There are no accurate mass screening methods for early detection of central nervous system (CNS) tumors. Recently, liquid biopsy has received a lot of attention for less-invasive cancer screening. Unlike other cancers, CNS tumors require efforts to find biomarkers due to the blood–brain barrier, which restricts molecular exchange between the parenchyma and blood. Additionally, because a satisfactory way to collect urinary biomarkers is lacking, urine-based liquid biopsy has not been fully investigated despite the fact that it has some advantages compared to blood or cerebrospinal fluid-based biopsy. Here, we have developed a mass-producible and sterilizable nanowire-based device that can extract urinary microRNAs efficiently. Urinary microRNAs from patients with CNS tumors (n = 119) and noncancer individuals (n = 100) were analyzed using a microarray to yield comprehensive microRNA expression profiles. To clarify the origin of urinary microRNAs of patients with CNS tumors, glioblastoma organoids were generated. Glioblastoma organoid-derived differentially expressed microRNAs (DEMs) included 73.4% of the DEMs in urine of patients with parental tumors but included only 3.9% of those in urine of noncancer individuals, which suggested that many CNS tumor-derived microRNAs could be identified in urine directly. We constructed the diagnostic model based on the expression of the selected microRNAs and found that it was able to differentiate patients and noncancer individuals at a sensitivity and specificity of 100 and 97%, respectively, in an independent dataset. Our findings demonstrate that urinary microRNAs extracted with the nanowire device offer a well-fitted strategy for mass screening of CNS tumors.
Abstract Although high-dose methotrexate (HD-MTX)-based chemotherapy, such as rituximab, HD-MTX, procarbazine and vincristine (R-MPV) regimen, has significantly prolonged the survival of patients with primary central nervous system lymphoma (PCNSL), predictive factors for response to R-MPV have not yet been investigated. Then, we investigated the correlation of MYD88 L265P and CD79B Y196 mutations, which are the most frequently found molecular alterations in PCNSL, with prognosis of patients with PCNSL treated with R-MPV. 47 and 21 patients with PCNSL treated with R-MPV and HD-MTX respectively were included, and correlation of their MYD88 and CD79B status with prognosis was analyzed. R-MPV achieved an excellent tumor control rate (61.6% and 69.9% of 5-year progression-free and overall survival rates, respectively). Among the 47 patients, 36 harbored MYD88 L265P or CD79B Y196 mutations. While the MYD88 L265P mutation had no significant effect on survival, patients with CD79B Y196 mutations exhibited prolonged survival (P < 0.05). However, the association of the CD79B Y196 mutation with a better prognosis was not observed in the HD-MTX cohort, which indicated that the CD79B Y196 mutation was a predictive marker for a favorable response to R-MPV. Furthermore, we established an all-in-one rapid genotyping system for these genetic mutations. This system enabled the detection of these genetic mutations in a small amount of biopsy samples within 90 min. In conclusion, we revealed that the CD79B Y196 mutation is associated with a good response to R-MPV, and the rapid and accurate genotyping system for MYD88 L265P and CD79B Y196 mutations that we developed in this study will enable reliable rapid molecular diagnosis and early prediction of response to R-MPV, which might help to determine the best treatment strategy for PCNSL.
Abstract Meningioma is the most frequently occurring intracranial neoplasms in adults. Tumor removal surgery and radiotherapy were the widely accepted standard treatment for meningioma. Most meningioma cases were cured by extended total removal. However, some tumors develop in locations less amenable to resection, resulting in tumor recurrence after incomplete tumor removal followed by radiotherapy. Although several comprehensive studies have revealed frequently found molecular alterations of meningiomas, effective treatment reagents targeting specific molecular alterations have not been identified yet because of limited number of representative research models such as tumor cell lines or animal models of meningiomas. Recently developed 3D culture technologies have led to the development of novel cancer models, termed organoid models, due to their quite high efficiency of establishment. In this study, we established primary organoid culture methods using malignant meningioma cell lines (e.g. HKBMM and IOMM-Lee) and patient-derived meningioma tissues. Using this novel method, we have been able to establish six organoid models (four WHO grade I meningiomas, one WHO grade III one and one solitary fibrous tumor (SFT)) using tumor tissues derived from six consecutive patients with 100% success rate. Histological analyses, whole exome sequencing and copy number analyses revealed that these organoids exhibited consistent histological features and molecular profiling with those of parental tumors. Using public database, we identified upregulated FOXM1 was correlated with increased tumor proliferation. Over-expression of FOXM1 in benign meningioma organoids increased organoid proliferation, while depletion of FOXM1 in malignant ones decreased their proliferation. We revealed that novel organoid model for meningioma enable to shed light on the tumor biology of meningioma.
The precise assessment of both tumor factor and the liver function is of a crucial value the surgical treatment with the greatest guarantee of hepatocellular carcinoma (HCC), as the balance between the operative procedure and the remnant liver function is the most important concern in patients with chronic liver disease. The mortality rate in liver resection has decreased significantly worldwide, according to various surgical criteria for liver resection. Among countries where HCC is prevalent Japan is a leading country in doing liver resection. The Japanese evidence-based guidelines for the surgical treatment for HCC were generated in 2005, and the third revised version is now available. A strict evaluation policy for surgical indications and management based on such evidence helps to minimize the mortality rate in these patients. Herein, we report a series of unique approaches to the perioperative management of liver resection based on the available evidence with the goal of achieving 'no mortality' in liver resection for HCC.
Various strategies exist to reduce graft loss after organ transplantation, including the use of immunosuppressants, steroids, and postoperative antivirotic agents. Combined treatment with an immunosuppressant and a corticosteroid after liver transplantation is the standard protocol to improve graft survival. However, immunosuppressants can have numerous side effects including neurological complications, and steroids can have positive effects on hepatitis C virus (HCV) reinfection (1). Transplantation-related thrombotic microangiopathy (TA-TMA) is a serious complication of organ transplantation that is associated with a variety of transplantation-related factors, including the use of immunosuppressive agents, conditioning regimens, ABO incompatibility, and opportunistic infections (2–4). Immunosuppressants such as cyclosporine A and tacrolimus (FK506) are often linked with the occurrence of TA-TMA (2, 3). Transplantation-related thrombotic microangiopathy typically presents with sudden onset thrombosis and acute organ dysfunction without clinical manifestations. We report on a rapidly progressing case of TA-TMA in a 43-year-old woman with HCV-related cirrhosis, which was strongly associated with the use of an immunosuppressant and anti-HCV preemptive therapy. The patient underwent living- donor liver transplantation because of HCV-related cirrhosis. The patient had a history of three subacute graft rejections, and underwent steroid recycle therapy (1) followed by liver biopsy. She experienced a temporary rise in FK506 level (to >18.0 ng/mL) during the steroid recycle therapy, so the dose was adjusted. She was readmitted 40 days after surgery for additional preemptive therapy for HCV. The treatment regimen comprised 80 ng pegylated interferon (INF)-α2b weekly and 800 mg ribavirin daily. Sudden onset of TA-TMA developed after the start of the therapy. Her blood chemistry measurements abruptly shifted into the abnormal range: her platelet count dropped from 36.5 to 7.8×104 mm3, her serum lactate dehydrogenase level increased from 258 to 688 IU/mL, and her peripheral blood contained more than 1.5% schistocytes. Each parameter reflected the treatment state of TA-TMA. Magnetic-resonance imaging of the brain revealed a hyperintense signal of the left temporal lobe on T2-weighted images, indicating cerebral infarction with hemorrhage, which persisted for 3 weeks. Angiography showed narrowing and irregularity of the middle cerebral artery bilaterally, and a "string of beads" pattern was observed in the posterior cerebral artery bilaterally. A biopsy specimen from the temporal artery failed to show systemic arteritis, and there was no evidence of infection. These findings suggested an FK506-mediated toxic effect of the preemptive therapeutic agent on the cerebral vessels (Fig. 1).FIGURE 1.: The MRI T2-weighted sequence shows hyperintense regions (arrowheads) in the left lateral area at the initial presentation of headache (A). The areas increased bilaterally within 3 weeks (B). The "string of beads" pattern changes resulting from narrowing and irregularity of the cerebral artery were observed bilaterally in angiography (C).A combination of INF-α2b and ribavirin preemptive antiviral therapy is becoming the standard protocol for HCV-related liver transplantation, and might provide long-term benefits in graft survival and delaying the time to HCV recurrence (5, 6). However, INF itself has a number of side effects. It enhances cellular immunity and can lead to the production of autoantibodies, even antiendothelial antibodies. There is a close correlation between the FK506 level and clinical complications related to endothelial cell injury. Thus, the preemptive therapy may have a trigger role in the occurrence of TA-TMA in present case. The ribavirin and steroid therapy was immediately discontinued, and FK506 was replaced with cyclosporine A. Intravenous heparinization (10,000 units/day), prostaglandin E1 (prostandin, 500 μg/day), and the free-radical scavenger (edaravone, 60 mg/day) were continuously administered. Although the disease followed a radical and a repetitive clinical course, the patient recovered as a result of the aggressive early intervention; she made a full recovery with the presence of mild logaphasia and left hemiplasia within 4 weeks. This case highlights the fact that HCV preemptive therapy after steroid-recycle therapy with an immunosuppressant should be performed with caution. Hepatitis C virus-related living-donor liver transplantation is a strong indicator of TA-TMA, and 9 of 26 patients in recent reports had HCV infection (2, 4). We recommend that patients who are receiving preemptive therapy for HCV after high-immunosuppressant trough levels should be closely monitored for the development of TA-TMA, to ensure early diagnosis. Earlier detection and intervention will provide opportunities to improve patient outcomes. Shintaro Yamazaki Tadatoshi Takayama Kazuto Inoue Tokio Higaki Department of Digestive Surgery Nihon University School of Medicine Tokyo, Japan Masatoshi Makuuchi Japanese Red Cross Medical Center Tokyo, Japan
Abstract Background Surgical treatment for hepatocellular carcinoma (HCC) is advancing, but a robust prediction model for survival after resection is not available. The aim of this study was to propose a prognostic grading system for resection of HCC. Methods This was a retrospective, multicentre study of patients who underwent first resection of HCC with curative intent between 2000 and 2007. Patients were divided randomly by a cross-validation method into training and validation sets. Prognostic factors were identified using a Cox proportional hazards model. The predictive model was built by decision-tree analysis to define the resection grades, and subsequently validated. Results A total of 16 931 patients from 795 hospitals were included. In the training set (8465 patients), four surgical grades were classified based on prognosis: grade A1 (1236 patients, 14.6 per cent; single tumour 3 cm or smaller and anatomical R0 resection); grade A2 (3614, 42.7 per cent; single tumour larger than 3 cm, or non-anatomical R0 resection); grade B (2277, 26.9 per cent; multiple tumours, or vascular invasion, and R0 resection); and grade C (1338, 15.8 per cent; multiple tumours with vascular invasion and R0 resection, or R1 resection). Five-year survival rates were 73.9 per cent (hazard ratio (HR) 1.00), 64.7 per cent (HR 1.51, 95 per cent c.i. 1.29 to 1.78), 50.6 per cent (HR 2.53, 2.15 to 2.98), and 34.8 per cent (HR 4.60, 3.90 to 5.42) for grades A1, A2, B, and C respectively. In the validation set (8466 patients), the grades had equivalent reproducibility for both overall and recurrence-free survival (all P < 0.001). Conclusion This grade is used to predict prognosis of patients undergoing resection of HCC.
Abstract Since 2020, tirabrutinib which is a Bruton’s tyrosine kinase (BTK) inhibitor has been available for recurrent or refractory PCNSL cases. The number of studies reporting efficiency and adverse effect of tirabrutinib treatment for recurrent or refractory PCNSL has been limited yet. In this study, we investigated clinical course of eight refractory or recurrent PCNSL cases treated with tirabrutinib in our institute. Eight PCNSL cases treated with tirabrutinib included four recurrent cases and four refractory cases. Five cases obtained CR or PR after 26.8 days administration of tirabrutinib and other two cases also exhibited obvious improvement of clinical symptoms after 23.5 days administration of tirabrutinib. Among three cases exhibiting intraocular lesions, two cases revealed improvement of visual dysfunction and the other case obtained SD status of intraocular lesion. The most frequently found adverse effect was the skin rash. CTCAE grade 2 (n=2) or 3 (n=2) rash was found after mean 16 days or 94 days of tirabrutinib administration, respectively. Two cases with grade 3 rash could start taking the low-dose tirabrutinib after improvement of rash. Althouth one case experienced shingles, no other case experienced serious adverse effects. Although adverse effect of rash was frequently found, we could obtain high response rate of tirabrutinib treatment for recurrent or refractory PCNSL cases. We need to establish quantitative assessment method for analysis of treatment response of tirabrutinib for intraocular lesions.
