Genomic medicine advances for brain tumors.

Cancer genome profiling has revealed important genetic alterations that serve as prognostic indicators and guides for treatment decisions, enabling precision medicine. The shift to molecular diagnosis of brain tumors, as reflected in the 2021 World Health Organization Classification of Tumors of the Central Nervous System, is a crucial role for treatment decision-making. This review discusses the significance and role of cancer genome profiling in precision medicine for malignant brain tumors, particularly gliomas. Furthermore, we explore the progress in cancer genome analysis, focusing on cancer gene panel testing, integration of genomic information in brain tumor classification, and hereditary tumors. Additionally, we discuss the transformative effect of genomic medicine on early detection, risk assessment, and precision medicine strategies. The tumor mutational burden in brain tumors is considered low, but the application of molecular targeted drugs, such as isocitrate dehydrogenase inhibitors, v-raf murine sarcoma viral oncogene homolog B1 inhibitors, fibroblast growth factor receptor inhibitors, neurotrophic tyrosine receptor kinase, mechanistic target of rapamycin inhibitors, and anti-programmed death receptor-1 antibody drugs are promising for glioma treatment. We also discuss the future prospects of molecular targeted drugs.

Mesenchymal stem cells as therapeutic vehicles for glioma.

Glioma is a disease with a poor prognosis despite the availability of multimodality treatments, and the development of novel therapies is urgently needed. Challenges in glioma treatment include the difficulty for drugs to cross the blood-brain barrier when administered systemically and poor drug diffusion when administered locally. Mesenchymal stem cells exhibit advantages for glioma therapy because of their ability to pass through the blood-brain barrier and migrate to tumor cells and their tolerance to the immune system. Therefore, mesenchymal stem cells have been explored as vehicles for various therapeutic agents for glioma treatment. Mesenchymal stem cells loaded with chemotherapeutic drugs show improved penetration and tumor accumulation. For gene therapy, mesenchymal stem cells can be used as vehicles for suicide genes, the so-called gene-directed enzyme prodrug therapy. Mesenchymal stem cell-based oncolytic viral therapies have been attempted in recent years to enhance the efficacy of infection against the tumor, viral replication, and distribution of viral particles. Many uncertainties remain regarding the function and behavior of mesenchymal stem cells in gliomas. However, strategies to increase mesenchymal stem cell migration to gliomas may improve the delivery of therapeutic agents and enhance their anti-tumor effects, representing promising potential for patient treatment.

Midline invasion predicts poor prognosis in diffuse hemispheric glioma, H3 G34-mutant: an individual participant data review.

INTRODUCTION: Diffuse hemispheric glioma, H3 G34-mutant (DHGs), is a newly categorized tumor in pediatric-type diffuse high-grade gliomas, World Health Organization grade 4, with a poor prognosis. Although prognostic factors associated with genetic abnormalities have been reported, few reports have examined the clinical presentation of DHGs, especially from the viewpoint of imaging findings. In this study, we investigated the relationship between clinical factors, including imaging findings, and prognosis in patients with DHGs. METHODS: We searched Medline through the PubMed database using two search terms: "G34" and "glioma", between 1 April 2012 and 1 July 2023. We retrieved articles that described imaging findings and overall survival (OS), and added one DHG case from our institution. We defined midline invasion (MI) as invasion to the contralateral cerebrum, brainstem, corpus callosum, thalamus, and basal ganglia on magnetic resonance imaging. The primary outcome was 12-month survival, estimated using Kaplan-Meier curves and logistic regression. RESULTS: A total of 96 patients were included in this study. The median age was 22 years, and the proportion of male patients was 48.4%. Lesions were most frequently located in the frontal lobe (52.6%). MI was positive in 39.6% of all patients. The median OS was 14.4 months. Univariate logistic regression analysis revealed that OS was significantly worse in the MI-positive group compared with the MI-negative group. Multivariate logistic regression analysis revealed that MI was an independent prognostic factor in DHGs. CONCLUSIONS: In this study, MI-positive cases had a worse prognosis compared with MI-negative cases. PREVIOUS PRESENTATIONS: No portion of this study has been presented or published previously.

[Innovations in Combined Surgery of Endoscopic Transsphenoidal Surgery and Craniotomy].

Combined endoscopic transsphenoidal surgery and craniotomy may be useful for tumors extending into the suprasellar region or ventricles and for tumors extending simultaneously into the nasal sinuses and intracranial space. This method allows two surgeons to share the surgical field while compensating for each other's blind spots and allows for safe tumor removal by separating the normal structure from the tumor and protecting the normal structure. Simultaneous combined endoscopic transsphenoidal surgery and craniotomy require a lot of equipment; however, by devising the layout of the equipment in the operating room, the staff involved in the surgery can perform their roles more effectively. However, this method results in extensive dural and cranial defects, and prevention of cerebrospinal fluid leakage and perioperative surgical site infection is essential. Skull base reconstruction using autologous tissues and medical materials at appropriate locations can reduce the risk of postoperative cerebrospinal fluid leakage and surgical site infection. Furthermore, multilayered reconstruction using restorative medical materials eliminates the need for autologous tissue, is minimally invasive, shortens the operative time, reduces postoperative stress, and shortens the length of hospital stay. A combination of endoscopic transsphenoidal surgery and craniotomy will contribute to the improvement of the safety of highly difficult tumorectomies under a reliable skull base reconstruction method.

Multidrug chemotherapy, whole-brain radiation and cytarabine therapy for primary central nervous system lymphoma in elderly patients with dose modification based on geriatric assessment: study protocol for a phase II, multicentre, non-randomised study.

INTRODUCTION: Multidrug chemoimmunotherapy with rituximab, high-dose methotrexate, procarbazine and vincristine (R-MPV) is a standard therapy for younger patients with primary central nervous system lymphoma (PCNSL); however, prospective data regarding its use in elderly patients are lacking. This multi-institutional, non-randomised, phase II trial will assess the efficacy and safety of R-MPV and high-dose cytarabine (HD-AraC) for geriatric patients with newly diagnosed PCNSL. METHODS AND ANALYSIS: Forty-five elderly patients will be included. If R-MPV does not achieve complete response, the patients will undergo reduced-dose, whole-brain radiotherapy comprising 23.4 Gy/13 fractions, followed by local boost radiotherapy comprising 21.6 Gy/12 fractions. After achieving complete response using R-MPV with or without radiotherapy, the patients will undergo two courses of HD-AraC. All patients will undergo baseline geriatric 8 (G8) assessment before HD-AraC and after three, five and seven R-MPV courses. Patients with screening scores of ≥14 points that decrease to <14 points during subsequent treatment, or those with screening scores <14 points that decrease from the baseline during subsequent treatment are considered unfit for R-MPV/HD-AraC. The primary endpoint is overall survival, and the secondary endpoints are progression-free survival, treatment failure-free survival and frequency of adverse events. The results will guide a later phase III trial and provide information about the utility of a geriatric assessment for defining chemotherapy ineligibility. ETHICS AND DISSEMINATION: This study complies with the latest Declaration of Helsinki. Written informed consent will be obtained. All participants can quit the study without penalty or impact on treatment. The protocol for the study, statistical analysis plan and informed consent form have been approved by the Certified Review Board at Hiroshima University (CRB6180006) (approval number: CRB2018-0011). The study is ongoing within nine tertiary and two secondary hospitals in Japan. The findings of this trial will be disseminated through national and international presentations and peer-reviewed publications. TRIAL REGISTRATION: jRCTs061180093.

Potent bystander effect and tumor tropism in suicide gene therapy using stem cells from human exfoliated deciduous teeth.

Herpes simplex virus thymidine kinase (HSVTK)/ganciclovir (GCV) suicide gene therapy has a long history of treating malignant gliomas. Recently, stem cells from human exfoliated deciduous teeth (SHED), which are collected from deciduous teeth and have excellent harvestability, ethical aspects, and self-renewal, have been attracting attention mainly in the field of gene therapy. In the present study, we assessed SHED as a novel cellular vehicle for suicide gene therapy in malignant gliomas, as we have previously demonstrated with various cell types. SHED was transduced with the HSVTK gene (SHEDTK). In vitro experiments showed a significant bystander effect between SHEDTK and glioma cell lines in coculture. Furthermore, apoptotic changes caused by caspase 3/7 activation were simultaneously observed in SHEDTK and glioma cells. Mice implanted with a mixture of U87 and SHEDTK and treated with intraperitoneal GCV survived for longer than 100 days. Additionally, tumors in treatment model mice were significantly reduced in size during the treatment period. SHEDTK implanted at the contralateral hemisphere migrated toward the tumor crossing the corpus callosum. These results suggested that SHEDTK-based suicide gene therapy has potent tumor tropism and a bystander-killing effect, potentially offering a new promising therapeutic modality for malignant gliomas.

[Prevention of and Countermeasures for Surgical Site Infection in the Field of Skull Base Surgery].

In neurosurgery, perioperative surgical site infection(SSI)is associated with complicated postoperative management, prolonged hospital stay, and patient stress. In this article, we review SSI in the field of skull base surgery, including endoscopic endonasal surgery, and discuss ways to prevent SSI. In a craniotomy, in which the frontal sinus is revealed, prevention of cerebrospinal fluid(CSF)leakage by reliable repair of the dura and frontal sinus reduces SSI. In addition, prevention of postoperative CSF leakage by reliable skull base reconstruction in endoscopic endonasal surgery contributes to the prevention of SSI. Prophylactic antibiotics are often reported to be useful, and cephalosporin or sulbactam/ampicillin intravenous injections are generally used. There are insufficient data to recommend lumbar drainage for the management of SSI and postoperative CSF leak. Skull base surgery is often a clean-contaminated surgery, and serious complications can be prevented by proper understanding and performance of the appropriate method as required. However, no studies with a high level of evidence on SSI in the field of skull base surgery exist. New large randomized controlled trials are expected to evaluate the efficacy of prophylactic antibiotics in skull base surgery.

Efficacy of HSV-TK/GCV system suicide gene therapy using SHED expressing modified HSV-TK against lung cancer brain metastases.

Lung cancer is one of the most common cancers, and the number of patients with intracranial metastases is increasing. Previously, we developed an enzyme prodrug suicide gene therapy based on the herpes simplex virus thymidine kinase (HSV-TK)/ganciclovir (GCV) system using various mesenchymal stem cells to induce apoptosis in malignant gliomas through bystander killing effects. Here, we describe stem cells from human exfoliated deciduous teeth (SHED) as gene vehicles of the TK/GCV system against a brain metastasis model of non-small cell lung cancer (NSCLC). We introduced the A168H mutant TK (TKA168H) into SHED to establish the therapeutic cells because of the latent toxicity of wild type. SHED expressing TKA168H (SHED-TK) exhibited chemotaxis to the conditioned medium of NSCLC and migrated toward implanted NSCLC in vivo. SHED-TK demonstrated a strong bystander effect in vitro and in vivo and completely eradicated H1299 NSCLC in the brain. SHED-TK cells implanted intratumorally followed by GCV administration significantly suppressed the growth of H1299 and improved survival time. These results indicate that the TKA168H variant is suitable for establishing therapeutic cells and that intratumoral injection of SHED-TK followed by GCV administration may be a useful strategy for therapeutic approaches.

Molecular Mechanisms and Clinical Challenges of Glioma Invasion.

Glioma is the most common primary brain tumor, and its prognosis is poor. Glioma cells are highly invasive to the brain parenchyma. It is difficult to achieve complete resection due to the nature of the brain tissue, and tumors that invade the parenchyma often recur. The invasiveness of tumor cells has been studied from various aspects, and the related molecular mechanisms are gradually becoming clear. Cell adhesion factors and extracellular matrix factors have a strong influence on glioma invasion. The molecular mechanisms that enhance the invasiveness of glioma stem cells, which have been investigated in recent years, have also been clarified. In addition, it has been discussed from both basic and clinical perspectives that current therapies can alter the invasiveness of tumors, and there is a need to develop therapeutic approaches to glioma invasion in the future. In this review, we will summarize the factors that influence the invasiveness of glioma based on the environment of tumor cells and tissues, and describe the impact of the treatment of glioma on invasion in terms of molecular biology, and the novel therapies for invasion that are currently being developed.

Migration Capacity of Stem Cells from Human Exfoliated Deciduous Teeth Towards Glioma.

BACKGROUND: Stem cells from human exfoliated deciduous teeth (SHED) are a mesenchymal stem cell type and have recently attracted attention for their high proliferative rate, multipotency, and immunosuppressive properties. However, SHED have not yet been investigated for anticancer properties. We therefore investigated whether SHED can be used as a treatment modality, particularly for anti-glioma therapy. METHODS: In vitro, we examined the mobility of SHED and their ability to migrate towards glioma-conditioned medium and specific growth factors secreted by malignant gliomas. In vivo, we transplanted SHED into the left hemisphere of nude mice that had been previously implanted with human malignant glioma U87 cells into the right hemisphere. We assessed whether SHED had tumorigenic potential. RESULTS: SHED exhibited strong migration ability towards malignant glioma in both in vitro and in vivo assays. In vitro, SHED migrated towards glioma-conditioned medium and specific growth factors such as stem cell factor, platelet-derived growth factor BB, C-X-C motif chemokine ligand 12, and vascular endothelial growth factor. SHED were accumulated around tumor cells in the contralateral hemisphere 1 week after transplantation. Moreover, SHED remained in the brains of nude mice 150 days after transplantation. Finally, we verified that SHED had no malignant transformation or engraftment of SHED in the mouse brain. CONCLUSIONS: Our findings indicate that SHED can potentially be applied to track malignant glioma.

[Gene Therapy and Viral Therapy for Malignant Glioma].

Malignant gliomas have a poor prognosis despite advances in surgical procedures, radiotherapy, and the emergence of new treatments have improved outcomes. One of these new treatments is gene therapy, which has been developed as a new therapeutic strategy. Recently, new methods and approaches have been developed. Gene therapy involves the introduction of genes or cells into a glioma, or the human body, to treat gliomas; various genes such as cancer-suppressing genes, immunomodulation cytokine-related genes, and suicide genes are used in this treatment. Viral therapy is a treatment that oncolytic viral replicates in tumor cells to destroy tumors. Various viral genes can also be used as therapeutic genes. Currently, the most well-studied and accumulated viruses are adenoviruses and HSV-1. Various clinical trials have been conducted using gene therapy and viral therapy, some of which are scheduled to be approved in the near future. Gene therapy and viral therapy have dramatically improved and have developed progressively since their first clinical use.

A novel technique for fence-post tube placement in glioma using the robot-guided frameless neuronavigation technique under exoscope surgery: patient series.

BACKGROUND: Robotic technology is increasingly used in neurosurgery. The authors reported a new technique for fence-post tube placement using robot-guided frameless stereotaxic technology with neuronavigation in patients with glioma. OBSERVATIONS: Surgery was performed using the StealthStation S8 linked to the Stealth Autoguide cranial robotic guidance platform and a high-resolution three-dimensional (3D) surgical microscope. A surgical plan was created to determine the removal area using fence-post tube placement at the tumor and normal brain tissue boundary. Using this surgical plan, the robotic system allowed quick and accurate fence-post tube positioning, automatic alignment of the needle insertion and measurement positions in the brain, and quick and accurate puncture needle insertion into the brain tumor. Use of a ventricular drainage tube for the outer needle cylinder allowed placement of the puncture needle in a single operation. Furthermore, use of a high-resolution 3D exoscope allowed the surgeon to simultaneously view the surgical field image and the navigation screen with minimal line-of-sight movement, which improved operative safety. The position memory function of the 3D exoscope allowed easy switching between the exoscope and the microscope and optimal field of view adjustment. LESSONS: Fence-post tube placement using robot-guided frameless stereotaxic technology, neuronavigation, and an exoscope allows precise glioma resection.

Nicotine does not affect stem cell properties requisite for suicide gene therapy against glioma.

OBJECTIVE:: Glioblastoma is one of the most lethal tumors in adult central nervous system with a median survival of a year and half and effective therapeutic strategy is urgently needed. For that reason, stem cell-based suicide gene therapies have attracted much interest because of potent tumor tropism of stem cells and bystander effect. In this current clinical situation, stem cells are promising delivery tool of suicide genes for glioma therapy. Since habitual cigarette smoking still prevails worldwide, we investigated the effect of nicotine on stem cell tropism toward glioma and gap junctional intercellular communication (GJIC) function between glioma and stem cells, both of which are important for suicide gene therapies. Methods: Mouse induced pluripotent stem cell-derived neural stem cells (iPS-NSCs) and human dental pulp mesenchymal stem cells (DPSCs) were used. The effect of nicotine on tumor tropism to glioma-conditioned medium (CM) at a non-cytotoxic concentration was assessed with Matrigel invasion assay. Nicotine effect on GJIC was assessed with the scrape loading/dye transfer (SL/DT) assay for co-culture of glioma and stem cells and the parachute assay among glioma cells using high-content analysis. Results: Tumor tropism of iPS-NSCs toward GL261-CM and DPSCs toward U251-CM was not affected by nicotine (0.1 and 1 µM). Nicotine at the concentrations equivalent to habitual smoking (1 µM) did not affect GJIC of iPS-NSC/GL261 and DPSC/U251 and GJIC among each glioma cells. Conclusions: The study demonstrated that non-cytotoxic concentrations of nicotine did not significantly change the stem cell properties requisite for stem cell-based suicide gene therapy.

Acute and chronic hemorrhage from radiation-induced cavernous malformation associated with late-delayed radiation necrosis in long surviving glioma patients: A case report.

Although radiation therapy is a standard treatment strategy for patients with glioma, its delayed complications are not clearly understood. Radiation-induced cavernous malformation (RICM) is one of the complications in the delayed phase following radiation therapy, which usually occurs in children. Herein we present three cases of RICM with radiation necrosis in long surviving adult glioma patients, 2 with oligoastrocytoma and one with anaplastic ependymoma. Two of three patients had received an obvious overdose of radiation by additional stereotactic radiation therapy. Repeated episodes of either acute or chronic hemorrhages from RICM worsened the neurological symptoms in all cases. The interval between the last irradiation and the occurrence of symptoms was 45-173 months. The presence of hypointense rim on FLAIR or T2* on magnetic resonance imaging, which resembles the appearance of sporadic cavernous malformations, could be helpful in differentiating RICM from tumor recurrence. Surgical resection was effective in alleviating the symptoms. Microscopically, RICM is a vascular lesion with vulnerable vessels, which are observed in the center of the radiation necrosis. Repeated hemorrhages from these vessels cause either gradual or sudden worsening of neurological symptoms. Therefore, radiation overdose, which results in radiation injury, should be avoided in low grade glioma patients, who could potentially survive for a long period.

Cosmetic and Neuroprotective Placement of Custom-Made Ultra-High-Molecular-Weight Polyethylene Cranial Plate (SKULPIO) in Single-Step Surgery: Technical Note and Case Report.

BACKGROUND: Cranioplasty is a common procedure in neurosurgery. However, cosmetic and neuroprotective reconstructions are necessary after cranioplasty. Treatment of patients with a meningioma with bone infiltration requires removal of the tumor-infiltrated bone and subsequent cranioplasty. We report an efficient technique for cosmetic and neuroprotective reconstructions using a custom-made ultra-high-molecular-weight polyethylene cranial plate (SKULPIO, Kyocera Medical, Kyoto, Japan) in a single-step surgery involving tumor removal and skull reconstruction. METHODS: We present 2 illustrative cases of a 49-year-old female with a right frontal convexity meningioma and 69-year-old male with a bilateral parasagittal atypical meningioma, both involving extensive skull invasion. We preoperatively planned craniotomy size to facilitate the removal of the tumor-infiltrated skull bone using the patients' 3-dimensional cranial models followed by the construction of a custom-made cranial plate. After tumor removal, we drilled out the outer table and the diploe of the cranial edge until the custom-made bone plate accurately fit the bone defect. Finally, the cranial plate was fixed using titanium plates and screws. RESULTS: Postoperative magnetic resonance imaging for each case revealed total meningioma removal and an aesthetically reconstructed skull. Using this technique, precise adjustment of the cranial edge to the plate contributes to a gapless and aesthetic reconstruction. Furthermore, the intact inner table of the skull firmly supports the custom-made bone plate. CONCLUSIONS: This technique involving the placement of a custom-made cranial plate during a single-step surgery was found to be efficient for cosmetic and neuroprotective reconstructions.

Fluid-Blood Level and Hematoma Expansion in a Cerebral Amyloid Angiopathy-Associated Intracerebral Hematoma.

BACKGROUND Cerebral amyloid angiopathy (CAA) results from progressive deposition of amyloid-ß in the walls of cortical and leptomeningeal vessels, leading to CAA-associated intracerebral hemorrhage (ICH). Hematoma expansion is a common early complication of spontaneous ICH, and is a strong independent predictor of poor outcome. However, there are limited reports of hematoma expansion related to CAA-associated ICH. Herein, we describe a novel case of hematoma expansion with a fluid-blood level in the cystic cavity of CAA-associated ICH. CASE REPORT A 76-year-old male was initially diagnosed with probable CAA according to the modified Boston criteria, and presented with lobar ICH in the left frontal lobe 4 months later. Admission computed tomography scans showed an ICH including a high-density hematoma within a cystic cavity, revealing a clearly lower-density fluid component. Serial computed tomography scans showed no evidence of an expansion of the high-density clot, but obvious expansion of the fluid component containing a fluid-blood level. We recognized a bleeding site with no enhancement on preoperative magnetic resonance imaging. Left frontal craniotomy revealed a liquefied hematoma, which was removed by suction. We subsequently evacuated the blood clot extending into the left frontal sulcus, and confirmed and cauterized the bleeding site, leading to successful hemostasis. CONCLUSIONS We report a CAA-associated ICH case showing hematoma expansion with a fluid-blood level. Intraparenchymal fluid-blood level suggests extravasation of blood into pre-existing cystic cavities because of hematoma liquefaction. Thus, fluid-blood levels are an important finding of hematoma expansion in acute CAA-associated ICH, and early treatment should be considered.

Anaplastic changes of diffuse leptomeningeal glioneuronal tumor with polar spongioblastoma pattern.

Diffuse leptomeningeal glioneuronal tumor (DLGNT) is a rare glioneuronal neoplasm with oligodendroglioma-like cells confined in the subarachnoid spaces. A great majority of DLGNT are histologically low grade. However, some tumors show features of anaplasia with increased mitotic and proliferative activity. Due to the limited number of patients and inadequate clinical follow-up reported to date, the WHO classification does not yet assign a distinct WHO grade to this entity. Polar spongioblastoma pattern, in which bipolar cells are arranged in parallel with palisading nuclei, remains poorly understood about the pathological process of forming this pattern. We experienced a case of 22-year-old man developing DLGNT with extensively distributed anaplastic changes involving polar spongioblastoma pattern and the secondary tumor invasion to brain parenchyma in 4½ years before the autopsy. Clinical and pathological courses of the patient are presented with radiological, histopathological, and genetic examinations. This is the first report demonstrating the immunohistological and genetic evaluation of a DLGNT with polar spongioblastoma pattern.

Genetically Engineered Multilineage-Differentiating Stress-Enduring Cells as Cellular Vehicles against Malignant Gliomas.

Malignant glioma, the most common malignant brain tumor in adults, is difficult to treat due to its aggressive invasive nature. Enzyme/prodrug suicide gene therapy based on the herpes simplex virus thymidine kinase (HSVtk)/ganciclovir (GCV) system is an efficient strategy for treating malignant gliomas. In the present study, we evaluated treatment with multilineage-differentiating stress-enduring (Muse) cells, which are endogenous non-tumorigenic pluripotent-like stem cells that are easily collectable from the bone marrow as SSEA-3+ cells, as carriers of the HSVtk gene. Human Muse cells showed potent migratory activity toward glioma cells both in vitro and in vivo. HSVtk gene-transduced Muse cells (Muse-tk cells) at a cell number of only 1/32 that of U87 human glioma cells completely eradicated U87 gliomas in nude mouse brains, showing a robust in vivo bystander effect. Pre-existing intracranial U87 gliomas in nude mouse brains injected intratumorally with Muse-tk cells followed by intraperitoneal GCV administration were significantly reduced in size within 2 weeks, and 4 of 10 treated mice survived over 200 days. These findings suggest that intratumoral Muse-tk cell injection followed by systemic GCV administration is safe and effective and that allogeneic Muse-tk cell-medicated suicide gene therapy for malignant glioma is clinically feasible.

Congenital dysfibrinogenemia in a Japanese family with fibrinogen Naples (BßAla68Thr) manifesting as superior sagittal sinus thrombosis.

: Congenital dysfibrinogenemia refers to the presence of a dysfunctional fibrinogen molecule, typically because of mutations in the fibrinogen gene. About 20% of fibrinogen gene mutations are responsible for thrombosis. Here, we described the case of a 17-year-old Japanese boy, who had a sudden stroke because of superior sagittal sinus thrombosis associated with dysfibrinogenemia. Genetic testing confirmed the presence of homozygous fibrinogen Naples (BßAla68Thr) mutation, which was previously reported as a causative mutation for thrombotic dysfibrinogenemia only in an Italian family. In this Japanese family, the patient's 12-year-old asymptomatic sister was also homozygous for this mutation. She, like her brother, was started on warfarin therapy. This report highlights the occurrence of fibrinogen Naples that has caused severe thrombotic complications in a young member of a Japanese family.