Sea-blue histiocytosis in a patient with acute myeloid leukemia with myelodysplasia-related changes harboring isolated trisomy 9: pathognomonic or a coincidence?

Although isolated trisomy 9, a form of chromosome aneuploidy, is rare in acute myeloid leukemia (AML), up to 30 cases of AML involving isolated trisomy 9 have been reported to date. We report the case of a 77-year-old female with AML, in which trisomy 9 was detected as an isolated aberration. In addition, the patient's bone marrow displayed so-called sea-blue histiocytosis. The accumulation of further cases of isolated trisomy 9-harboring AML involving sea-blue histiocytosis is necessary to determine whether the coexistence of these findings is pathognomonic or a coincidence.

Prevalence and associated factors of orphan symptoms in advanced cancer patients: a multicenter observational study.

PURPOSE: The aims of this study were to examine the prevalence of myoclonus, sweating, pruritus, hiccup, and vesical and rectal tenesmus, and to explore associated factors in patients with advanced cancer. METHODS: This multicenter prospective cohort study was conducted in 23 inpatient hospices/palliative care units in Japan from January to December 2017. The prevalence and characteristics of each symptom were assessed on admission and in the 3 days before death. We selected factors that might influence the occurrence of each symptom and investigated the association. RESULTS: A total of 1896 patients were enrolled. The prevalence of orphan symptoms rose from admission to the 3 days before death: myoclonus 1.3 to 5.3% (95% CI 0.9-1.9%/4.3-6.5%), sweating 1.8 to 4.1% (95% CI 1.3-2.6%/3.1-5.1%), hiccup 1.1 to 1.8% (95% CI 0.7-1.7%/1.2-2.6%), and tenesmus 0.7 to 0.9% (0.4-1.2%/0.5-1.5%). Prevalence of pruritus fell from 3.5 to 2.5% (95% CI 2.7-4.4%/1.8-3.4%). Sweating, pruritus, and hiccups persisted throughout the day in nearly half of the patients. Myoclonus was significantly associated with brain tumors, sweating with opioids and antipsychotics, pruritus with liver and biliary tract cancer, cholestasis and severe diabetes, hiccup with male gender, digestive tract obstruction, severe diabetes, and renal failure. Vesical tenesmus was associated with urinary cancer, antipsychotics, and anticholinergics and rectal tenesmus with pelvic cavity cancer. CONCLUSION: We found that orphan symptoms occurred in 0.5-5.0% of patients, increased over time except for pruritus, and persisted in half of the patients.

Clinical Value of Fused PET/MRI for Surgical Planning in Patients With Oral/Oropharyngeal Carcinoma.

OBJECTIVES/HYPOTHESIS: To evaluate the usefulness of fused positron emission tomography (PET)/magnetic resonance (MR) images for surgical planning in patients with oral/oropharyngeal cancer and suspected mandibular invasion. STUDY DESIGN: Individual cohort study. METHODS: Eleven of 17 patients with suspected mandibular invasion of squamous cell carcinoma of the lower gingiva, oropharynx, and buccal mucosa who underwent 18F-fluorodeoxyglucose (FDG) PET/computed tomography (CT) and contrast-enhanced MR imaging (MRI) and had fused PET/MR images were enrolled in this study. The area for surgical resection was determined based on the fused images. The usefulness of these images was confirmed by comparing them with the histopathologic findings in the resected tumors. RESULTS: Histopathologic evaluation of the surgical specimens revealed that nine of the 11 patients had invasion into the mandible and/or medial pterygoid muscle. All patients had a negative surgical margin. The sensitivity and specificity for detection of mandibular/medial pterygoid muscle invasion was 100%/40% and 83%/100% by fused PET/MRI, respectively, and 100%/20% and 100%/60% by PET/CT, respectively. Interobserver reproducibility between two radiologists/nuclear medicine physicians and two head and neck surgeons showed that the only statistically significant κ values were for PET/MRI. CONCLUSIONS: PET/MRI can be easily understood by head and neck surgeons, who are not diagnostic imaging professionals, and can be used when planning the area to be surgically resected in patients with oral/oropharyngeal cancer and clinically suspected mandibular invasion. Considering the expense of a hybrid PET/MRI system, creation of a fused PET/MR image would provide a reasonable and reliable tool for clinical use in these patients. LEVEL OF EVIDENCE: 2b Laryngoscope, 130:367-374, 2020.

An isolated der(1;21)(q10;q10) translocation in a patient with myelodysplastic syndrome: a case report.

Whole-arm translocations are relatively rare among hematological malignancies. There are a few reports on myeloid malignancies harboring der(1;21)(q10;q10). A 65-year-old male was referred to our hospital due to squamous cell carcinoma of the lung. Pembrolizumab monotherapy resulted in progression, and so chemotherapy involving nab-paclitaxel and carboplatin was administered thereafter. The patient developed cytopenia, and his bone marrow exhibited dysplasia. Chromosomal analysis revealed a whole-arm translocation, der(1;21)(q10;q10). Thus, the patient was diagnosed with myelodysplastic syndrome. The der(1;21)(q10;q10) translocation is a rare variant of the der(1;7)(q10;p10) translocation, which is an adverse prognostic factor for myeloid neoplasms. Clarifying the clinical features of myeloid neoplasms in patients with der(1;21)(q10;q10) would facilitate the elucidation of their tumorigenic mechanisms.

Image quality and variability for routine diagnostic FDG-PET scans in a Japanese community hospital: current status and possibility of improvement.

PURPOSE: In Japan, commercially delivered FDG is manufactured in three batches per day at fixed constant activity and distributed in vials. Consequently, the amount of activity administered to the patient varies depending on the timing of injection. We evaluated a method for adjusting the scan time according to the body mass index (BMI) to obtain equivalent image quality for every patient. METHODS: We examined a total of 301 routine clinical oncology PET scans using commercially delivered FDG. The relation between the injected activity and the noise equivalent count per scan length (NECpatient) was evaluated as a marker of image quality; its association with BMI was also examined. RESULTS: The injected activity and NECpatient exhibited large variations (230.4 ± 55.8 MBq and 19.9 ± 2.9 Mcounts/m). There was a weak correlation between the injected activity and NECpatient (r ~ 0.3) for thin patients (BMI < 21 kg/m(2)), but no correlation for patients with higher BMIs. However, a significant correlation was found between BMI and NECpatient (p < 0.0001). CONCLUSION: In a community hospital using commercially delivered FDG, it is possible to reduce the variability of the NECpatient and obtain uniform image quality by changing the scan time as a function of patient BMI, even with uncontrollable injected activity.

Elevated cell invasion in a tumor sphere culture of RSV-M mouse glioma cells.

Cancer stem cells (CSCs) are the sole population possessing high self-renewal activity in tumors, with their existence affecting tumor recurrence. However, the invasive activity of CSCs has yet to be fully understood. In this article, we established a tumor sphere culture of RSV-M mouse glioma cells (RSV-M-TS) and evaluated their migration and invasion activities. Histological analysis of a tumor formed by cranial injection of the RSV-M-TS cells showed highly invasive properties and similarities with human malignant glioma tissues. When the migration activity of both RSV-M and RSV-M-TS cells were compared by intracranial injection, rapid migration of RSV-M-TS cells was observed. To confirm the invasive capabilities of RSV-M-TS cells, a three-dimensional collagen invasion assay was performed in vitro using RSV-M, RSV-M-TS, and RSV-M-TS cells cultured with medium containing serum. RSV-M and RSV-M-TS cultured with medium containing serum for 8 days indicated low migration activity, while moderate invasion activity was observed in RSV-M-TS cells. This activity was further enhanced by incubation with medium containing serum overnight. To identify the genes involved in this invasion activity, we performed quantitative polymerase chain reaction (PCR) array analysis of RSV-M and RSV-M-TS cells. Of 84 cancer metastasis-related genes, up-regulation was observed in 24 genes, while 4 genes appeared to be down-regulated in RSV-M-TS cells. These results suggest that the enhanced invasive activity of glioma sphere cells correlates with a number of tumor metastasis-related genes and plays a role in the dissemination and invasion of glioma cells.

A modified combined transseptal/transnasal binostril approach for pituitary lesions in patients with a narrow nasal space: technical note.

We describe a modification of the combined transseptal/transnasal binostril approach using a two-surgeon, four-handed technique (modified Stamm's approach) for pituitary lesions in patients with narrow nasal spaces. This approach comprises of a transseptal route through one nostril and a transnasal route without harvesting a pedicled nasoseptal flap (NSF) through the other. On the transseptal side, the nasal septum was removed using an endoscopic septoplasty technique. On the transnasal side, the mucosa containing the septal branch of the sphenopalatine artery over the face of the sphenoid and nasal septum was preserved for harvesting the NSF if an intraoperative cerebrospinal fluid leak was encountered. This approach was performed in six patients with pituitary lesions, including four non-functioning macroadenomas, one growth hormone-producing macroadenoma, and one Rathke's cleft cyst, all of which were associated with a severe deviation of the nasal septum and/or narrow nasal space. The meticulous and comfortable manipulation of an endoscope and instruments were achieved in all six patients without surgical complications. Our findings, although obtained in a limited number of cases, suggest that the modified Stamm's approach may be useful for selected patients, particularly those with a severe deviation of the nasal septum, without considerable damage to the nasal passages.

[A case of small bowel cancer with positive peritoneal cytology and five-year recurrence-free survival].

Small bowel cancer is frequently detected at an advanced stage and its prognosis is poor. We report on a patient with small bowel cancer with positive peritoneal cytology who survived for 5 years without recurrence after surgery.The case involved a 73-year-old woman who had undergone partial resection of the small intestine and lymphadenectomy for a small bowel tumor with obstruction. Pathological examination confirmed papillary adenocarcinoma with partial serosal invasion. Ascites cytology indicated a class V tumor. Adjuvant chemotherapy with TS-1 was administered for 20 months, and the patient has survived without evidence of disease for over 5 years.In this case, it is possible that TS-1 chemotherapy was effective for prevention against small bowel cancer recurrence.Furthermore , peritoneal cytology in patients with small bowel cancer should be evaluated as a predictor of prognosis.

Autonomous cure of damaged human intestinal epithelial cells by TLR2 and TLR4-dependent production of IL-22 in response to Spirulina polysaccharides.

In order to analyze the damage of human epithelial cells, we used human quasi-normal FPCK-1-1 cells derived from a colonic polyp in a patient with familial adenomatous polyposis as a monolayer, which is co-cultured with peptidoglycan (PGN)-stimulated THP-1 cells. Co-cultured FPCK-1-1 cells showed a decreased transepithelial electrical resistance (TER) and the lower level of claudin-2. When Spirulina complex polysaccharides were added one day before the start of the co-culture, there was no decrease of TER and claudin-2 (early phase damage). In contrast, when Spirulina complex polysaccharides were added to FPCK-1-1 cells after the level of TER had decreased, there was no recovery at the level of claudin-2, though the TER level recovered (late phase damage). The mucosa reconstitution is suggested to be involved in the recovery from the damaged status. Interestingly, autonomous recovery of FPCK-1-1 cells from both the early and late phase damage requires the production of IL-22, because anti-IL-22 antibodies inhibited recovery in these cases. Antibodies against either TLR2 or TLR4 inhibited the production of IL-22 from FPCK-1-1 colon epithelial cells, suggesting that signals through TLR2 and TLR4 are necessary for autonomous recovery of FPCK-1-1 colon epithelial cells by producing IL-22. In conclusion, we have established a useful model for the study of intestinal damage and recovery using human colon epithelial cells and our data suggest that damage to human colon epithelial cells can, at least in part, be recovered by the autonomous production of IL-22 in response to Spirulina complex polysaccharides.

Preoperative acetazolamide SPECT is useful for predicting outcome of shunt operation in idiopathic normal pressure hydrocephalus patients.

PURPOSE OF THE REPORT: Good outcome of shunt surgery for idiopathic normal pressure hydrocephalus (iNPH) patients are highly dependent on accurate preoperative assessments. Acetazolamide ethylcysteinate-dimer-single photon emission computer tomography (SPECT) was applied to iNPH patients for more exact preoperative evaluation. PATIENTS AND METHODS: Sixty-five patients were categorized into 3 groups: group I (normals, n = 30), group II (with ventriculomegaly due to age-relating changes, n = 10), and group III (who underwent shunt surgery based on the diagnosis of iNPH, n = 25). Acetazolamide SPECT was performed in all patients, and mini-mental state examination (MMSE) was performed before and 1 month after the surgery in group III. RESULTS: Acetazolamide SPECT study demonstrated normal increase of cerebral blood flow (CBF, more than 40%) in groups I and II. Group III was classified into 2 subgroups on the examination; a mean increasing percentage (%increase) of CBF was less than 20% in group IIIa and more than 40% in group IIIb. One month after the surgery, acetazolamide SPECT showed normal %increase of CBF in IIIa, and the increase in postoperative MMSE score was significantly greater in group IIIa than IIIb (P < 0.05). In iNPH patients, less than 20% increase in preoperative acetazolamide SPECT predicted improvement of MMSE score with 100% sensitivity and 60% specificity. CONCLUSIONS: Poor %increase of CBF by acetazolamide implies a low capacity for vasodilation in the brain due to compression and stretching by ventriculomegaly. Acetazolamide SPECT study is not an absolute examination but one of the valuable supplementary objective examinations to determine the surgical indication in iNPH-suspected patients.

Evaluation of two- and three-dimensional visualization for endoscopic endonasal surgery using a novel stereoendoscopic system in a novice: a comparison on a dry laboratory model.

BACKGROUND: Three-dimensional (3-D) stereoscopic vision is theoretically superior to two-dimensional (2-D) vision in endoscopic endonasal surgery. However, only few reports have quantitatively compared endoscopic performance under the two visual conditions. We introduced a newly designed stereoendoscopic system with a "dual-lens and single camera" for endoscopic endonasal surgery and objectively compared the performances under 3-D and high-definition 2-D visualizations on a dry laboratory model. METHODS: Thirty subjects without experience performing endoscopic surgery, computer-simulated training or any 3-D video system were recruited and divided into two groups (Group A and Group B) for performing two different tasks. The novel 4.7-mm-diameter stereoendoscope provided high-definition (HD) images. In Task 1, Group A started the task under the 3-D condition followed by the 2-D condition, and Group B vice versa. In Task 2, Group A started the task under the 2-D condition followed by the 3-D condition, and Group B vice versa. The performance accuracy and speed under the two visual conditions were analyzed. RESULTS: Significant improvement in performance accuracy and speed was seen under 3-D conditions in the both "3-D first" and "2-D first" subgroups during both tasks (P < .001). Regardless of order, the inaccuracy rate and performance time under 3-D conditions was significantly lower than that under 2-D conditions in each subject. CONCLUSIONS: We demonstrated the advantage of 3-D visualization over 2-D visualization for inexperienced subjects. Further quantitative clinical studies are required to confirm whether stereoendoscopy actually provides benefits in clinical settings.

Regulatory effects of Spirulina complex polysaccharides on growth of murine RSV-M glioma cells through Toll-like receptor 4.

This study is the first to report that Spirulina complex polysaccharides (CPS) suppress glioma growth by down-regulating angiogenesis via a Toll-like receptor 4 signal. Murine RSV-M glioma cells were implanted s.c. into C3H/HeN mice and TLR4 mutant C3H/HeJ mice. Treatment with either Spirulina CPS or Escherichia coli (E. coli) lipopolysaccharides (LPS) strongly suppressed RSV-M glioma cell growth in C3H/HeN, but not C3H/HeJ, mice. Glioma cells stimulated production of interleukin (IL)-17 in both C3H/HeN and C3H/HeJ tumor-bearing mice. Treatment with E. coli LPS induced much greater IL-17 production in tumor-bearing C3H/HeN mice than in tumor-bearing C3H/HeJ mice. In C3H/HeN mice, treatment with Spirulina CPS suppressed growth of re-transplanted glioma; however, treatment with E. coli LPS did not, suggesting that Spirulina CPS enhance the immune response. Administration of anti-cluster of differentiation (CD)8, anti-CD4, anti-CD8 antibodies, and anti-asialo GM1 antibodies enhanced tumor growth, suggesting that T cells and natural killer cells or macrophages are involved in suppression of tumor growth by Spirulina CPS. Although anti-interferon-γ antibodies had no effect on glioma cell growth, anti-IL-17 antibodies administered four days after tumor transplantation suppressed growth similarly to treatment with Spirulina CPS. Less angiogenesis was observed in gliomas from Spirulina CPS-treated mice than in those from saline- or E. coli LPS-treated mice. These findings suggest that, in C3H/HeN mice, Spirulina CPS antagonize glioma cell growth by down-regulating angiogenesis, and that this down-regulation is mediated in part by regulating IL-17 production.

Involvement of Akt/NF-κB pathway in antitumor effects of parthenolide on glioblastoma cells in vitro and in vivo.

BACKGROUND: Glioblastoma is the most common and most aggressive form of malignant glioma and is very difficult to treat. Controlling tumour cell invasion and angiogenesis is essential to improve the prognosis of glioblastoma patients. Since constitutive activation of nuclear factor-κB (NF-κB) is necessary for tumour progression, NF-κB may be an important pharmacological target for this disease. Our study aimed to evaluate the antitumour effects of parthenolide, a NF-κB inhibitor, in two human glioblastoma cell lines (U87MG and U373) and in glioblastoma xenografts. Furthermore, we aimed to investigate the molecular mechanisms underlying these effects. METHODS: The anti-invasive and anti-angiogenic effects of parthenolide were analysed using in vitro invasion and angiogenesis assays. Parthenolide-induced growth inhibition of glioblastoma cells in vitro was determined using the MTT (methyl thiazolyl tetrazolium) assay. In addition, the effect of parthenolide on orthotropic implantation in vivo was evaluated using an intracerebral human glioblastoma xenograft model. RESULTS: We found that parthenolide suppresses proliferation, invasion, and tumour- induced angiogenesis of glioblastoma cells. Molecular studies demonstrated that parthenolide suppresses gene and protein expression of angiogenic factors. Furthermore, parthenolide reduced Akt phosphorylation and activated mitochondrial signalling, suggesting that the antitumour function of parthenolide may be mediated not only by the inhibition of NF-κB but also by the inhibition of Akt signalling and the activation of apoptotic proteins. Parthenolide suppressed neovascularity and tumour growth in glioblastoma xenografts. CONCLUSION: The present study identified parthenolide as a new therapeutic agent for glioblastomas.

Whole-body distribution and radiation dosimetry of [11C]telmisartan as a biomarker for hepatic organic anion transporting polypeptide (OATP) 1B3.

INTRODUCTION: Telmisartan, a nonpeptide angiotensin II AT1 receptor antagonist used as an antihypertensive drug, is specifically taken up by the liver through the OATP1B3. PET imaging with [(11)C]telmisartan is expected to provide information about the whole body pharmacokinetics of telmisartan as well as its transport property by OATP1B3. The purpose of the study was to determine the biodistribution and radiation dosimetry of [(11)C]telmisartan in humans. METHODS: Biodistribution of [(11)C]telmisartan was measured in three rats and six healthy male human volunteers. In the rat study, a dynamic emission scan was performed for 90 min. In the human study, dynamic whole-body PET images were acquired after intravenous injection of [(11)C]telmisartan. ROIs were defined for source organs on the PET images to measure time-course of [(11)C]telmisartan uptake as percentage injected dose and the number of disintegration for each organ. Radiation dosimetry was calculated with OLINDA/EXM. RESULTS: In the rat study, most radioactivity was rapidly taken up by the liver and part of it was excreted into the biliary tract and intestine. Extrapolating from the rat data, the effective dose for the adult human being was estimated to be 3.65±0.01 microSv/MBq (n=3). In the human study, most of the tracer was taken up by the liver as well, although not as rapidly as in the rat. The activity in the gall bladder and intestine increased gradually. The effective dose for the adult human being was 4.24±0.09 microSv/MBq (n=6). CONCLUSIONS: [(11)C]Telmisartan is a safe PET tracer with a dosimetry profile comparable to other common (11)C PET tracers.

Identification and functional characterization of glioma-specific promoters and their application in suicide gene therapy.

Suicide gene therapy has been shown to be effective in inducing tumor regression. In this study, a human brain tumor-specific promoter was identified and used to develop transcriptionally targeted gene therapy. We searched for genes with brain tumor-specific expression. By in silico and reverse-transcription polymerase chain reaction screening, MAGE-A3 and SSX4 were found to be expressed in a tumor-specific manner. SSX4 gene promoter activity was high in human brain tumor cells but not in normal human astrocyte cells, whereas the MAGE-A3 promoter showed activity in both tumor and normal cells. A retrovirus vector carrying a suicide gene, the herpes simplex virus thymidine kinase gene controlled by the SSX4 promoter, was constructed to evaluate the efficacy of the promoter in tumor-specific gene therapy. Glioma and human telomerase catalytic subunit-immortalized fibroblast BJ-5ta cell lines transduced with retrovirus vectors were assayed for killing activity by ganciclovir. Glioma cell lines were effectively killed by ganciclovir in a concentration-dependent manner, whereas BJ-5ta cells were not. By contrast, MAGE-A3 promoter failed to induce cytotoxicity in a brain tumor-specific manner. In addition, mouse glioma RSV-M cells transduced with retrovirus vector also showed suppressed tumor formation activity in syngeneic mice in response to ganciclovir administration. Therefore, the SSX4 promoter is a candidate for brain tumor-specific gene therapy and supports the efficacy and safety of suicide gene therapy for malignant brain tumors.

HA1077, a Rho kinase inhibitor, suppresses glioma-induced angiogenesis by targeting the Rho-ROCK and the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK) signal pathways.

Malignant gliomas are characterized by high invasive potential and strong angiogenic ability. Constitutive activation of Rho and its downstream target Rho-kinase are crucial for tumor progression. We investigated the effect of the Rho-kinase inhibitor HA1077 on tumor-induced angiogenesis of malignant glioma cells and explored the molecular mechanisms underlying the effect of HA1077. Here, we demonstrated that HA1077 suppressed tube formation of endothelial cells in human umbilical vein endothelial cell (HUVEC)-glioma cell co-culture assay. Western blot, RT-PCR, ELISA and zymography demonstrated that HA1077 suppressed gene and protein expressions of vascular endothelial growth factor (VEGF), matrix metalloproteinase (MMP)-2 and MMP-9 in glioma cells. Furthermore, HA1077 attenuated the phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and the DNA binding activity of activator protein-1, a key downstream transcriptional factor of ERK1/2. HA1077 also suppressed the migration of HUVEC in vitro. Thus, it is suggested that the anti-angiogenic effect of HA1077 may be due to the combination of ROCK inhibition and mitogen-activated protein kinase kinase (MEK)/ERK pathway inhibition. Moreover, an in vivo intracerebral human glioma cell xenograft mouse model demonstrated that HA1077 suppressed neovascularity and tumor growth. The results of the present study suggest that HA1077 has a therapeutic potential as an anti-angiogenic agent against malignant gliomas.

A cystic meningioma misdiagnosed as malignant glioma by radiologic and intraoperative histological examinations.

Cystic meningiomas are radiologically difficult to differentiate from malignant brain tumors, particularly when the tumors are intraparenchymally located. In such cases, a surgical strategy relies on intraoperative histological diagnosis. A 60-year-old man had a tumor with multiple cysts in the left parietal lobe that was diagnosed radiologically as malignant glioma. In operative findings, there was no dural attachment of the tumor, and the border between the tumor and normal brain tissue was unclear. Intraoperative histological examination supported the diagnosis of malignant glioma based on a high cellularity and an existence of a multinuclear giant cell in the tumor tissue. We finished the surgery with partial tumor resection; however, postoperative histological diagnosis of the tumor was a typical meningothelial meningioma showing characteristic whorl formations, and in conclusion, a definite diagnosis of the tumor was an intraparenchymal cystic meningioma. In further histological investigations, the tumor tissue around cysts exhibited significantly different features from meningothelial meningioma, demonstrating small lymphocytes and histiocytes with a large nucleus, which resembled intraoperative histological findings. We deliberated that the removal of the tumor tissue from the degenerated portion for intraoperative histological examination might lead to the misdiagnosis of malignant glioma. Operative strategy is strongly influenced by intraoperative histological diagnosis. Therefore, surgeons are obliged to facilitate more precise intraoperative histological examinations by obtaining sufficient tissue from different parts of the tumor.

Anti-invasive and antiangiogenic effects of MMI-166 on malignant glioma cells.

BACKGROUND: The constitutive overexpression of matrix metalloproteinases (MMPs) is frequently observed in malignant tumours. In particular, MMP-2 and MMP-9 have been reported to be closely associated with invasion and angiogenesis in malignant gliomas. Our study aimed to evaluate the antitumour effects of MMI-166 (Nalpha-[4-(2-Phenyl-2H- tetrazole-5-yl) phenyl sulfonyl]-D-tryptophan), a third generation MMP inhibitor, on three human glioma cell lines (T98G, U87MG, and ONS12) in vitro and in vivo. METHODS: The effects of MMI-166 on the gelatinolytic activity was analysed by gelatine zymography. The anti-invasive effect of MMI-166 was analysed by an in vitro invasion assay. An in vitro angiogenesis assay was also performed. In vitro growth inhibition of glioma cells by MMI-166 was determined by the MTT assay. The effect of MMI-166 on an orthotropic implantation model using athymic mice was also evaluated. RESULTS: Gelatine zymography revealed that MMP-2 and MMP-9 activities were suppressed by MMI-166. The invasion of glioma cells was suppressed by MMI-166. The angiogenesis assay showed that MMI-166 had a suppressive effect on glioma cell-induced angiogenesis. However, MMI-166 did not suppress glioma cell proliferation in the MTT assay. In vivo, MMI-166 suppressed tumour growth in athymic mice implanted orthotropically with T98G cells and showed an inhibitory effect on tumour-induced angiogenesis and tumour growth. This is the first report of the effect of a third generation MMP inhibitor on malignant glioma cells. CONCLUSIONS: These results suggest that MMI-166 may have potentially suppressive effects on the invasion and angiogenesis of malignant gliomas.

Preoperative surgical approach planning for metastatic pituitary stalk tumor using multimodal fusion imaging in a neuronavigation system--case report.

A 72-year-old woman presented with a metastatic brain tumor around the pituitary stalk compressing the chiasm anteriorly and upward. After tumor resection by a left pterional approach failed, a three-dimensional (3D) image of the area of interest was reconstructed using the Vecter Vision navigation system and iPlan Cranial planning software version 2.5. Preoperative 3D computed tomography and magnetic resonance imaging data were fused to demonstrate the anatomical relationship between vessels, nerves, and tumor. Clearer demonstration of the optic nerves utilized thin slice axial and sagittal views along the nerves. The 3D reconstructed image demonstrated the spatial relationship of the tumor and surrounding tissue, and suggested the necessity of a right orbitozygomatic approach to create adequate working space for tumor resection. Second surgery according to this preoperative planning was successful. High quality multimodal fusion images in a navigation system has distinct advantages in preoperative assessment of essential structural relationships allowing adequate exposure of certain lesions and surrounding structures in individual patients by defining specific surgical approaches.

Enhanced expression of cancer testis antigen genes in glioma stem cells.

Cancer stem cells are an important target for effective therapy, since they show tumorigenicity, chemoresistance, and radioresistance. We isolated cancer stem cells from glioma cell lines and tissues and examined the expression of cancer testis antigen (CTA) genes as potential target molecules for cancer vaccine therapy. CTA genes were highly and frequently expressed in cancer stem cells compared with differentiated cells. In addition, histone acetylation levels in the promoter regions of CTA genes were high in cancer stem cells and low in differentiated cells, while DNA methylation analysis of the promoter regions revealed hypomethylation in cancer stem cells. This epigenetic difference between cells leads to heterogeneous expression of CTA genes in the tumor mass, which consists of cells at various levels of differentiation. Moreover, the expression level of HLA class I antigens was not affected by the differentiation status, suggesting that CTA genes may present as surface antigens in cancer stem cells. Taken together, these findings suggest that CTA genes may be attractive candidates for targeted vaccine therapy against cancer stem cells in glioma patients.