Referral Patterns and Outcome of Patients With Synchronous Brain Metastases From Non-small Cell Lung Cancer Treated With Gamma Knife Radiosurgery in a Third-Line Treatment Centre in The Netherlands - A Retrospective Analysis.

AIMS: Little understanding exists of referral patterns for patients with brain metastasis from non-small cell lung cancer (NSCLC) towards treatment with Gamma Knife radiosurgery (GKRS). Therefore, we explored current clinical daily practice and prognosis. MATERIAL AND METHODS: In total, 1129 patients with synchronously diagnosed brain metastasis from NSCLC diagnosed between 2008 and 2014 were selected from the population-based Netherlands Cancer Registry; 242 patients were treated with GKRS. RESULTS: Patients receiving GKRS were younger (62 years versus 64 years) and had lower tumour burden: the presence of T2 was higher and T4 was lower (43% versus 33%; P = 0.0158, 19% versus 28%; P = 0.0044, respectively). They more frequently had cN0 (32% versus 19%; P ≤ 0.0001), less frequently had N3 disease (18% versus 29%; P = 0.0004) and there were fewer metastatic sites. In multivariable logistic regression analysis, only age ≤60 years (odds ratio 1.4; 95% confidence interval 1.0-2.0) and patients with N0 stage, compared with those with N2, N3 and NX (odds ratio 0.6 [0.4-0.9], 0.3 [0.2-0.6], 0.3 [0.1-0.6], respectively), were more likely to receive GKRS. Gender, T-stage, histology, number of comorbidities, country of birth as proxy for ethnicity and socioeconomic status were not associated. The median survival was 9.6 months after GKRS versus 4.0 months in the noGKRS group (Log-rank: P ≤ 0.0001). Multivariably, GKRS, female, lower T-/N-stage, <2 comorbidities, adenocarcinoma and higher socioeconomic status were associated with a significantly reduced hazard of death. For the patients with at least one follow-up magnetic resonance image (80%), local intracranial tumour control was achieved in 93% at the last follow-up. CONCLUSION: Patients presenting with synchronic brain metastasis from NSCLC who are referred to a third-line treatment centre for GKRS are younger and have a lower tumour load. Due to a high level of local control, GKRS is able to provide a significant window of opportunity for additional treatment of the primary tumour.

Fatal outcome of a hypersensitivity reaction to paclitaxel: a critical review of premedication regimens.

Hypersensitivity reactions (HSRs) to paclitaxel are frequently encountered in patients receiving this antitumour drug. Administration of histamine H1- and H2-receptor antagonists and corticosteroids has been shown to reduce significantly the risk of developing an HSR in patients receiving taxanes. In this case report, we describe the fatal outcome of an HSR in a patient receiving paclitaxel despite short-course premedication. The level of evidence supporting the short-course i.v. premedication schedule is challenged, as it is not compatible with the pharmacokinetic properties of dexamethasone.

A rat cytomegalovirus strain with a disruption of the r144 MHC class I-like gene is attenuated in the acute phase of infection in neonatal rats.

We previously generated an RCMV strain in which the r144 gene, encoding a major histocompatibility complex class I homolog, had been deleted (RCMVdelta r144). To investigate the role of r144 during acute infection of neonatal rats, we infected three days-old neonatal rats with either RCMVdelta r144 or wild type (wt) RCMV and the presence of infectious virus as well as viral DNA in various organs was determined at either 3, 5 or 21 days p.i.. In addition, we assessed both type and number of inflammatory cells in these organs. Interestingly, a significantly lower concentration of infectious virus as well as viral DNA was found in spleens of RCMVdelta r144-infected rats than in those of wt RCMV-infected animals at 3 days p.i.. At the same time point, a significantly lower amount of infiltrating NK cells and monocytes/macrophages was seen in the spleens of RCMVdelta r144-infected rats than in spleens of rats infected with wt RCMV. At 21 days p.i., RCMVdelta r144-infected rats were found to have lower virus titers in the salivary glands than wt RCMV-infected animals. Significant differences between RCMVdelta r144- and wt RCMV-infected rats were detected neither at other time points nor at other sites. We conclude that after infection of neonatal rats, the replication of RCMVdelta r144 is severely restricted compared to wt RCMV.

Rat cytomegalovirus replication in the salivary glands is exclusively confined to striated duct cells.

The salivary gland is the preferred organ for cytomegalovirus (CMV) replication and viral persistence. In order to identify the nature of infected cells and to study viral replication in more detail, several experiments were conducted. Using the rat CMV (RCMV) model, acutely infected young adult rats (6 weeks of age) and new-born rats (3 days of age) were infected, and submandibular, parotid and sublingual glands were harvested at different time points after infection. For identification of the nature of infected cells, immunohistochemistry, in situ hybridisation and electron microscopic techniques were used. In young adult animals, the submandibular gland was the preferred organ for RCMV replication. The parotid and sublingual glands contained fewer viruses than the submandibular gland. In contrast, in new-born rats, the main site of RCMV replication was the sublingual gland, while the submandibular and parotid glands contained low amounts of virus. No virus could be detected in the parotid glands. In all glands of RCMV-infected animals, the infection was exclusively confined to striated duct cells. Infection resulted in a cellular inflammatory response which was mostly located in the interlobular duct region, whereas only few inflammatory cells were found in the neighbourhood of infected striated duct cells. This phenomenon may contribute to the long persistence of the virus in this organ.

Rat cytomegalovirus infection in kidney allograft recipients is associated with increased expression of intracellular adhesion molecule-1 vascular adhesion molecule-1, and their ligands leukocyte function antigen-1 and very late antigen-4 in the graft.

BACKGROUND: Cytomegalovirus (CMV) infection is suggested to be a risk factor for chronic rejection. We have recently shown that rat CMV (RCMV) increases the inflammatory response and accelerates chronic rejection in a model of rat kidney allograft. In this study, the early inflammatory response and time-related expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) and their ligands, leukocyte function antigen-1 (LFA-1) and very late antigen-4 (VLA-4), in the grafts were investigated in RCMV-infected rats and compared to noninfected rats developing chronic rejection. METHODS: Transplantations were performed in a rat strain combination of DA (RT1a)->BN (RT1n) receiving triple drug immunosuppression. One group of rats was infected with RCMV, and the other was left uninfected. The grafts were harvested at different time points after transplantation. The adhesion molecules, their ligands and activation markers, MHC class II antigens and interleukin-2-receptors (IL-2-R), were demonstrated by monoclonal antibodies and immunoperoxidase staining from frozen sections of the grafts. Graft histology was evaluated according to the Banff criteria. RESULTS: RCMV caused a significant, prolonged increase of VCAM-1 and ICAM-1 expression in the vascular endothelium compared to the noninfected grafts. Also, the number of cells expressing activation markers, LFA-1 and VLA-4 was significantly enhanced in these animals. Significantly enhanced histological changes of chronic rejection were seen in the RCMV-infected group. CONCLUSIONS: Prolonged, increased expression of ICAM-1 and VCAM-1, and increased numbers of inflammatory cells expressing their ligands in the CMV infected grafts, were associated with accelerated chronic allograft nephropathy.

The r144 major histocompatibility complex class I-like gene of rat cytomegalovirus is dispensable for both acute and long-term infection in the immunocompromised host.

The rat cytomegalovirus (RCMV) r144 gene encodes a polypeptide homologous to major histocompatibility complex class I heavy chains. To study the role of r144 in virus replication, an RCMV r144 null mutant strain (RCMVDeltar144) was generated. This strain replicated with efficiency similar to that of wild-type (WT) RCMV in vitro. Additionally, WT RCMV and RCMVDeltar144 were found not to differ in their replication characteristics in vivo. First, the survival rate was similar among groups of immunosuppressed rats infected with either RCMVDeltar144 or WT RCMV. Second, the dissemination of virus did not differ in either RCMVDeltar144- or WT RCMV-infected, immunosuppressed rats, either in the acute phase of infection or approximately 1 year after infection. These data indicate that the RCMV r144 gene is essential neither for virus replication in the acute phase of infection nor for long-term infection in immunocompromised rats. Interestingly, in a local infection model in which footpads of immunosuppressed rats were inoculated with virus, a significantly higher number of infiltrating macrophage cells as well as of CD8(+) T cells was observed in WT RCMV-infected paws than in RCMVDeltar144-infected paws. This suggests that r144 might function in the interaction with these leukocytes in vivo.

Effect of desferrioxamine (DFO) and calcium trinatrium diethylenetriaminepentaacetic acid (DTPA) on rat cytomegalovirus replication in vitro and in vivo.

Cytomegalovirus (CMV) infection is a major problem in the immunosuppressed patient. It is thought that besides direct CMV induced cell lysis, immunological damage is part of CMV pathogenesis. New antiviral drugs, which combine immunomodulating and antiviral qualities, could be beneficial. Recently, it has been described that desferrioxamine (DFO) and calcium trinatrium diethylenetriaminepentaacetic acid (DTPA) exhibit both properties. In this report the antiviral effects of both compounds against rat CMV (RCMV) are described in vitro and in vivo using a generalised and local infection model. In vitro, both compounds exhibited a significant antiviral effect, DTPA being more potent than DFO. However, in the generalised infection model no effect was seen on mortality, morbidity or presence of virus in internal organs. In rats infected subcutaneously in the hind paw, no effect was seen locally on paw thickness, presence of viral antigens and inflammatory response. In addition, these rats suffered from a generalised infection of low magnitude at 15 days post infection, although both DFO and DTPA were able to lower the level of viral replication. In conclusion, our data indicate that despite in vitro activity, in vivo usage of DFO or DTPA for acute CMV infection is not warranted.

Effective treatment of experimental cytomegalovirus-induced encephalo-meningitis in immunocompromised rats with HPMPC.

Cytomegalovirus (CMV)-induced encephalomeningitis is a dramatic complication in patients with the acquired immunodeficiency syndrome (AIDS) and treatment of this infection remains a major clinical problem. In order to study the pathogenesis and treatment of CMV-induced encephalomeningitis, we experimentally induced intracranial rat CMV (RCMV) infection in rats that were immunosuppressed by total body X-irradiation. CMV infection was monitored by viral plaque assay for estimation of the viral load. CMV-induced pathology, the presence of CMV-infected cells, as well as the presence of T-lymphocytes and monocytes/macrophages were studied by histopathologic and immunohistochemical staining techniques. The meninges showed CMV infection in mononuclear infiltrative cells and in endothelium of small blood vessels 8 days after intracerebral inoculation. This was accompagnied by multiple haemorraghes and inflammatory cell infiltration. The infection and inflammatory response persisted for at least 21 days p.i. Animals were treated with (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC), 9-(1,3-dihydroxy-2-propoxymethyl)guanine (DHPG), hyperimmune serum (HIS) and both DHPG and HIS combined. Treatment with one dosage of HPMPC at 20 mg/kg effectively reduced virus titers. However, all other treatment modalities were not effective. In conclusion, the pathology of RCMV-induced encephalomeningitis in immunocompromised rats closely resembles that of AIDS patients. The infection is effectively treated by HPMPC.

Combinations of ganciclovir and antibody for experimental CMV infections.

The effect of combined treatment with ganciclovir and hyper immune serum (HIS) was evaluated in three animal models. It concerned a generalized CMV infection model, a meningo-encephalitis model and an interstitial lung disease (ILD) model in immunocompromised rats. In the generalized model, the ganciclovir and HIS had a moderate synergistic effect on survival and greatly decreased virus titers in internal organs. In contrast, in the meningoencephalitis model, combined treatment had no effect on the local virus titers and the histopathology. Combined treatment with ganciclovir and HIS, however, effectively abolished CMV-induced ILD.