An underestimated side effect of rituximab is late-onset neutropenia (R-LON), which often resolves spontaneously and rarely results in a severe infection. We herein report a case of febrile ...neutropenia due to R-LON in a 91-year-old woman with renal failure who was treated with rituximab to induce remission of MPO-ANCA-associated vasculitis. Fifty-four days after the last rituximab administration, the patient was hospitalized for febrile neutropenia due to R-LON, which improved with granulocyte colony-stimulating factor and antibiotics. Although R-LON may resolve spontaneously and remain unnoticed, it can cause severe infections in the elderly and patients with renal failure.
Telomeres are tandem repeats of the TTAGGG sequence at chromosomal ends and afford protection against chromosomal instability. To investigate the contribution of telomere dysfunction in meningiomas, ...here we estimate the associations between telomere length, tumor grade, and proliferation index in a series of 14 archived samples, using quantitative-fluorescence in situ hybridization, Ki67 immunostaining, and pathological analysis. The number of mitoses per 10 high-power fields (HPF) and Ki67 index was higher in grade III cases than in grade I or grade II cases. Telomere length was negatively associated with both the number of mitoses/10HPF and Ki67 index. Meningioma cases with atypical mitosis, a morphological marker of chromosomal instability, exhibited shortened telomeres. Among telomere-shortened meningioma cases, 40% were grade I, 20% were grade II, and 100% were grade III. In grade I or II meningiomas, shortened telomeres lacked high proliferation activity and atypical mitosis. In conclusion, telomere shortening might be pivotal in the development of high-grade meningioma. Analysis of telomere length might be a selective marker for meningiomas with high-grade malignant potential.
Incident fatty liver increases the risk of non-alcoholic fatty liver disease (NAFLD), which may lead to end-stage liver diseases, and increase the risk of cardiovascular disease and diabetes. For its ...prevention, modeling the natural history of fatty liver is useful to demonstrate which lifestyle-related risk factors (e.g. body mass index and cholesterol) play the greatest role in the life-course of fatty liver.
Model predictors and their predictive algorithms were determined by prospective regression analyses using 5-year data from approximately 2000 Japanese men aged 20-69 years. The participants underwent health examinations and completed questionnaires on their lifestyle behaviors annually from 2012 to 2016. The life-course of fatty liver was simulated based on this participant data using Monte Carlo simulation methods. Sensitivity analyses were performed. The validity of the model was discussed.
The body mass index (BMI) and low-density/high-density lipoprotein cholesterol (LDL-C/HDL-C) ratio significantly aided in predicting incident fatty liver. When the natural history of fatty liver was simulated using the data of participants aged 30-39 years, the prevalence increased from 20% to 32% at 40-59 years before decreasing to 24% at 70-79 years. When annual updates of BMI and LDL-C/HDL-C ratio decreased/increased by 1%, the peak prevalence of fatty liver (32%) changed by -8.0/10.7% and -1.6/1.4%, respectively.
We modeled the natural history of fatty liver for adult Japanese men. The model includes BMI and LDL‒C/HDL‒C ratio, which played a significant role in predicting the presence of fatty liver. Specifically, annual changes in BMI of individuals more strongly affected the life‒course of fatty liver than those in the LDL-C/HDL-C ratio. Sustainable BMI control for individuals may be the most effective option for preventing fatty liver in a population.
Statins have pleiotropic effects that are considered beneficial in preventing cerebral vasospasm and delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage (aSAH). Many studies using ...statins have been performed but failed to show remarkable effects. We hypothesized that a long-acting statin would be more effective, due to a longer half-life and stronger pleiotropic effects. Patients with aSAH were randomly assigned to a pitavastatin group (4 mg daily; n = 54) and a placebo group (n = 54) after repair of a ruptured aneurysm. The primary efficacy end point was vasospasm-related delayed ischemic neurological deficits (DIND), and the secondary end points were cerebral vasospasm evaluated by digital subtraction angiography (DSA), vasospasm-related new cerebral infarctions, and outcome at three months. Severe cerebral vasospasms on DSA were statistically fewer in the pitavastatin group than in the placebo group (14.8% vs. 33.3%; odds ratio, 0.32; 95% confidence interval, 0.11–0.87, p = 0.042); however, the occurrence of DIND and new infarctions and outcome showed no statistically significant differences between the groups. The present study is the first to prove the definite, statin-induced amelioration of cerebral vasospasm on DSA. However, administration of any type of statin at the acute phase of aSAH is not recommended.
Background
Elderly patients with primary central nervous system malignant lymphoma (EL-PCNSL) may not be given sufficient treatment due to their poor pre-treatment Karnofsky Performance Status (KPS) ...and comorbidities. Therefore, a retrospective, cohort study was performed to evaluate risk factors associated with a poor prognosis of EL-PCNSL in the Tohoku Brain Tumor Study Group.
Methods
Patients aged ≥ 71 years with PCNSL were enrolled from eight centers. Univariate analysis was performed with the log-rank test. A Cox proportional hazards model was used for multivariate analysis.
Results
Three of the total 142 cases received best supportive care (BSC). Treatment was given to 30 cases without a pathological diagnosis, 3 cases with cerebrospinal fluid (CSF) cytology, and 100 cases with a pathological diagnosis. After confirmation of no differences in progression-free survival (PFS) and overall survival (OS) between the group treated without pathology and the groups diagnosed by pathology or CSF cytology and between median age ≥ 76 years and < 76 years, a total of 133 patients were studied. The median pre-treatment KPS was 50%. Median PFS and median OS were 16 and 24 months, respectively. Risk factors associated with poor prognosis on Cox proportional hazards model analysis were pre-treatment cardiovascular disease and central nervous system disease comorbidities, post-treatment pneumonia and other infections, and the absence of radiotherapy or chemotherapy.
Conclusions
Pre-treatment comorbidities and post-treatment complications would affect the prognosis. Radiation and chemotherapy were found to be effective, but no conclusions could be drawn regarding the appropriate content of chemotherapy and whether additional radiotherapy should be used.
Pleomorphic xanthoastrocytoma (PXA) is a rare glial tumor, however, its histological differentiation from high-grade gliomas is often difficult. Molecular characteristics may contribute to a better ...diagnostic discrimination. Prognostic factors of PXA are also important but few relevant reports have been published. This study investigated the molecular features and prognostic factors of PXAs. Seven university hospitals participated in this study by providing retrospective clinical data and tumor samples of PXA cases between 1993 and 2014. Tumor samples were analyzed for immunohistochemical (IHC) neuronal and glial markers along with Ki67. The status of the BRAF and TERT promoter (TERTp) mutation was also evaluated using the same samples, followed by feature extraction of PXA and survival analyses. In all, 19 primary cases (17 PXA and 2 anaplastic PXA) were included. IHC examination revealed the stable staining of nestin and the close association of synaptophysin to NFP. Of the PXA cases, 57% had the BRAF mutation and only 7% had the TERTp mutation. On univariate analysis, age (≥60 years), preoperative Karnofsky performance status (KPS) (≤80%), and marked peritumoral edema were significantly associated with progression-free survival (PFS). No independent factor was indicated by the multivariate analysis. In conclusion, PXA was characterized by positive nestin staining and a few TERTp mutations. The neuronal differential marker and BRAF status may help in diagnosis. Patient age, preoperative KPS, and marked perifocal edema were associated with PFS. The present study is limited because of small number of cases and its retrospective nature. Further clinical study is needed.
Clinicopathological risk factors for a poor prognosis were investigated in elderly patients with malignant lymphoma of the central nervous system. A total of 82 pathologically confirmed, ...CD20-positive, diffuse large B-cell lymphoma patients aged 71 years or older who underwent therapeutic intervention in the Tohoku and Niigata area in Japan were retrospectively reviewed. A univariate analysis was performed by the log-rank test using the Kaplan–Meier method. A Cox proportional hazards model was used for multivariate analysis of risk factors. Of the 82 patients, 39 were male and 43 were female, and their median age at onset was 75 years. At the end of the study, there were 34 relapse-free patients (41.5%), 48 relapse cases (58.5%), median progression-free survival was 18 months, and median overall survival (OS) was 26 months; there were 41 deaths and 41 survivors. Multivariate analysis of median OS showed that Karnofsky Performance Status less than 60% 3 months after treatment (
p
= 0.022, hazard ratio (HR) = 2.591) was the clinical risk factor, and double expressor lymphoma (
p
= 0.004, HR = 3.163), expression of programmed death-ligand 1 in tumor infiltrating lymphocytes or tumor-associated macrophages (
p
< 0.001, HR = 5.455), and Epstein–Barr virus infection (
p
= 0.031, HR = 5.304) were the pathological risk factors.
Giant cell glioblastoma (GC-GBM) consists of large cells with pleomorphic nuclei. As a contrast to GC-GBM, we defined monotonous small GBM (MS-GBM) as GBM that consists of small cells with monotonous ...small nuclei, and compared the DNA damage as well as other pathological features. GC-GBM showed minimal invasion (< 2 mm) and focal sarcomatous areas.
TERT
p was wild type in GC-GBM but mutant in MS-GBM. OLIG2 expression was significantly higher in MS-GBM (
P
< 0.01) (77% in MS-GBM and 7% in GC-GBM). GC-GBM showed significantly higher DNA double-strand breaks (DSBs) compared with MS-GBM (
P
< 0.01) (76% in GC-GBM and 15% in MS-GBM). Nearly, all large cells in GC-GBM underwent DSBs. Thus, significant DSBs in GC-GBM might be induced by an innate lesser stemness characteristic and be followed by mitotic slippage, resulting in polyploidization and the large pleomorphic nuclei. We conclude that GC-GBM is a distinctive subtype of glioma characterized by its vulnerability to DNA damage and that wild-type
TERT
p and lower OLIG2 function might induce this feature. Notably, even large pleomorphic nuclei with severe DSBs demonstrated Ki67 positivity, which alerts pathologists to the interpretation of Ki67 positivity, because cells with large nuclei undergoing severe DSBs cannot be recognized as proliferating cells that contribute to tumor aggressiveness.
Abstract
Background
This investigator-initiated, open-label, single-arm, single-institute study was conducted to investigate the effectiveness of induction combination chemoradiotherapy and long-term ...maintenance therapy with temozolomide (TMZ) plus interferon (IFN)-β for glioblastoma.
Methods
The initial induction combination chemoradiotherapy comprised radiotherapy plus TMZ plus vincristine plus IFN-β. Maintenance chemotherapy comprised monthly TMZ, continued for 24–50 cycles, plus weekly IFN-β continued for as long as possible. The primary endpoint was 2-year overall survival (2y-OS). The study protocol was to be considered valid if the expected 2y-OS was over 38% and the lower limit of the 95% confidence interval (CI) was no less than 31.7% compared with historical controls, using Kaplan-Meier methods. Secondary endpoints were median progression-free survival (mPFS), median OS (mOS), 5-year OS rate (5y-OS), and mPFS and mOS classified according to
MGMT
promoter methylation status.
Results
Forty-seven patients were analyzed. The 2y-OS was 40.7% (95%CI, 27.5–55.4%). The mPFS and mOS were 11.0 months and 18.0 months, respectively, and 5y-OS was 20.3% (95%CI, 10.9–34.6%). The mPFS in groups with and without
MGMT
promoter methylation in the tumor was 10.0 months and 11.0 months (
p
= 0.59), respectively, and mOS was 24.0 months and 18.0 months (
p
= 0.88), respectively. The frequency of grade 3/4 neutropenia was 19.1%.
Conclusions
The 2y-OS with induction multidrug combination chemoradiotherapy and long-term maintenance therapy comprising TMZ plus IFN-β tended to exceed that of historical controls, but the lower limit of the 95%CI was below 31.7%. Although the number of cases was small, this protocol may rule out
MGMT
promoter methylation status as a prognostic factor.
Trial registration
University Hospital Medical Information Network (number
UMIN000040599
).
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