Reprogramming the immunosuppressive microenvironment of IDH1 wild-type glioblastoma by blocking Wnt signaling between microglia and cancer cells.

The vast majority (>90%) of glioblastoma (GBM) patients belong to the isocitrate dehydrogenase 1 wild type (IDH1WT) group which exhibits a poor prognosis with a median survival of less than 15 months. This study demonstrated numerous immunosuppressive genes as well as ß-catenin gene, pivotal for Wnt/ß-catenin signaling, were upregulated in 206 IDH1WT glioma patients using the Chinese Glioma Genome Atlas (CGGA) database. The increase in microglia with an immunosuppressive phenotype and the overexpression of ß-catenin protein were further verified in IDH1WT GBM patients and IDH1WT GL261 glioma allografts. Subsequently, we found that IDH1WT GL261 cell-derived conditioned medium activated Wnt/ß-catenin signaling in primary microglia and triggered their transition to an immunosuppressive phenotype. Blocking Wnt/ß-catenin signaling not only attenuated microglial polarization to the immunosuppressive subtype but also reactivated immune responses in IDH1WT GBM allografts by simultaneously enhancing cytotoxic CD8+ T cell infiltration and downregulating regulatory T cells. Positron emission tomography imaging demonstrated enhanced proinflammatory activities in IDH1WT GBM allografts after the blockade of Wnt signaling. Finally, gavage administration of a Wnt signaling inhibitor significantly restrained tumor proliferation and improved the survival of model mice bearing IDH1WT GBM allografts. Depletion of CD8+ T cells remarkably abrogated the therapeutic efficacy induced by the Wnt signaling inhibitor. Overall, the present work indicates that the crosstalk between IDH1WT glioma cells and immunosuppressive microglia is important in maintaining the immunosuppressive glioma microenvironment. Blocking Wnt/ß-catenin signaling is a promising complement for IDH1WT GBM treatment by improving the hostile immunosuppressive microenvironment.

Imaging epileptic foci in mouse models via a low-density lipoprotein receptor-related protein-1 targeting strategy.

BACKGROUND: In the setting of drug-resistant epilepsy (DRE), the success of surgery depends on the ability to accurately locate the epileptic foci to be resected or disconnected. However, the epileptic foci in a considerable percentage of the DRE patients cannot be adequately localised. This warrants the need for a reliable imaging strategy to identify the "concealed" epileptic regions. METHODS: Brain specimens from DRE patients and kainate-induced epileptic mouse models were immuno-stained to evaluate the integrity of the blood-brain barrier (BBB). The expression of low-density lipoprotein receptor-related protein-1 (LRP1) in the epileptic region of DRE patients and kainate models was studied by immunofluorescence. A micellar-based LRP1-targeted paramagnetic probe (Gd3+-LP) was developed and its ability to define the epileptic foci was investigated by magnetic resonance imaging (MRI). FINDINGS: The integrity of the BBB in the epileptic region of DRE patients and kainate mouse models were demonstrated. LRP1 expression levels in the epileptic foci of DRE patients and kainate models were 1.70-2.38 and 2.32-3.97 folds higher than in the control brain tissues, respectively. In vivo MRI demonstrated that Gd3+-LP offered 1.68 times higher (P < 0.05) T1-weighted intensity enhancement in the ipsilateral hippocampus of chronic kainite models than the control probe without LRP1 specificity. INTERPRETATION: The expression of LRP1 is up-regulated in vascular endothelium, activated glia in both DRE patients and kainate models. LRP1-targeted imaging strategy may provide an alternative strategy to define the "concealed" epileptic foci by overcoming the intact BBB. FUNDING: This work was supported by the National Natural Science Foundation, Shanghai Science and Technology Committee, Shanghai Municipal Science and Technology, Shanghai Municipal Health and Family Planning Commission and the National Postdoctoral Program for Innovative Talents.

A pH ratiometrically responsive surface enhanced resonance Raman scattering probe for tumor acidic margin delineation and image-guided surgery.

Surgery remains the mainstay for most solid tumor treatments. However, surgeons face challenges in intra-operatively identifying invasive tumor margins due to their infiltrative nature. Incomplete excision usually leads to early recurrence, while aggressive resection may injure adjacent functional tissues. Herein, we report a pH responsive ratiometric surface-enhanced Raman scattering (SERRS) probe that determined physiological pHs with a high sensitivity and tissue penetration depth via an innovative mechanism named spatial orientation induced intramolecular energy transfer (SOIET). Due to the positive correlation between tumor acidity and malignancy, an acidic margin-guided surgery strategy was implemented in live animal models by intra-operatively assessing tissue pH/malignancy of the suspicious tissues in tumor cutting edges. This surgery remarkably extended the survival of animal models and minimized their post-surgical complications, showing promise in precisely identifying invasive tumor boundaries and achieving a balance between maximum tumor debulking and minimal functional impairment.

[Clinical characteristics and management of gestational trophoblastic disease in women aged 50 years or more].

OBJECTIVE: To investigate the clinical characteristics, management and prognosis of gestational trophoblastic disease in women aged 50 years or more. METHODS: Thirty-eight cases of gestational trophoblastic disease in women aged 50 years or more, who were treated in Peking Union Medical College Hospital between 1992 and 2002, were reviewed retrospectively. RESULTS: The median age was 52 years (range from 50 to 58 years). The lesions included 5 hydatidiform moles (13%), 19 invasive moles (50%), 12 choriocarcinomas (32%) and 2 placenta site trophoblastic tumors (5%). All of 38 cases presented with abnormal vaginal bleeding. Twenty-three cases of hydatidiform moles were diagnosed at their first visit to the hospital, and 15 of them received prophylactic chemotherapy, of whom 10 progressed to invasive mole, 3 developed lung metastasis. All of the other 8 cases without prophylactic chemotherapy progressed to malignant changes with metastasis of lung. The use of prophylactic chemotherapy reduced the incidence of subsequent metastasis. All of 38 cases received chemotherapy. Thirty-two cases underwent hysterectomy, complete remission was achieved in 91% of patients; complete remission was achieved in 2 of 6 patients without hysterectomy. CONCLUSIONS: The diagnosis of pregnancy and pregnancy-related disease should be considered in the elderly women presenting with abnormal vaginal bleeding. Once gestational trophoblastic disease in women aged 50 years or more is diagnosed, chemotherapy should be given as soon as possible. Hysterectomy is frequently required to improve the prognosis of gestational trophoblastic disease in the elderly women.

[Floxuridine-containing regime in the treatment of gestational trophoblastic tumor].

OBJECTIVE: To analyse the efficacy of the floxuridine (FUDR)-containing regime (single agent or in combination) in the treatment of gestational trophoblastic tumor. METHODS: Seventy-four patients with gestational trophoblastic tumors (GTT), 47 invasive mole and 27 choriocarcinoma, were treated with FUDR-containing regime. The clinical staging of the disease were: 33 cases of stage I, 3 cases of stage II, 31 cases of stage IIIa, 6 cases of stage IIIb, and 1 case of stage IV. RESULTS: The cure rate of FUDR-containing regime in the treatment of GTT was 91.9% (68 out of 74 cases). Twenty-one out of these 74 patients showed drug resistant to 5-FU-containing or MTX-containing regime and were cured after they changed to the FUDR-containing regime. All 7 patients of advanced stage (> or = III b) got cured. The major adverse event of FUDR-containing regime was myelodepression and gastrointestinal toxicity: III-IV degree granulopenia 26%, III-IV thrombopenia 6.2%, III degree vomiting 57.1%, and III degree diarrhea 4.3%. CONCLUSION: FUDR-containing regime is efficient for the treatment of GTT, even for those with advanced stage or drug-resistant disease.