six hours after surgery. RESULTS: Age range was between 25-62 years. The appearance of symptoms was between four days and three weeks. Nine patients had silent chronic urinary tract infection. Twenty-nine patients had re-exploration while the others did well on conservative treatment. Neurological deficit was not recorded. All recovered well within six to nine months. CONCLUSION: Re-exploration is recommended if no response is achieved after four day's conservative treatment for or if the patient's condition is critical.