Recent Status of Phase I Clinical Trials for Brain Tumors: A Regulatory Science Study of Exploratory Efficacy Endpoints.

BACKGROUND: Appropriate exploratory efficacy data from Phase I trials are vital for subsequent phases. Owing to the uniqueness of brain tumors (BTs), use of different strategies to evaluate efficacy is warranted. We studied exploratory efficacy evaluation in Phase I trials involving BTs. METHODS: Using Clarivate's Cortellis™, 42 Phase I trials of BT interventions conducted from 2020 to 2022 were analyzed for efficacy endpoints, which were set as primary endpoints (PEs) or secondary endpoints (SEs). Additionally, these metrics were compared in two subgroups: trials including only BTs (Group-A) and those including BTs among mixed solid tumors (Group-B). RESULTS: Selected studies included a median of 1.5 PEs (range, 1-6) and 5 SEs (range, 0-19). Efficacy endpoints were included as PEs and SEs in 2 (5%) and 31 (78%) trials, respectively. Among the latter 31 trials that included 94 efficacy endpoints, 24, 22, 20, 9, and 8 reflected overall response rate (ORR), progression-free survival (PFS), overall survival (OS), duration of response (DOR), and disease control rate (DCR), respectively. ORR for BT was determined using various methods; however, the Response Evaluation Criteria in Solid Tumors (RECIST) was used less frequently in Group-A than in Group-B (p = 0.0039). CONCLUSIONS: Recent Phase I trials included efficacy endpoints as SEs, with ORR, PFS, or OS included in ~ 50% trials and DOR or DCR in ~ 25%. No established criteria exist for imaging evaluation of BTs. Phase I trials involving mixed solid tumor cohorts revealed challenges in designing methods to assess the exploratory efficacy of BTs.

Early Response to Radiation Therapy without Surgical Intervention in a Giant Cavernous Sinus Hemangioma with Hydrocephalus: A Case Report.

Cavernous sinus hemangioma (CSH) is a rare vascular malformation, arising from the cavernous sinus. Because of its anatomically complex location, a large lesion can cause a variety of symptoms due to cranial nerve compression. A 69-year-old woman with an unsteady gait was admitted to our hospital, and magnetic resonance imaging revealed an extra-axial giant tumor in the cavernous sinus and enlarged ventricles. A radiographic diagnosis of CSH was made. As the risk of surgical removal was considered high, the patient underwent intensity-modulated radiation therapy of 50.4 Gy in 28 fractions. The size of the tumor decreased markedly over time, and the symptoms improved soon after treatment. A 61.8% reduction in tumor size was confirmed immediately after irradiation, and a 75.9% reduction was revealed at a follow-up visit one year later. We reported a case of a giant CSH with hydrocephalus, where tumor shrinkage was confirmed immediately after radiation therapy, and the symptoms of hydrocephalus improved without surgical intervention.

Efficacy Endpoints in Phase II Clinical Trials for Meningioma: An Analysis of Recent Clinical Trials.

BACKGROUND: Response Evaluation Criteria in Solid Tumors (RECIST)-based response rates are commonly used as efficacy endpoints in phase II clinical trials for solid tumors. However, no consensus has been reached concerning adequate efficacy endpoints for phase II clinical trials targeting meningioma. Irregularity of lesions after resection, and varying degrees of dysplasia and histologic subtypes make establishing an appropriate efficacy evaluation difficult. METHODS: We analyzed primary efficacy endpoints (PEEs) and background factors from 48 trials retrieved from ClinicalTrials.gov ( https://clinicaltrials.gov/ ) using the search criteria "meningioma," "interventional," "phase II," and "study start 4/1/2001 to 3/31/2021." Primary purpose of the study was efficacy endpoint setting in overall population and three subgroups. RESULTS: Among 45 PEEs set in the 39 trials included; 33 trials with single PEE, and six trials with double PEEs, 17/45 (38%) trials adopted progression-free survival (PFS) rate, 15/45 (33%) trials response rate (seven Macdonald criteria or modified, three RECIST, three volumetric estimation, one RANO criteria, one unknown), 10/45 (22%) PFS, 1/45 (2%) OS, and 2/45 (4%) other endpoints. Although 26 PEEs were time-to-event endpoints, 19 of the 26 PEEs were single-arm studies. CONCLUSIONS: Time-to-event efficacy endpoints were often compared to historical data, and two-dimensional evaluation is more suitable than one-dimensional one. Accumulation of prognostic data is essential to standardize time-to-event efficacy endpoints. Considering the difficulty of setting design for phase II clinical studies targeting meningioma, evaluation might be done with multiple efficacy endpoints.

Risk Factors for Postoperative Cerebrospinal Fluid Leak after Graded Multilayer Cranial Base Repair with Suturing via the Endoscopic Endonasal Approach.

This study analyzed risk factors for postoperative cerebrospinal fluid (CSF) leak after graded multilayer cranial base repair method with dural suturing. We performed surgery via the endoscopic endonasal approach (EEA) from 2012.6 to 2018.4, and those consecutive clinical data were prospectively accumulated and retrospectively analyzed. We tailored the repair method according to the intraoperative CSF leak grade. Among 388 surgeries via the EEA, there were 10 (2.6%) cases of postoperative CSF leak after graded repair with suturing. Postoperative CSF leak occurred in two of the 150 cases without intraoperative CSF leak (grade 0), one of the 104 cases with small (grade 1) intraoperative CSF leak, two of the 60 cases with moderate (grade 2) leak, and five of the 74 cases with large (grade 3) leak. Univariate analysis indicated that chordoma (P = 0.023), estimated tumor volume ≥ 7400 mm3 (P = 0.003), and maximum tumor diameter ≥ 32.5 mm (P = 0.001) were significant risk factors for postoperative CSF leak. Additionally, among cases with intraoperative grade 3 CSF leak, chordoma (P = 0.021), estimated tumor volume ≥ 23000 mm3 (P = 0.003), and maximum tumor diameter ≥ 45.5 mm (P = 0.001) were significant risk factors for postoperative CSF leak. Maximum tumor diameter, estimated tumor volume, and chordoma tumor pathology are related to a higher risk of postoperative CSF leak.

Conservative Treatment of Chronic Subdural Hematoma with Gorei-san.

Most asymptomatic patients with chronic subdural hematoma (CSDH) are followed conservatively but can require surgical treatment if the hematoma expands. We conducted a retrospective evaluation of the effect of Gorei-san on CSDH. This study included patients treated between April 2013 and March 2015. In total, 289 patients were diagnosed with CSDH and 110 patients received conservative management. Finally, 39 patients who met the requirements were registered. We retrospectively examined the age, gender, medical history, hematoma thickness, clarity of sulci below hematomas, and midline shift of the patients. The primary outcome was the median surgery-free interval, and the secondary results were the rate of CSDH shrinkage and surgery avoidance. A comparison of patient characteristics between the Gorei-san (G) and non-Gorei-san (NG) groups found no significant differences in the percentage of men, average ages, past history, thickness of CSDH (15.0 ± 3.1 mm vs. 15.3 ± 2.6 mm, p = 0.801), or midline shift (2.0 ± 2.7 mm vs. 4.0 ± 5.0 mm, p = 0.230). The median surgery-free interval was significantly different between the G and NG groups [n. r. vs. 41 days (95% CI: 5-79), log-rank p = 0.047]. The CSDH avoidance rate was not significantly different between the two groups (70.0% vs. 34.4%, p = 0.071). Additionally, the CSDH shrinkage rate was significantly different between the two groups (60.0% vs. 10.3%, p = 0.004). This retrospective study demonstrated that CSDH treatment with Gorei-san reduces hematoma significantly more than treatment that does not include Gorei-san.

Frontal sinus giant osteoma with radiologically unusual component suggesting blood supply: A case report.

Osteoma is a common, slow growing bone tumor, and often affects the paranasal sinus. Typically, it shows a very hyperdense osseous lesion on computed tomography (CT) scan and low-intensity change on T2-weighted image on magnetic resonance imaging (MRI). No report has mentioned osteomas in blood supply on MRI. A 57-year-old male patient presented with a prolonged declined activity and a gigantic osseous tumor that originated from the frontal sinus, which markedly compressed the bilateral frontal lobe. MRI revealed a slightly enhanced front basal part of the tumor by gadolinium, with blood supply from ethmoidal arteries. The patient underwent surgery, and the diagnosis of osteoma was made based on histological findings. We reported a case of giant osteoma originating from the frontal sinus with unusual blood supply on 4-dimensional MR angiography.

Factors Influencing Craniospinal Relapse of Intracranial Germinoma After Complete Remission.

OBJECTIVE: To evaluate the pathomechanism of the recurrence of intracranial germinoma after complete response and to confirm the association of the initial magnetic resonance imaging and therapeutic factors with recurrence. METHODS: This study included patients who were followed up for ≥5 years and who were treated in our hospital from 1980 to 2021. Those with germinoma and germinoma with syncytiotrophoblastic giant cells were diagnosed pathologically. Data were categorizedbased on "gender," "single region," "intraventricular dissemination at the initial diagnosis," "hydrocephalus," "types of radiation therapy (RT)," and "chemotherapy." Fisher's exact probability test was used to assess differences between the no recurrence and recurrence groups. RESULTS: Among 43 patients, 34 had no recurrence, 5 had delayed recurrence (≥60 months), and 4 had early recurrence (<60 months). Follow-up periods were 143.5 (60-380), 198 (88-222), and 132.5 (75-291) months for the no recurrence, delayed recurrence, and early recurrence groups, respectively. Five patients with delayed recurrence showed 3 intracranial lesions and 2 spinal lesions. Four patients with early recurrence showed 3 intracranial lesions and 1 spinal lesion. Differences in delayed recurrences (focal RT vs. RT including whole-ventricle system; P = 0.0491) were significant in Fisher's exact test. CONCLUSIONS: RT including the whole-ventricle system reduces delayed craniospinal relapses including dissemination, local, and distant recurrences even ≥5 years after complete response in patients with primary central nervous system germinoma.

Levetiracetam Versus Levetiracetam Plus Sodium Channel Blockers for Postoperative Epileptic Seizure Prevention in Brain Tumor Patients.

Background Brain tumor patients tend to develop postoperative epileptic seizures, which can lead to an unfavorable outcome. Although the incidence of postoperative epileptic seizures and adverse events are improved with the advent of levetiracetam (LEV), postoperative epilepsy occurs at a frequency of 4.6% or higher. In brain tumor patients, the addition of sodium channel blockers (SCBs) to LEV significantly reduces seizures, though confirmed in a non-postoperative study. Thus, the combination of SCBs with LEV might be promising. Objective In this prospective randomized controlled trial we investigated the safety, evaluated by adverse events during one and two weeks after surgery, and the efficacy, evaluated by the incidence of early epilepsy, including non-convulsive status epilepticus (NCSE), of using LEV alone or SCBs added to LEV in patients who underwent craniotomy or biopsy for brain tumors or brain mass lesions. Methods Patients with brain tumors or brain mass lesions undergoing surgical interventions, excluding endoscopic endonasal surgery (EES), with a diagnosis of epilepsy were eligible for this study. Patients are randomized into either Group A or B (B1 or B2) after the informed consents are taken; LEV alone in Group A patients, while LEV and SCBs in Group B patients (GroupB1, intravenous fosphenytoin plus oral lacosamide (LCM) and GroupB2, intravenous LCM plus oral LCM) were administered postoperatively. Fifty-three patients were enrolled during the first two and a half years of the study and four of them were excluded, resulting in the accumulation of 49 patients' data. Results Postoperative epileptic seizures occurred only in three out of 49 patients during the first week (6.1%) and in seven patients within two weeks after surgery (14.3%, including the three patients during the first week). In Group A, epileptic seizures occurred in two out of 26 patients during the first week (7.7%) and in five patients within two weeks (19.2%) after surgery. In Group B, epileptic seizures occurred in one out of 23 patients during the first week (4.3%) and in two patients during the first two weeks (8.7%). Low complication grade of epileptic seizures was observed in Group B rather than in Group A, however, without significant difference (p=0.256). There was no difference in the frequency of adverse effects in each group. Conclusion Although not statistically significant, the incidence of epileptic seizures within one week after surgery was lesser in LEV+SCBs groups than in LEV alone. No hepatic damage or renal function worsening occurred with the addition of LCM, suggesting the safety of LEV+SCBs therapy.

Inducing substances for chondrogenic differentiation of dental pulp stem cells in the conditioned medium of a novel chordoma cell line.

We successfully established a chordoma cell line, designated TSK-CHO1, derived from the clival chordoma. Currently, there is only one skull base chordoma cell line, UM-chor1, freely available to researchers. The established TSK-CHO1 cells were neoplastic, exhibited pleomorphic features, and secreted brachyury, as revealed by immunocytochemical staining or ELISA of conditioned medium (CM). Cells also secreted SOX9, which enhanced brachyury production. The CM of TSK-CHO1 cells promoted the production of hyaluronic acid and type II collagen during differentiation of human dental pulp stem cells (DPSCs) into fibrocartilage cells. Culture of DPSC pellets in a growth medium supplemented with 10% CM of TSK-CHO1 cells for 2 weeks resulted in the induction of fibrocartilage tissue under normoxic conditions. Brachyury produced by TSK-CHO1 cells promoted the production of collagen type II, peculiar to cartilage, in a dose-dependent manner. The newly established skull base chordoma cell line, TSK-CHO1, is expected to be used for elucidating the pathogenesis of skull base chordoma and for investigating the mechanism underlying the production of fibrocartilage.

Involvement of the optic pathway and outcome of visual function in patients with neurohypophyseal germ cell tumor.

BACKGROUND: Patients with neurohypophyseal germ cell tumors (GCTs) typically present with visual problems. Hence, this study aimed to assess optic pathway involvement based on clinical and radiological findings and to validate the outcome of visual function. METHODS: A total of 16 patients with newly diagnosed neurohypophyseal GCTs who were treated at the University of Tsukuba Hospital between 2000 and 2020 were included in this study. RESULTS: The median interval from symptom onset to diagnosis was 173.5 days (range, 33-1588 days). Patients with visual disturbance at diagnosis had a longer time to diagnosis compared with those without. Ophthalmologic abnormalities were frequently observed, with an incidence rate of 69%. Fifty percent of patients exhibited optic pathway involvement detected via magnetic resonance imaging (MRI). Visual impairment was more severe in the patients with optic pathway involvement (p = 0.002). Post-treatment visual impairment was improved but was still significantly severe in patients with optic pathway involvement than in those without involvement (p = 0.010). Visual field deficit more likely remained with an improvement rate of 50%, whereas the improvement rate of visual acuity was 78%. Further, none developed late-onset visual deterioration during the follow-up period. CONCLUSIONS: Visual disturbance and optic pathway involvement are common in neurohypophyseal GCTs. Visual impairment particularly in patients with optic pathway involvement on MRI is more likely to remain at follow-up, although the outcome of visual function is acceptable in most cases.

Maximum resection and immunotherapy improve glioblastoma patient survival: a retrospective single-institution prognostic analysis.

Glioblastoma (GBM) is a refractory disease with a poor prognosis and various methods, including maximum resection and immunotherapy, have been tested to improve outcomes. In this retrospective study we analyzed the prognostic factors of 277 newly diagnosed GBM patients over 11 years of consecutive cases at our institution to evaluate the effect of these methods on prognosis. Various data, including the extent of removal (EOR) and type of adjuvant therapy, were examined and prognostic relationships were analyzed. The median overall survival (OS) of the entire 277-case cohort, 200 non-biopsy cases, and 77 biopsy cases was 16.6 months, 19.7 months, and 9.7 months, respectively. Gross total removal (GTR; 100% of EOR) was achieved in 32.9% of the cases. Univariate analysis revealed younger age, right side, higher Karnofsky performance status, GTR, intraoperative magnetic resonance imaging (MRI) use for removal, proton therapy, combination immunotherapy, and discharge to home as good prognostic factors. Intraoperative MRI use and EOR were closely related. In the multivariate analysis, GTR, proton therapy, and a combination of immunotherapies, including autologous formalin-fixed tumor vaccine, were the significant prognostic factors. A multivariate analysis of 91 GTR cases showed that immunotherapy contributed to prognostic improvements. The median OS and 5-year OS % values were 36.9 months and 43.3% in GTR cases receiving immunotherapy. In conclusion, GTR, proton therapy, and immunotherapy were good prognostic factors in single-center GBM cases. Tumor vaccine therapy for GTR cases achieved a notably high median survival time and long-term survival ratio, indicating its usefulness in GTR cases.

Anti-angiogenic and macrophage-based therapeutic strategies for glioma immunotherapy.

As a new concept of glioma therapy, immunotherapy combined with standard therapies is a promising modality to improve glioma patient survival. VEGF and its signaling pathway molecules not only inhibit angiogenesis but also may reinforce the immunosuppressive tumor microenvironment, including promotion of the accumulation of immunosuppressive tumor-associated macrophages (TAMs). In this review, we discuss VEGF-targeted therapy as a new treatment option of the TAM-targeted therapy for high-grade gliomas, as well as other TAM-targeted therapies. The authors also discuss the potential of these therapies combined with conventional immunotherapies.

Combined simultaneous endoscopic endonasal and microscopic transventricular surgery using a port retractor system for giant pituitary adenoma: A technical case report.

BACKGROUND: We report a case of a giant pituitary adenoma with marked extension into the third ventricle that was successfully removed using combined simultaneous endoscopic endonasal surgery (EES) and microscopic transventricular port surgery. CASE DESCRIPTION: A 47-year-old woman, who complained of memory disturbance, had a giant pituitary adenoma with marked extension into the third ventricle that was causing obstructive hydrocephalus. She underwent combined EES and microscopic transventricular surgery using a port retractor system. Most of the tumor was resected from the EES side with assistance from the transcranial side with minimum cortical trajectory damage. The tumor was completely excised without any complications. CONCLUSION: For giant pituitary adenoma with marked extension into the third ventricle, combined simultaneous EES and transventricular surgery using a port retractor system is effective to maximize the extent of tumor resection while also preventing complications. Using port surgery on the transcranial side, microscopic secure dissection is possible with minimum additional cortical damage.

Bufadienolide glycosides and bufadienolides from the whole plants of Helleborus lividus, and their cytotoxic activity.

Cytotoxicity-guided fractionation of the MeOH extract of Helleborus lividus Aiton ex Curtis (Ranunculaceae) resulted in the isolation of five undescribed bufadienolide glycosides and two undescribed bufadienolides, along with three known compounds. Their structures were determined by detailed spectroscopic analysis and hydrolysis studies. The isolated compounds showed cytotoxicity against HL-60 human leukemia cells and A549 human lung adenocarcinoma cells, with IC50 values ranging from 2.20 ± 0.01 nM to 0.77 ± 0.01 µM. The undescribed compound 3ß-[(O-ß-d-glucopyranosyl-(1 â†’ 4)-α-l-rhamnopyranosyl)oxy]-14ß,16ß-dihydroxy-5ß-bufa-20,22-dienolide induced apoptosis in HL-60 cells via a mitochondria-dependent apoptotic pathway. The average IC50 values of bufadienolide monorhamnosides for HL-60 and A549 cells were 10-20 times lower than those for Na+/K+ ATPase, implying that they induce tumor cell death via a mechanism of action other than Na+/K+ ATPase inhibition.

Novel Steroidal Glycosides from the Whole Plants of Helleborus foetidus.

Phytochemical analysis of the whole Helleborus foetidus plants identified 28 steroidal glycosides (1-28), including 20 novel spirostanol glycosides (1-20) and a novel furostanol glycoside (21). The structures of the newly identified compounds were elucidated by two-dimensional NMR spectroscopy and hydrolytic cleavage. Compounds 12, 13, and 15 were determined to be spirostanol trisdesmosides bearing sugar moieties at the C-1, -21, and -24 hydroxy groups of the aglycone unit. The isolated compounds were subsequently evaluated for cytotoxic activity against HL-60 human promyelocytic leukemia cells and A549 human lung carcinoma cells. In particular, 7 showed cytotoxic activity against the HL-60 and A549 cells, with IC50 values of 5.9 and 6.6 µM, respectively, whereas 19 was selectively cytotoxic to A549 cells with an IC50 value of 5.5 µM.

Infiltration of CD163-positive macrophages in glioma tissues after treatment with anti-PD-L1 antibody and role of PI3Kγ inhibitor as a combination therapy with anti-PD-L1 antibody in in vivo model using temozolomide-resistant murine glioma-initiating cells.

Although chemoimmunotherapy often lengthens glioblastoma (GBM) survival, early relapses remain problematic as immunosuppressive M2 macrophages (Mϕ) that function via inhibitory cytokine and PD-L1 production cause immunotherapy resistance. Here, we detail anti-PD-L1 antibody effects on the tumor microenvironment, including Mϕ infiltration, using a temozolomide (TMZ)-treated glioma model. In addition, we tested combinations of anti-PD-L1 antibody and the M2Mϕ inhibitor IPI-549 on tumor growth. We simulated late TMZ treatment or relapse stage, persistent GBM cells by generating TMZ-resistant TS (TMZRTS) cells. M2Mϕ-associated cytokine production and PD-L1 expression in these cells were investigated. TMZRTS cells were then subcutaneously implanted into C57BL/6 mice to determine the effectiveness of an anti-PD-L1 antibody and/or IPI-549 treatment on infiltration of CD163-positive Mϕ, usually considered as an M2Mϕ marker into tumor tissues. CD163 expression in samples from human GBM patients were also evaluated. CD163-positive Mϕ heavily infiltrated TMZRS tumor tissues after in vivo anti-PD-L1 antibody treatment. Tumor growth was strongly inhibited by anti-PD-L1 antibody and IPI-549 combination therapy. Anti-PD-L1 antibody treatment significantly reduced infiltration of CD163-positive Mϕ into tumors, while combined PD-L1 antibody and IPI-549 therapy remarkably inhibited tumor growth. These therapies may be useful for recurrent or chronic GBM after TMZ treatment, but clinical safety and effectiveness studies are needed.

Endoscopic endonasal cyst fenestration into the sphenoid sinus using the mucosa coupling method for symptomatic Rathke's cleft cyst: a novel method for maintaining cyst drainage to prevent recurrence.

OBJECTIVE: Rathke's cleft cyst (RCC) is a benign cystic lesion with a relatively high incidence of local recurrence that occasionally requires repeat surgery. To prevent recurrence, simple cyst fenestration and drainage of the cyst contents to the sphenoid sinus is recommended, but it occasionally recurs. The authors postulated that obstruction of fenestration is a main cause of recurrence, and they developed a method, named the "mucosa coupling method (MC method)," that maintains persistent drainage. In this method, the RCC epithelium and the mucosa of the sphenoid sinus are connected, which promotes re-epithelialization between the two epithelia, maintaining persistent drainage. The outcome of this method was compared with that of conventional cyst fenestration. METHODS: In a consecutive series of 40 patients with RCC, the surgical strategy was changed during the study period: from December 2009 to September 2014 (the conventional period), 24 patients were scheduled to be treated using the conventional fenestration method, whereas from September 2014 to September 2017 (the MC period), 16 patients were scheduled to be treated using the MC method. However, because of an intraoperative CSF leak, the fenestration was closed during surgery in 3 patients in the conventional period and 2 in the MC period; therefore, these 5 patients were excluded from the analysis. Twenty-one patients treated with the conventional fenestration method (conventional group) and 14 patients treated with the MC method (MC group) were analyzed. All patients regularly underwent MRI after surgery to detect reaccumulation of cyst contents. The rate of reaccumulation with and without reoperation, visual outcomes, endocrinological outcomes, and postoperative complications were compared between these two groups. RESULTS: The median follow-up period in all 35 patients was 48.0 months (range 1-96 months), 54.0 months (range 1-96 months) in the conventional group and 35.5 months (range 12-51 months) in the MC group. No reaccumulation was detected on MRI in the 14 patients in the MC group, whereas it was noted in 9 (42.9%) of 21 patients in the conventional group, and 2 of these 9 patients required repeat surgery. There were no significant differences in visual and endocrinological outcomes and complications between these two groups. CONCLUSIONS: The MC method for RCC is effective for preventing obstruction of cyst fenestration, which contributes to preventing cyst reaccumulation. Furthermore, this method is equivalent to the conventional fenestration method in terms of visual and endocrinological outcomes and the complication rate.

Pure germinoma occurring 11 years after total pineal mature teratoma removal: a case report and review of the literature.

Intracranial mature teratomas have good prognoses and are usually treated by total tumor resection. We report a rare case of a germinoma that occurred 11 years after total removal of a pineal mature teratoma. A 5-year-old boy presented with headache and nausea and was diagnosed with a pineal tumor and obstructive hydrocephalus on MRI. He underwent total removal of the lesion, which was pathologically diagnosed as a mature teratoma without any other germ cell tumor components. MR images after 11 years showed a newly developed pineal tumor, which was confirmed as a germinoma after neuroendoscopic biopsy. Chemoradiotherapy resulted in complete remission, without any symptoms. This case demonstrated possible late occurrence of germinoma even after total removal of a mature teratoma had been achieved. A long-term follow-up of 10 years or more should be planned for these patients.

Random Skin Biopsies Before Brain Biopsy for Intravascular Large B-Cell Lymphoma.

OBJECTIVE: To evaluate effectiveness of random skin biopsies for intravascular large B-cell lymphoma (IVLBCL) with or without central nervous system (CNS) involvement. METHODS: Data from 21 patients with suspected IVLBCL (7 with CNS involvement and 14 without CNS involvement) who underwent single (4 patients), double (1 patient), and random (16 patients) skin biopsies were retrospectively analyzed. RESULTS: IVLBCL was diagnosed in 16 patients (including 6 with CNS involvement). Sensitivity, specificity, and positive predictive value of random skin biopsies were 75%, 100%, and 100%. Ratio of tumor-positive biopsy samples to plasma soluble interleukin-2 receptor (sIL-2R) values was significantly correlated in cases with data on both variables. sIL-2R values in the 6 tumor-negative skin samples (median, 1415 U/mL; range, 487-3200 U/mL) were significantly lower than in tumor-positive skin samples (median, 3550 U/mL; range, 595-8700 U/mL) with at least 1 skin specimen obtained. Mean ratio of tumor-positive biopsy samples in IVLBCL cases with low sIL-2R (<3000 U/mL) was only 45%, indicating a requirement for 3-site multiple sampling. No differences in median sIL-2 values between cases of IVLBCL with and without CNS involvement were found (2795 U/mL vs. 3550 U/mL). Steroids administered before diagnosis yielded false-negative results in 3 of 5 IVLBCL cases (all false-negative cases were IVLBCL with CNS involvement), whereas none of 11 IVLBCL cases without steroid administration yielded false-negative results. CONCLUSIONS: Random skin biopsies before brain biopsy are recommended in patients with suspected IVLBCL regardless of CNS involvement, but low sIL-2R values and steroids may yield false-negative results.

Genetic evidence implies that primary and relapsed tumors arise from common precursor cells in primary central nervous system lymphoma.

Primary central nervous system lymphoma (PCNSL) is a rare subtype of lymphoma that arises within the brain or the eyes. PCNSL recurs within the central nervous system (CNS) in most relapsed cases, whereas extra-CNS relapse is experienced in rare cases. The present study aimed at identifying the presence of common precursor cells (CPC) for primary intra- and relapsed extra-CNS tumors, and further assessing the initiating events in bone marrow (BM). Targeted deep sequencing was carried out for five paired primary intra- and relapsed extra-CNS tumors of PCNSL. Two to five mutations were shared by each pair of intra- and extra-CNS tumors. In particular, MYD88 mutations, L265P in three and P258L in one, were shared by four pairs. Unique somatic mutations were observed in all five intra-CNS tumors and in four out of five extra-CNS tumors. Remarkably, IgH clones in the intra- and the extra-CNS tumors in two pairs were distinct from each other, whereas one pair of tumors shared identical monoclonal IgH rearrangement. In a cohort of 23 PCNSL patients, L265P MYD88 mutations were examined in tumor-free BM mononuclear cells (MNC) in which the PCNSL tumors had L265P MYD88 mutations. L265P MYD88 mutations were detected by a droplet digital PCR method in nine out of 23 bone marrow mononuclear cells. These results suggest that intra- and extra-tumors are derived from CPC with MYD88 mutations in most PCNSL, arising either before or after IgH rearrangement. The initiating MYD88 mutations may occur during B-cell differentiation in BM.