Non-deep-seated primary CNS lymphoma: therapeutic responses and a molecular signature

The survival of patients with primary CNS lymphoma (PCNSL) has been improved by high-dose methotrexate (HD-MTX). Since the combination therapy of HD-MTX and whole-brain radiotherapy (WBRT) carries a significant risk for delayed neurotoxicity, it is important to know the therapeutic potential and prognostic factors for HD-MTX without WBRT. We retrospectively reviewed 46 consecutive patients with PCNSL treated with a HD-MTX (3.5 g/m²) and deferred WBRT. Patients who achieved complete response or partial response after three courses of HD-MTX were cautiously followed-up without additional treatment. Patients who had either stable disease, progressive disease, or disease relapse were offered salvage therapy. The median progression-free survival period was 10 months and the median overall survival period was 52 months, with a 5-year survival rate of 39 %. Nineteen patients (49 % of the evaluable patients) achieved a complete response at the initial response assessment. Involvement of deep structures of the brain (corpus callosum, basal ganglia and brainstem) was significantly associated with the worse progression-free survivals (p = 0.0058) and overall survivals (p = 0.0177). Gene expression profiling analysis by microarray was compared in eight patients between PCNSLs located in the deep structures of the brain and non-deep-seated tumors. The result showed that up-regulation of signal transduction-related genes and down-regulation of catalytic activity-related genes in the non-deep-seated PCNSL compared with the deep-seated tumors. The present study shows that PCNSL located in non-deep structures of the brain responds better to HD-MTX alone than those involved deep-structures.     

Urokinase-Targeted Fusion by Oncolytic Sendai Virus Eradicates Orthotopic Glioblastomas by Pronounced Synergy With Interferon-�� Gene

Glioblastoma multiforme (GM), the most frequent primary malignant brain tumor, is highly invasive due to the expression of proteases, including urokinase-type plasminogen activator (uPA). Here, we show the potential of our new and powerful recombinant Sendai virus (rSeV) showing uPA-specific cell-to-cell fusion activity [rSeV/dMFct14 (uPA2), named “BioKnife”] for GM treatment, an effect that was synergistically enhanced by arming BioKnife with the interferon-β (IFN-β) gene. BioKnife killed human GM cell lines efficiently in a uPA-dependent fashion, and this killing was prevented by PA inhibitor-1. Rat gliosarcoma 9L cells expressing both uPA and its functional receptor uPAR (9L-L/R) exhibited high uPA activity on the cellular surface and were highly susceptible to BioKnife. Although parent 9L cells (9L-P) were resistant to BioKnife and to BioKnife expressing IFN-β (BioKnife-IFNβ), cell–cell fusion of 9L-L/R strongly facilitated the expression of IFN-β, and in turn, IFN-β significantly accelerated the fusion activity of BioKnife. A similar synergy was seen in a rat orthotopic brain GM model with 9L-L/R in vivo; therefore, these results suggest that BioKnife-IFNβ may have significant potential to improve the survival of GM patients in a clinical setting.     

Challenge reactions in atopic dermatitis after percutaneous entry of mite antigen

We succeeded in reproducing an eczematous lesion on the apparently normal skin of a patient with atopic dermatitis by scratching and continuous application of an ointment containing ferritin-labelled mite antigen. Percutaneous entry of mite antigen was demonstrated in skin biopsies by Fe-staining. Scratched skin first showed an urticarial reaction typical of type I allergy which later changed into an eczematous reaction typical of type IV allergy. This change was also shown histologically.     

Transthoracic Collis-Nissen repair for massive type IV paraesophageal hernia

An 80-year-old woman presented with type IV massive hiatal hernia with intrathoracic upside-down stomach and transverse colon. She was dyspneic and vomited upon consuming food or water. Consequently, she developed aspiration pneumonia. Both esophagoscopy and upper gastrointestinal series demonstrated significant cephalad displacement of the gastroesophageal junction. A Collis-Nissen hernial repair by muscle-sparing mini-thoracotomy was performed successfully. To date, 3 years after surgery, the patient is enjoying normal oral intake, has an excellent activities of daily living level, and there is no hernia recurrence. Cases of massive paraesophageal hernia are frequently associated with esophageal shortening that causes tension on the repairs and late failure. Advantages of the transthoracic approach in such cases include feasibility of direct esophageal mobilization, accurate assessment of esophageal tension, and facilitation of Collis gastroplasty. The true indication for transthoracic Collis-Nissen repair among cases of paraesophageal hiatal hernia with a short esophagus should be acknowledged more in the era of laparoscopy.     

Acrolein, IL-6 and CRP as markers of silent brain infarction

We found previously that increased levels of polyamine oxidase (PAO) [acetylpolyamine oxidase (AcPAO) plus spermine oxidase (SMO)], and acrolein (CH(2)CHCHO) are good markers of stroke. We then investigated whether silent brain infarction (SBI) can be detected by measuring acrolein, PAO, or other biomarkers. Several biomarkers were measured in the plasma of 53 normal subjects and 44 subjects with SBI. It was found that the levels of protein-conjugated acrolein (PC-Acro), interleukin-6 (IL-6) and C-reactive protein (CRP) were significantly higher in SBI than in normal subjects. PAO was slightly higher in SBI than in normal subjects. Since the probability of SBI was increased with age, values were analyzed including age as a factor. When the combined measurements of PC-Acro, IL-6 and CRP were evaluated together with age using a receiver operating characteristic curve, SBI was indicated with 89% sensitivity and 91% specificity. The results indicate that measurement of PC-Acro together with IL-6 and CRP makes it possible to identify SBI with high sensitivity and specificity.