Primary central nervous system lymphoma (PCNSL) is a rare malignancy confined to the central nervous system (CNS), and majority of PCNSL is pathologically classified as diffuse large B-cell lymphoma ...(DLBCL). We have now performed whole-exome sequencing for 41 tumor tissues of DLBCL-type PCNSL and paired normal specimens and also RNA-sequencing for 30 tumors, revealing a very high frequency of nonsynonymous somatic mutations in
PIM1
(100 %),
BTG2
(92.7 %), and
MYD88
(85.4 %). Many genes in the NF-κB pathway are concurrently mutated within the same tumors. Further, focal deletion or somatic mutations in the
HLA
genes are associated with poor prognosis. Copy number amplification and overexpression of genes at chromosome 7q35 were both found to predict short progression-free survival as well. Oncogenic mutations in
GRB2
were also detected, the effects of which in cultured cells were attenuated by inhibitors of the downstream kinases MAP2K1 and MAP2K2. Individuals with tumors positive for
MYD88
mutations also harbored the same mutations at a low frequency in peripheral blood mononuclear cells, suggesting that
MYD88
mutation-positive precancerous cells originate outside of the CNS and develop into lymphoma after additional genetic hits that confer adaptation to the CNS environment.
Purpose
Measuring serum and cerebrospinal fluid human chorionic gonadotropin (hCG) is essential for the diagnosis of intracranial germ cell tumors. There are three types of hCG-related markers in ...clinical use: hCGβ, intact hCG, and total hCG. The best marker for the diagnosis of intracranial germ cell tumors, especially germinoma, is currently unknown. This study aimed to evaluate the usefulness of these hCG-related markers.
Methods
We investigated 19 serum samples obtained from 6 patients with histologically diagnosed germinoma treated in our institute. Serum hCGβ, intact hCG, and total hCG values were measured before, during, and after treatment. Samples with hCG values above the lower limits were considered positive.
Results
The positivity rates of serum hCGβ, intact hCG, and total hCG were 6% (1/17), 47% (7/15), and 42% (8/19), respectively, with the latter two having significantly higher positivity rates than hCGβ (
p
= 0.041). Both intact and total hCGs showed similar values. The median values of hCGβ, intact hCG, and total hCG before treatment were 0.1 ng/mL, 4.6 mIU/mL, and 4.5 mIU/mL, respectively.
Conclusion
Serum intact and total hCGs have higher detection rates than hCGβ in patients with germinoma using available commercial measurement tools.
Pineal parenchymal tumors (PPTs) are clinically rare and a biopsy is often required for a definitive diagnosis. To improve the accuracy of histological assessment of PPTs, we examined the ...proliferative capacity of PPT cells and investigated DICER1 expression and
KBTBD4
mutations. This study included 19 cases of PPTs 3 pineocytomas (PCs), 10 PPTs of intermediate differentiation (PPTID), and 6 pineoblastomas (PBs). Immunohistochemistry for Ki-67, PHH3, and DICER1, as well as Sanger sequencing analysis for
KBTBD4
mutations, was performed using formalin-fixed paraffin-embedded tissue specimens that were resected during surgery. Tumor cell proliferation was quantified using an image analysis software. For the PHH3 and MIB-1 indices, a significant difference was observed between the PPTIDs and PBs (
P
< 0.05). Loss of DICER1 was not specific for PB; 0/3 PCs (0.0%), 2/9 PPTIDs (22.2%), and 2/4 PBs (50.0%).
KBTBD4
mutations were detected in 1/3 PCs (33.3%), 6/9 PPTIDs (66.7%), and 0/4 PBs (0.0%). Thus, combined application of the proliferative marker index and
KBTBD4
mutation analysis may be useful for the differential diagnosis of PPTs. Furthermore, detection of
KBTBD4
mutations using Sanger sequencing analysis may support the diagnosis of PPTID.
Two hot spot mutations (C228T, C250T) in the telomerase reverse transcriptase (
TERT
) gene are frequently identified in glioblastoma and oligodendroglioma.
TERT
mutations predicts an aggressive ...clinical course in isocitrate dehydrogenase (
IDH
) wild-type astrocytic tumors. Therefore, it is important to accurately detect
TERT
promoter mutations in glioma. Sanger DNA sequencing is the currently standard method for analyzing
TERT
mutations. However, PCR amplification in the first step of the sequencing has proven technically difficult because of the high GC content around the
TERT
mutation. In this report, we described a novel droplet digital PCR (ddPCR) assay to evaluate
TERT
hot spot mutations in fresh frozen and formalin-fixed paraffin-embedded (FFPE) specimens of glioma and verified the difference in results from the Sanger DNA sequencing results. We obtained the mutant allele fraction for
TERT
mutations of in a single ddPCR run in all cases, including the micro-dissected FFPE sections. On the contrary, up to twice the DNA sequences were required from fresh frozen tissue to obtain the results, consistent with ddPCR assay. When FFPE specimens were used, more time was required to evaluate
TERT
mutations through DNA sequencing. DdPCR is an effective and sensitive assay compared to the conventional standard Sanger DNA sequencing.
Most elderly patients with tuberculosis (TB) have previously been infected with Mycobacterium tuberculosis, which remains dormant in the body for decades and may reactivate when their immunity ...declines due to underlying diseases. Elderly cancer patients are at a high risk for TB, and the treatment of TB reactivation in these patients is challenging. Among cancer patients, the incidence of TB reactivation is the highest in lymphoma patients. However, the impact of chemotherapy on TB reactivation in lymphoma patients is unknown. We report the case of an immunocompetent elderly patient with primary central nervous system lymphoma (PCNSL) having no prior history of TB, who developed miliary TB during multiagent chemotherapy consisting of rituximab, high-dose methotrexate, procarbazine, and vincristine (R-MPV therapy). Retrospectively, the chest computed tomography showed calcification of the pleura, suggesting that the patient had a latent tuberculosis infection (LTBI) and developed miliary TB from the reactivation of TB triggered by the R-MPV therapy. Our case emphasizes that when chemotherapy is administered to patients with PCNSL, interferon-gamma release assay (IGRA) should be performed if there are findings on chest examination suggestive of LTBI, such as pleural calcification, and if IGRA is positive, chemotherapy should be given concurrently with LTBI treatment.
We report effective treatment with nivolumab of a patient with recurrent primary central nervous system lymphoma (PCNSL) after multiple therapies. A 41-year-old woman with a right parietal PCNSL ...underwent treatment with high-dose methotrexate and radiotherapy. After recurrence in the left frontal lobe, the patient received several chemotherapies, including methotrexate and rituximab, and underwent surgery. The tumor was refractory to these treatments, and the patient then underwent intensity-modulated radiotherapy (IMRT). Multiple small, new recurrent tumors appeared in the right frontal lobe and the left frontoparietal region 2 months after IMRT. The patient received nivolumab 3 mg/kg with dendritic cell vaccination. Complete remission of the tumors was achieved after six cycles of nivolumab, and remission was maintained for 10 months after the initiation of nivolumab. Nivolumab could be a novel treatment for intractable recurrent PCNSL in the future.
Spinal epidermoid cysts are very rare tumors, especially in the thoracic spine; they represent 0.8% of all spinal epidermoids. In adult cases, they are often associated with surgical procedures such ...as lumbar puncture. We report a rare case of spinal epidermoid cyst in the thoracic spine of an elderly patient who had never undergone lumber puncture, thoracic spinal surgery, or trauma.
A 78-year old woman presented with a 1-month history of rapidly progressive impairment of sensation in both the lower limbs, with gait disturbance. She had no history of spinal surgery, trauma, or lumbar puncture. Her past medical history was unremarkable. Magnetic resonance imaging of the whole spine revealed an intraspinalextramedullary tumor at the Th 1–2 level. Diffusion-weighted imaging revealed significant homogeneous high intensity. We performed complete resection without damaging the spinal cord or nerve roots. The final histological examination indicated epidermoid cyst without malignancy. Her gait disturbance was completely resolved at 4-month follow-up.
Epidermoid cysts must be considered among spinal tumors in elderly patients. Early detection by diffusion-weighted imaging and complete resection may lead to good neurological outcome.
Astroblastoma is an extremely rare brain tumor that has recently attracted attention owing to its association with
MN1
gene alteration. However, its long-term clinical course remains unclear. We ...report a late recurrence of
MN1
-altered astroblastoma with unique pathological findings. A 24-year-old woman presented with seizures due to a left frontal lobe tumor. Gross total resection (GTR) was achieved, and the diagnosis was
MN1
-altered astroblastoma, which presented cell wrapping, i.e., presence of tumor cells enveloping one another. She received local radiotherapy (50 Gy). However, the tumor recurred after 12 years, and its size increased rapidly. The second surgery achieved GTR and confirmed increasing anaplasia. The patient was tumor-free for 1 year without any neurological deficits. This case implies the importance of long-term follow-up of
MN1
-altered astroblastoma. The pathological significance of cell wrapping in this case is unclear, but it may be associated with
MN1
-altered astroblastoma and should be noted in future cases.
Tenascin‐C is an extracellular matrix glycoprotein implicated in embryogenesis, wound healing and tumor progression. We previously revealed that tenascin‐C expression is correlated with the prognosis ...of patients with glioblastoma. However, the exact role of endogenous tenascin‐C in regulation of glioblastoma proliferation and invasion remains to be established. We show here that endogenous tenascin‐C facilitates glioblastoma invasion, followed by reactive change of the surrounding brain tissue. Although shRNA‐mediated knockdown of endogenous tenascin‐C does not affect proliferation of glioblastoma cells, it abolishes cell migration on a two‐dimensional substrate and tumor invasion with brain tissue changes in a xenograft model. The tyrosine phosphorylation of focal adhesion kinase, a cytoplasmic tyrosine kinase that associates with integrins, was decreased in tenascin‐C‐knockdown cells. In the analysis of clinical samples, tenascin‐C expression correlates with the volume of peritumoral reactive change detected by magnetic resonance imaging. Interestingly, glioblastoma cells with high tenascin‐C expression infiltrate brain tissue in an autocrine manner. Our results suggest that endogenous tenascin‐C contributes the invasive nature of glioblastoma and the compositional change of brain tissue, which renders tenascin‐C as a prime candidate for anti‐invasion therapy for glioblastoma. (Cancer Sci 2009)
The initial presentation of central nervous system (CNS) tumors in children frequently mimics other more common and less serious conditions, resulting in diagnostic difficulty and a prolonged time to ...diagnosis. Yet whether early diagnosis contributes to better life prognosis and functional outcome has not been elucidated. Only a few such reports have originated from Japan, where neuroimaging techniques are the best in the world. We examined the time to diagnosis, the so-called prediagnostic symptomatic interval (PSI), and its impact on prognosis and functional outcome in children with CNS tumors.
We reviewed the records of 127 patients aged <15 years with CNS tumors, who were treated at our two institutions between November 1993 and October 2011.
The median age at diagnosis was 7.2 years (range, 3 weeks-14.9 years). The male-to-female ratio was 63:64. Median PSI was 1.5 months (0-36 months). Overall survival and progression-free survival did not differ significantly between the groups, regardless of whether the PSI was longer than the median PSI. The PSI was significantly longer in patients with long-lasting clinical signs after the initial treatment than in patients with temporary symptoms only at onset. Both univariate and multivariate analysis showed that high histological grading was statistically correlated with short PSI.
A short PSI was significantly associated with high-grade tumors. Earlier diagnosis did not lead to better life prognosis, but possibly to better functional outcome in children with CNS tumors.
PDF
