Benefit of re-operation and salvage therapies for recurrent glioblastoma multiforme: results from a single institution.

The optimal management of recurrent glioblastoma (GBM) has yet to be determined. We aim to assess the benefits of re-operation and salvage therapies (chemotherapy and/or re-irradiation) for recurrent GBM and to identify prognostic factors associated with better survival. All patients who underwent surgery for GBM between January 2005 and December 2012 followed by adjuvant radiotherapy, and who developed GBM recurrence on imaging were included in this retrospective study. Univariate and multivariate analysis was performed using Cox models in order to identify factors associated with overall survival (OS). One hundred and eighty patients treated to a dose of 60 Gy were diagnosed with recurrent GBM. At a median follow-up time of 6.2 months, the median survival (MS) from time of recurrence was 6.6 months. Sixty-nine patients underwent repeat surgery for recurrence based on imaging. To establish the benefits of repeat surgery and salvage therapies, 68 patients who underwent repeat surgery were matched to patients who did not based on extent of initial resection and presence of subventricular zone involvement at recurrence. MS for patients who underwent re-operation was 9.6 months, compared to 5.3 months for patients who did not have repeat surgery (p < 0.0001). Multivariate analysis in the matched pairs confirmed that repeat surgery with the addition of other salvage treatment can significantly affect patient outcome (HR 0.53). Re-operation with additional salvage therapies for recurrent GBM provides survival prolongation at the time of progression.

Progression pattern and adverse events with bevacizumab in glioblastoma.

BACKGROUND: The use of bevacizumab in the management of glioblastoma multiforme (gbm) remains controversial. In Canada, bevacizumab is approved for the treatment of recurrent gbm. We describe a pattern of progression across treatment lines in gbm. METHODS: During 2008-2014, 64 patients diagnosed with gbm were treated with bevacizumab at McGill University hospitals. Of those patients, 30 (46.9%) received bevacizumab in the first line (B1L), and 34 (53.1%) received it in the second line and beyond (B2L+). The average length of treatment with bevacizumab was 24.4 weeks (range: 0-232.7 weeks). The patterns of progression were categorized as local, distant, diffuse, multifocal, or multi-pattern. RESULTS: Local progression was seen in 46.7% of B1L patients and 26.5% of B2L+ patients, distant in 3.3% and 2.9%, diffuse in 20% and 47%, multifocal in 10% and 8.8%, and multi-pattern in 3.3% and 11.8%. No differences between the groups were observed for the distant (p = 0.3) or diffuse (p = 0.4) patterns. Grades 3 and 4 adverse events in the B1L and B2L+ groups were fatigue (33.3% vs. 17.6% respectively), hypertension (26.7% vs. 5.9%), thrombocytopenia (26.7% vs. 11.8%), neutropenia (26.7% vs. 11.8%), anemia (23.3% vs. 11.8%), leucopenia (20% vs. 8.8%), deep vein thrombosis (23.3% vs. 5.9%), seizure (16.7% vs. 8.8%), brain hemorrhage (6.7% vs. <1%), and delayed wound healing (6.7% vs. 2.9%). More total grades 3 and 4 adverse events occurred in the B1L group (p = 0.000519). CONCLUSIONS: In our cohort, patterns of progression were not different in B1L and B2L+ patients. Moreover, both groups experienced similar adverse events, although more grades 3 and 4 events occurred in the B1L group, implying that severe adverse events in B1L patients could negatively affect survival outcomes.

Synchronous metastatic skull base chordoma to the breast: case report and literature review.

CLINICAL SCENARIO: During routine staging work-up for a left breast mass, a 68-year-old woman complained of dysphagia and dysphonia. During further investigations, a left-sided lesion at the foramen magnum was observed on brain imaging. Both lesions were biopsied and showed a classical chordoma. MANAGEMENT: The skull-base lesion and the breast lesion were surgically resected, and adjuvant radiotherapy was given. SUMMARY: Chordoma is a rare primary central nervous system tumour that seldom metastasizes. The lung is the most common site of metastasis. Synchronous breast metastasis from a skull-base chordoma is very rare, and a safe management option includes a maximum resection followed by adjuvant radiotherapy.

Clinical significance of molecular biomarkers in glioblastoma.

AIM: To review the impact of molecular biomarkers on response to therapy and survival in patients with primary glioblastoma (GBM). MATERIALS & METHODS: Tissue specimens were analyzed for p53 mutations, EGFR amplification, loss of PTEN and p16, and O6-methylguanine DNA methyltransferase (MGMT) promoter methylation. Demographic and clinical data were gathered from medical records. RESULTS: Clinical and pathological data of 125 patients were collected and analysed. MGMT promoter methylation was associated with improved median overall survival (OS) (61 vs. 42 weeks, p = 0.01) and was an important prognosticator independent of age at diagnosis, extent of resection and post-operative ECOG performance status (HR 2.04, 95% CI 1.11-3.75). Among patients with MGMT promoter methylation, survival was significantly improved with chemoradiotherapy (CRT) over radiotherapy (RT) alone (71 vs. 14 weeks, p < 0.01). Furthermore, amongst those treated with temozolomide (TMZ) based CRT, the presence of EGFR amplification, maintenance of PTEN and wild-type p53 and p16 were each associated with trends towards improved survival. CONCLUSION: MGMT promoter methylation is a strong, independent prognostic factor for OS in GBM. EGFR amplification, maintenance of PTEN, wild-type p53 and p16 all appear to be associated with improved survival in patients treated with CRT. However, the prognostic value of these biomarkers could not be ascertained and larger prospective studies are warranted.

TLR7 ligand prevents allergen-induced airway hyperresponsiveness and eosinophilia in allergic asthma by a MYD88-dependent and MK2-independent pathway.

Asthma is one of the leading causes of childhood hospitalization, and its incidence is on the rise throughout the world. Currently, the standard treatment for asthma is the use of corticosteroids to try to suppress the inflammatory reaction taking place in the bronchial tree. Using a murine model of atopic allergic asthma employing a methacholine-hyperresponsive (A/J) as well as a hyporesponsive (C57BL/6) strain of mice sensitized and challenged with ovalbumin, we show that treatment with a synthetic Toll-like receptor 7 (TLR7) ligand (S-28463, a member of the imidazoquinoline family) prevents development of the asthmatic phenotype. Treatment with S-28463 resulted in a reduction of airway resistance and elastance following ovalbumin sensitization and challenge. This was accompanied by a dramatic reduction in infiltration of leukocytes, especially eosinophils, into the lungs of both C57BL/6 and A/J mice following OVA challenge. Treatment with S-28463 also abolished both the elevation in serum IgE level as well as the induction of IL-4, IL-5, and IL-13 by OVA challenge. The protective effects of S-28463 were also observed in MK2 knockout, but not MYD88 knockout, mice. We did not observe a switch in cytokine profile from T(H)2 to T(H)1, as both IL-12p70 and IFN-gamma levels were reduced following S-28463 treatment. These results clearly demonstrate the anti-inflammatory effect of imidazoquinolines in an allergic asthma model as well as the clinical potential of TLR7 ligands in the treatment of allergic diseases.

Cystic fibrosis lung disease following infection with Pseudomonas aeruginosa in Cftr knockout mice using novel non-invasive direct pulmonary infection technique.

To better understand the mechanism of lung infection with Pseudomonas aeruginosa (P. aeruginosa), many techniques have been developed in order to establish lung infection in rodents. A model of chronic lung infection, using tracheotomy to inoculate the bacteria, has been extensively used in the cystic fibrosis (CF) mouse model of lung infection. The cystic fibrosis transmembrane channel (Cftr) knockout (KO) mice are smaller than normal mice and are more sensitive to housing and nutritional conditions, leading to small amounts of animals being available for experiments. Because of these characteristics, and because of the invasiveness of the infection procedure which we, and others, have been using to mimic the lung infection, we sought to find an alternative way to study the inflammatory response during lung P. aeruginosa infection. The technique we describe here consists of the injection of bacterial beads directly into the lungs through the mouth without the need of any tracheal incisions. This technique of direct pulmonary delivery enables much faster infection of the animals compared with the intratracheal technique previously used. The use of this less invasive technique allows the exclusion of the surgery-related inflammation. Our results show that, using the direct pulmonary delivery technique, the KO mice were more susceptible to P. aeruginosa lung infection compared with their wild-type (WT) controls, as shown by their increased weight loss, higher bacterial burden and more elevated polymorphonuclear (PMN) alveolar cell recruitment into the lungs. These differences are consistent with the pathological profiles observed in CF patients infected with P. aeruginosa. Overall, this method simplifies the infection procedure in terms of its duration and invasiveness, and improves the survival rate of the KO mice when compared with the previously used intratracheal procedure.

Cellular immunity in measles vaccine failure: demonstration of measles antigen-specific lymphoproliferative responses despite limited serum antibody production after revaccination.

Measles antigen-specific immune responses were evaluated 1 and 6 months after revaccination in 60 previously vaccinated subjects (9.4 +/- 3.4 years of age) who had either undetectable or low plaque reduction neutralization (PRN) titers (< 200). PRN titers were increased in all subjects at 1 month (590 +/- 61; range, 129-2513) but fell again in 66% of subjects by 6 months (214 +/- 29; range, 30-794). At 6 months, 23 (38%) had subprotective (< 120) or borderline (< 200) PRN titers. Lymphoproliferative responses to measles virus antigens were low overall before revaccination (mean stimulation index [SI], 2.6 +/- 0.4; range, 0.5-13.5) but were readily detectable at 1 (SI, 145.8 +/- 2.6; range, 1.4-80) and 6 months after revaccination (SI, 9.4 +/- 1.8; range, 1.1-87). Before revaccination, 10 of the subjects (50%) with low positive PRN titers had SIs > or = 3. At 6 months after revaccination, 18 subjects (78%) with PRN titers < or = 200 had SIs > or = 3. These data suggest that cellular responses to measles virus may be better sustained than antibody titers after vaccination and revaccination in some subjects.

Activation of kappa B-specific proteins by estradiol.

The kappa B enhancer serves as a recognition site for the nuclear transcription factor NF-kappa B and other kappa B-specific proteins which are activated in many cell types in response to a variety of extracellular signals. But a steroid-dependent activation of NF-kappa B or any other kappa B-specific protein has not previously been reported, to our knowledge. In this report we demonstrate that estrogen can activate kappa B-specific protein in its target tissue, uterus. We have done this by analyzing the interaction of nuclear extracts with kappa B enhancers, using DNA mobility shift assays. The activation by estradiol was time dependent, reaching a maximum at approximately 2 hr after steroid treatment, and was not inhibited by prior cycloheximide treatment. The protein-DNA complexes formed in response to estradiol did not contain NF-kappa B and, when compared with other kappa B enhancer motifs, had a higher affinity to the kappa B enhancer corresponding to the PRDII element present in duplicate motifs. These protein-DNA complexes also did not appear to contain estrogen receptor, since antibodies to estrogen receptor were without any effect on either their formation or their mobility. The protein-DNA complexes formed in response to estradiol, however, exhibited a high affinity for the estrogen-responsive element, suggesting the participation of an estrogen-receptor-like molecule in the DNA binding. In contrast, the protein-DNA complexes formed constitutively contained NF-kappa B, had equivalent affinities to various kappa B enhancers, and did not have a high affinity for the estrogen-responsive element. On the basis of these findings, we propose that estrogen-dependent activation of the as-yet-unidentified kappa B-specific protein involves the association of this protein with an estrogen-receptor-related molecule and binding of the resulting complex to PRDII. The high affinity and specificity of this binding to PRDII suggests that this may serve as a composite regulatory element in mediating estrogen-dependent gene expression. The potential significance of such a mechanism for steroid hormone action is discussed.

Estrogen dependent regulation of estrogen receptor gene expression in normal mammary gland and its relationship to estrogenic sensitivity.

In the present study, we have examined the relationship between estradiol (E2)-dependent regulation of estrogen receptor (ER) gene expression in normal mammary glands and its relationship to progesterone receptor (PgR) gene expression using tissues from E2-sensitive and -insensitive states. Estradiol caused a time-dependent decrease in ER mRNA levels in E2-sensitive mammary glands reaching a maximum at approx 6 h, at which time the levels of PgR mRNA also reached a maximum. In contrast, in E2-insensitive mammary glands, there was no E2-dependent decrease in ER mRNA at all times tested. Experiments using dissociated cells revealed that although the epithelial cells of mammary glands from both E2-sensitive and -insensitive states contained ER mRNA, in the intact E2-sensitive mammary glands, it was the nonepithelial ER that was decreasing in response to E2. Since the epithelial cells of normal mammary glands are the primary target for E2-dependent PgR synthesis, our studies suggest that a positive correlation between E2-dependent PgR gene expression and E2-dependent downregulation of ER may simply be coincidental and may not bear any true biological relationship.

Immunohistologic diagnosis of multiple carcinomas. The role of monoclonal antibodies against carcinoembryonic antigen.

The occurrence of multiple malignant lesions in the same patient requires that management decisions be made from an accurate pathological identification of the tumours. The authors describe five patients who had colorectal adenocarcinoma preceded or followed by adenocarcinomas in other organs. Definitive identification could not be established from routine histopathologic findings. The use of immunohistochemistry helped to clarify the relationship between the various tumours; in particular, a monoclonal antibody (D14) directed against carcinoembryonic antigen (CEA) made a notable contribution. Because of the increasing number of monoclonal antibodies with well-defined tumour specificities, their use in the documentation of multiple malignant tumours has great clinical potential.

Definition of the human renal cell carcinoma phenotype using monoclonal and polyclonal antibodies: a tumor marker study.

Previous studies have demonstrated a high level of heterogeneity associated with human renal cell carcinoma (RCC). In order to probe further this heterogeneity monoclonal antibodies were produced after immunization of mice with extracts of fresh renal tumor specimens. Four monoclonal antibodies designated LD-M1, LD-M2, LD-M5, and LD-M8 were generated and characterized immunohistochemically on a panel of tissue sections. The LD monoclonal antibodies strongly stained paraffin sections obtained from 77 to 100% of cases of RCC. Testing the sections with a library of polyclonal and monoclonal antibodies resulted in the definition of the following immunohistochemical phenotype of RCC: positive with the LD-M1, LD-M2, Ld-M5, LD-M8, Uro-2, Uro-7, Uro-10, cytokeratin, keratin, TPA, vimentin, Fx1A, retinol binding protein, CALLA and B72 antibodies; negative with the prekeratin, desmin, A5.48, uromucoid, and CEA antibodies. The pattern of immunohistochemical activity indicates that some RCC tumor cells contain epitopes associated with distal tubules in addition to previously documented antigens present in proximal tubules. Using a solid-phase competition radioimmunoassay it was observed that the serum of patients with renal cell carcinoma contains a circulating LD-M5-reactive tumor-associated antigen.

[Toxoplasma encephalitis in acquired immunodeficiency syndrome]. / Encéphalite toxoplasmique au cours d'un syndrome immunodéficitaire acquis (S.I.D.A.).

Several outbreaks of fatal opportunistic infections and tumors have recently been reported among homosexual men in the United States. Almost all patients had evidence of cellular immunodeficiency. We have studied a French homosexual man with fatal central nervous system toxoplasmosis. Morphological features (light and electron microscopy) of toxoplasma encephalitis are described.