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Absence of the RNF213 p.R4810K variant may indicate a severe form of pediatric moyamoya disease in Japanese patients

Shoko Hara, Maki Mukawa, Hiroyuki Akagawa, Thiparpa Thamamongood, Motoki Inaji, Yoji Tanaka, Taketoshi Maehara, Hidetoshi Kasuya, and Tadashi Nariai

OBJECTIVE

The authors’ objective was to investigate the influence of the RNF213 p.R4810K variant on the clinical presentation and outcomes of Japanese pediatric patients with moyamoya disease.

METHODS

A total of 129 Japanese patients with pediatric-onset moyamoya disease (onset age ≤ 15 years) who visited the authors’ department from 2012 to 2020 participated in this study. After RNF213 p.R4810K genotyping of each patient was performed, the relationship between genotype and clinical presentation or outcomes, including onset age, initial presentation, surgical outcomes, and subsequent cerebrovascular events, was evaluated. Patients without the p.R4810K variant were tested for RNF213 variants other than p.R4810K. The authors especially focused on the results of patients who presented with moyamoya disease at younger than 1 year of age (infantile onset).

RESULTS

Compared with the patients with heterozygous variants, patients without the p.R4810K variant were younger at onset (7.1 ± 3.7 vs 4.4 ± 0.9 years), and all 4 patients with infantile onset lacked the p.R4810K variant. A greater proportion of patients without the p.R4810K variant presented with infarction than patients with the heterozygous variant (24.0% vs 7.6%) and a decreased proportion presented with transient ischemic attack (36.0% vs 71.7%). No significant correlation was observed between p.R4810K genotype and clinical outcomes, including surgical outcomes and subsequent cerebrovascular events; however, a decreased proportion of patients without the p.R4810K variant had good surgical outcomes compared with that of patients with the heterozygous variant (76.5% vs 92.2%). Among the 25 patients without the p.R4810K variant, 8 rare variants other than p.R4810K were identified. Three of 4 patients with infantile onset had RNF213 variants other than p.R4810K, which had a more severe functional effect on this gene than p.R4810K.

CONCLUSIONS

Absence of the RNF213 p.R4810K variant may be a novel biomarker for identification of a severe form of pediatric moyamoya disease.

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Stereotactic radiosurgery for patients with multiple brain metastases: a case-matched study comparing treatment results for patients with 2–9 versus 10 or more tumors

Clinical article

Masaaki Yamamoto, Takuya Kawabe, Yasunori Sato, Yoshinori Higuchi, Tadashi Nariai, Shinya Watanabe, and Hidetoshi Kasuya

Object

Although stereotactic radiosurgery (SRS) alone is not a standard treatment for patients with 4–5 tumors or more, a recent trend has been for patients with 5 or more, or even 10 or more, tumors to undergo SRS alone. The aim of this study was to reappraise whether the treatment results for SRS alone for patients with 10 or more tumors differ from those for patients with 2–9 tumors.

Methods

This was an institutional review board–approved, retrospective cohort study that gathered data from the Katsuta Hospital Mito GammaHouse prospectively accumulated database. Data were collected for 2553 patients who consecutively had undergone Gamma Knife SRS alone, without whole-brain radiotherapy (WBRT), for newly diagnosed (mostly) or recurrent (uncommonly) brain metastases during 1998–2011. Of these 2553 patients, 739 (28.9%) with a single tumor were excluded, leaving 1814 with multiple metastases in the study. These 1814 patients were divided into 2 groups: those with 2–9 tumors (Group A, 1254 patients) and those with 10 or more tumors (Group B, 560 patients). Because of considerable bias in pre-SRS clinical factors between groups A and B, a case-matched study, which used the propensity score matching method, was conducted for clinical factors (i.e., age, sex, primary tumor state, extracerebral metastases, Karnofsky Performance Status, neurological symptoms, prior procedures [surgery and WBRT], volume of the largest tumor, and peripheral doses). Ultimately, 720 patients (360 in each group) were selected. The standard Kaplan-Meier method was used to determine post-SRS survival times and post-SRS neurological death–free survival times. Competing risk analysis was applied to estimate cumulative incidence for local recurrence, repeat SRS for new lesions, neurological deterioration, and SRS-induced complications.

Results

Post-SRS median survival times did not differ significantly between the 2 groups (6.8 months for Group A vs 6.0 months for Group B; hazard ratio [HR] 1.133, 95% CI 0.974–1.319, p = 0.10). Furthermore, rates of neurological death were very similar: 10.0% for group A and 9.4% for group B (p = 0.89); neurological death–free survival times did not differ significantly between the 2 groups (HR 1.073, 95% CI 0.649–1.771, p = 0.78). The cumulative incidence of local recurrence (HR 0.425, 95% CI 0.0.181–0.990, p = 0.04) and repeat SRS for new lesions (HR 0.732, 95% CI 0.554–0.870, p = 0.03) were significantly lower for Group B than for Group A patients. No significant differences between the groups were found for cumulative incidence for neurological deterioration (HR 0.994, 95% CI 0.607–1.469, p = 0.80) or SRS-related complications (HR 0.541, 95% CI 0.138–2.112, p = 0.38).

Conclusions

Post-SRS treatment results (i.e., median survival time; neurological death–free survival times; and cumulative incidence for local recurrence, repeat SRS for new lesions, neurological deterioration, and SRS-related complications) were not inferior (neither less effective nor less safe) for patients in Group B than for those in Group A. We conclude that carefully selected patients with 10 or more tumors are not unfavorable candidates for SRS alone. A randomized controlled trial should be conducted to test this hypothesis.

Free access

A case-matched study of stereotactic radiosurgery for patients with multiple brain metastases: comparing treatment results for 1–4 vs ≥ 5 tumors

Clinical article

Masaaki Yamamoto, Takuya Kawabe, Yasunori Sato, Yoshinori Higuchi, Tadashi Nariai, Bierta E. Barfod, Hidetoshi Kasuya, and Yoichi Urakawa

Object

Although stereotactic radiosurgery (SRS) alone for patients with 4–5 or more tumors is not a standard treatment, a trend for patients with 5 or more tumors to undergo SRS alone is already apparent. The authors' aim in the present study was to reappraise whether SRS results for ≥ 5 tumors differ from those for 1–4 tumors.

Methods

This institutional review board–approved retrospective cohort study used the authors' database of prospectively accumulated data that included 2553 consecutive patients who underwent SRS, not in combination with concurrent whole-brain radiotherapy, for brain metastases (METs) between 1998 and 2011. These 2553 patients were divided into 2 groups: 1553 with tumor numbers of 1–4 (Group A) and 1000 with ≥ 5 tumors (Group B). Because there was considerable bias in pre-SRS clinical factors between Groups A and B, a case-matched study was conducted. Ultimately, 1096 patients (548 each in Groups A and B) were selected. The standard Kaplan-Meier method was used to determine post-SRS survival and the post-SRS neurological death–free survival times. Competing risk analysis was applied to estimate cumulative incidences of local recurrence, repeat SRS for new lesions, neurological deterioration, and SRS-induced complications.

Results

The post-SRS median survival time was significantly longer in the 548 Group A patients (7.9 months, 95% CI 7.0–8.9 months) than in the 548 Group B patients (7.0 months 95% [CI 6.2–7.8 months], HR 1.176 [95% CI 1.039–1.331], p = 0.01). However, incidences of neurological death were very similar: 10.6% in Group A and 8.2% in Group B (p = 0.21). There was no significant difference between the groups in neurological death–free survival intervals (HR 0.945, 95% CI 0.636–1.394, p = 0.77). Furthermore, competing risk analyses showed that there were no significant differences between the groups in cumulative incidences of local recurrence (HR 0.577, 95% CI 0.312–1.069, p = 0.08), repeat SRS (HR 1.133, 95% CI 0.910–1.409, p = 0.26), neurological deterioration (HR 1.868, 95% CI 0.608–1.240, p = 0.44), and major SRS-related complications (HR 1.105, 95% CI 0.490–2.496, p = 0.81).

In the authors' cohort, age ≤ 65 years, female sex, a Karnofsky Performance Scale score ≥ 80%, cumulative tumor volume ≤ 10 cm3, controlled primary cancer, no extracerebral METs, and neurologically asymptomatic status were significant factors favoring longer survival equally in both groups.

Conclusions

This retrospective study suggests that increased tumor number is an unfavorable factor for longer survival. However, the post-SRS median survival time difference, 0.9 months, between the two groups is not clinically meaningful. Furthermore, patients with 5 or more METs have noninferior results compared to patients with 1–4 tumors, in terms of neurological death, local recurrence, repeat SRS, maintenance of good neurological state, and SRS-related complications. A randomized controlled trial should be conducted to test this hypothesis.