Assessment of imaging risks for recurrence after stereotactic radiosurgery for brain metastases (IRRaS-BM).

BACKGROUND: The identification of viable tumors and radiation necrosis after stereotactic radiosurgery (SRS) is crucial for patient management. Tumor habitat analysis involving the grouping of similar voxels can identify subregions that share common biology and enable the depiction of areas of tumor recurrence and treatment-induced change. This study aims to validate an imaging biomarker for tumor recurrence after SRS for brain metastasis by conducting tumor habitat analysis using multi-parametric MRI. METHODS: In this prospective study (NCT05868928), patients with brain metastases will undergo multi-parametric MRI before SRS, and then follow-up MRIs will be conducted every 3 months until 24 months after SRS. The multi-parametric MRI protocol will include T2-weighted and contrast-enhanced T1-weighted imaging, diffusion-weighted imaging, and dynamic susceptibility contrast imaging. Using k-means voxel-wise clustering, this study will define three structural MRI habitats (enhancing, solid low-enhancing, and nonviable) on T1- and T2-weighted images and three physiologic MRI habitats (hypervascular cellular, hypovascular cellular, and nonviable) on apparent diffusion coefficient maps and cerebral blood volume maps. Using RANO-BM criteria as the reference standard, via Cox proportional hazards analysis, the study will prospectively evaluate associations between parameters of the tumor habitats and the time to recurrence. The DICE similarity coefficients between the recurrence site and tumor habitats will be calculated. DISCUSSION: The tumor habitat analysis will provide an objective and reliable measure for assessing tumor recurrence from brain metastasis following SRS. By identifying subregions for local recurrence, our study could guide the next therapeutic targets for patients after SRS. TRIAL REGISTRATION: This study is registered at ClinicalTrials.gov (NCT05868928).

Tumor habitat analysis by magnetic resonance imaging distinguishes tumor progression from radiation necrosis in brain metastases after stereotactic radiosurgery.

OBJECTIVES: The identification of viable tumor after stereotactic radiosurgery (SRS) is important for future targeted therapy. This study aimed to determine whether tumor habitat on structural and physiologic MRI can distinguish viable tumor from radiation necrosis of brain metastases after SRS. METHOD: Multiparametric contrast-enhanced T1- and T2-weighted imaging, apparent diffusion coefficient (ADC), and cerebral blood volume (CBV) were obtained from 52 patients with 69 metastases, showing enlarging enhancing masses after SRS. Voxel-wise clustering identified three structural MRI habitats (enhancing, solid low-enhancing, and nonviable) and three physiologic MRI habitats (hypervascular cellular, hypovascular cellular, and nonviable). Habitat-based predictors for viable tumor or radiation necrosis were identified by logistic regression. Performance was validated using the area under the curve (AUC) of the receiver operating characteristics curve in an independent dataset with 24 patients. RESULTS: None of the physiologic MRI habitats was indicative of viable tumor. Viable tumor was predicted by a high-volume fraction of solid low-enhancing habitat (low T2-weighted and low CE-T1-weighted values; odds ratio [OR] 1.74, p <.001) and a low-volume fraction of nonviable tissue habitat (high T2-weighted and low CE-T1-weighted values; OR 0.55, p <.001). Combined structural MRI habitats yielded good discriminatory ability in both development (AUC 0.85, 95% confidence interval [CI]: 0.77-0.94) and validation sets (AUC 0.86, 95% CI:0.70-0.99), outperforming single ADC (AUC 0.64) and CBV (AUC 0.58) values. The site of progression matched with the solid low-enhancing habitat (72%, 8/11). CONCLUSION: Solid low-enhancing and nonviable tissue habitats on structural MRI can help to localize viable tumor in patients with brain metastases after SRS. KEY POINTS: • Structural MRI habitats helped to differentiate viable tumor from radiation necrosis. • Solid low-enhancing habitat was most helpful to find viable tumor. • Providing spatial information, the site of progression matched with solid low-enhancing habitat.

Single- and hypofractionated stereotactic radiosurgery for large (> 2 cm) brain metastases: a systematic review.

PURPOSE: Since frameless stereotactic radiosurgery (SRS) techniques have been recently introduced, hypofractionated SRS (HF-SRS) for large brain metastases (BMs) is gradually increasing. To verify the efficacy and safety of HF-SRS for large BMs, we aimed to perform a systematic review and compared them with SF-SRS. METHODS: We systematically searched the studies regarding SF-SRS or HF-SRS for large (> 2 cm) BM from databases including PubMed, Embase, and the Cochrane Library on July 31, 2018. Biologically effective dose with the α/ß ratio of 10 (BED10), 1-year local control (LC), and radiation necrosis (RN) were compared between the two groups, with the studies being weighted by the sample size. RESULTS: The 15 studies with 1049 BMs that described 1-year LC and RN were included. HF-SRS tended to be performed in larger tumors; however, higher mean BED10 (50.1 Gy10 versus 40.4 Gy10, p < 0.0001) was delivered in the HF-SRS group, which led to significantly improved 1-year LC (81.6 versus 69.0%, p < 0.0001) and 1-year overall survival (55.1 versus 47.2%, p < 0.0001) in the HF-SRS group compared to the SF-SRS group. In contrast, the incidence of radiation toxicity was significantly decreased in the HF-SRS group compared to the SF-SRS group (8.0 versus 15.6%, p < 0.0001). CONCLUSION: HF-SRS results in better LC of large BMs while simultaneously reducing RN compared to SF-SRS. Thus, HF-SRS should be considered a priority for SF-SRS in patients with large BMs who are not suitable to undergo surgical resection.

Intracranial solitary fibrous tumor/hemangiopericytoma: tumor reclassification and assessment of treatment outcome via the 2016 WHO classification.

PURPOSE: As per the 2016 World Health Organization (WHO) guidelines on the classification of central nervous system tumors, solitary fibrous tumors (SFTs) and hemangiopericytomas (HPCs) constitute a single disease entity, known as SFT/HPC. This study provides a clinical analysis of these tumors and describes the treatment outcomes of SFT/HPCs. METHODS: This retrospective study included 76 patients with histopathologically proven SFT/HPC. Reclassification according to the 2016 WHO guideline was done for patients who were diagnosed with SFT or HPC based on the 2007 WHO classification. Recurrence-free survival (RFS) and overall survival (OS) were evaluated for all patients and subgroups. RESULTS: The median follow-up period was 77.9 months. The median RFS and OS were 126.5 and 136.8 months, respectively. The 1-, 5-, 10-, and 15-year RFS rates were 93%, 72%, 40%, and 40%, respectively. The 1-, 5-, 10- and 15-year OS rates were 97%, 89%, 54%, and 35%, respectively. In multivariable analyses, stereotactic radiosurgery (SRS; p = 0.009, hazard ratio [HR] 6.986), female sex (p = 0.023, HR 1.76), and age over 45 (p = 0.037, HR 2.74) were associated with shorter RFS. Patients who underwent SRS as initial treatment had a shorter OS than that of patients who underwent primary resection (p < 0.001, HR 12.86). CONCLUSIONS: High-grade tumors tended to have worse OS and occur extracranial metastases earlier than low-grade tumors. The median RFS was not different between grade II and III tumors. Male sex, younger age, and GTR were associated with a better RFS. A history of SRS before tumor resection was associated with a shorter RFS and OS.

Primary central nervous system lymphoma involving the hypothalamic-pituitary axis: a case series and pooled analysis.

PURPOSE: Primary central nervous system lymphoma (PCNSL) involving the hypothalamic-pituitary axis (H-P axis) is a rare intracranial neoplasm. We aimed to determine the unique characteristics and treatment outcomes of patients with PCNSL at the H-P axis and review the literature. METHODS: We retrospectively reviewed the electronic medical records of patients with PCNSL in our institute from 2000 to 2017. We analyzed patient characteristics, clinicopathologic features, imaging results, and treatment outcomes. Furthermore, we searched the PubMed database and gathered more cases from published studies to analyze patient treatment outcomes. RESULTS: A total of 488 patients were diagnosed with central nervous system lymphoma at our institute. Seven (1.4%) patients had H-P axis involvement, five had diffuse large B-cell lymphoma, and two had mucosa-associated lymphoid tissue lymphoma. All patients had anterior pituitary lobe dysfunction, and two had posterior lobe dysfunction. The median progression-free survival (PFS) for seven patients was 29.0 (range: 0.9-48.1) months, and the 3-year survival rate was 42.9%. Pooled analysis included 45 patients. The median PFS for these patients was 7.0 months (0.9-52.0), and the 2-year survival rate was 20%. Univariate and multivariate analyses revealed that the patients with visual field defects had better prognosis (p = 0.0153 and 0.043, respectively). CONCLUSION: PCNSL at the H-P axis is associated with a higher rate of pituitary dysfunction than other parasellar pathologies. PCNSL at the H-P axis has a worse treatment outcome than PCNSL at other sites. However, visual field defect is related to a favorable prognosis in these patients.

Hypofractionated stereotactic radiosurgery for large-sized skull base meningiomas.

PURPOSE: Although stereotactic radiosurgery (SRS) has been proven to be effective and safe for treating intracranial meningiomas, concerns have been raised about the use of SRS for large-sized tumors involving the skull base that frequently encroach onto adjacent critical neural structures. The purpose of this study was to investigate the role of hypofractionated SRS as a therapeutic option for large-sized skull base meningiomas. METHODS: Thirty-one consecutive patients (median age: 55 years, 9 men and 22 women) who had been treated with hypofractionated SRS using CyberKnife for large-sized skull base meningiomas (> 10 cm3 in volume, median of 18.9 cm3, range 11.6-58.2 cm3) were enrolled. All patients harbored middle or posterior skull base tumors, most frequently of cavernous sinus (n = 7, 22.6%), petroclival (n = 6, 19.4%), or tentorial edge (n = 6, 19.4%) locations. SRS was delivered in five daily fractions (range 3-5 fractions) with a median cumulative dose of 27.8 Gy (range 22.6-27.8 Gy). RESULTS: With a median follow-up of 57 months (range 9-98 months), tumor control was achieved for 28 (90.3%) of 31 patients. Treatment response on MRI included partial response (volume decrease > 20%) in 17 (54.8%) patients, stable in 11 (35.5%), and progression (volume increase > 20%) in 3 (9.7%). Of 21 patients with cranial neuropathy, 20 (95.2%) showed improved neurological status. CONCLUSIONS: Our current results suggest a promising role of hypofractionated SRS for large-sized skull base megningiomas in terms of tumor control and neurological outcomes. It is a reasonable therapeutic option for select patients.

Role of gamma knife radiosurgery for recurrent or residual World Health Organization grade II and III intracranial meningiomas.

Background: To analysis the role of gamma knife radiosurgery (GKRS) in treatment of the recurrent or residual World Health Organization (WHO) grade II and III meningiomas.Methods: Between 1995 and 2015, a total of 1163 meningioma patients were treated with GKRS at our single institute; 26 atypical and 6 anaplastic meningiomas were enrolled. The group consisted of 16 men and 16 women with a median age of 59.5 years (range 30-78 years). The median follow-up was 106.5 months (range 40-216 months). All were cases of tumour recurrence except 7 cases of residual lesions. Six patients were given fractionated radiotherapy before the initial course of GKRS (median dose, 56 Gy).Results: The median tumour volume was 3035 mm3 (range 247-11400 mm3). The median prescribed dose to high grade meningioma margin was 14 Gy (range 12-20 Gy,). The median prescribed dose to WHO II and III meningioma were 14 Gy (range 12-18 Gy) and 15 Gy (range 14-20 Gy), respectively. After radiosurgery, local tumour control rate was 50%. Tumour progression was observed in 28 patients; 16 recurrences were local (12 atypical and 4 anaplastic), 8 were marginal (7 atypical and 1 anaplastic), and 4 were distal (3 atypical and 1 anaplastic). Seven patients (21.88%) developed adverse radiation effects after GKRS. WHO grade was strongly associated with survival, with grade II showing a much longer survival (p = 0.01), and a prior history of radiation was associated with decreased survival (p = 0.003). Multivariate analysis showed that WHO grade (hazard ratio, HR: 5.051, p = 0.01) and prior radiation (HR: 5.763, p = 0.004) were independently associated with survival.Conclusions: WHO grade and a prior history of radiation therapy are reliable long-term predictors of overall outcome when treated with GKRS.

Tumor-infiltrating immune cell subpopulations and programmed death ligand 1 (PD-L1) expression associated with clinicopathological and prognostic parameters in ependymoma.

Ependymomas are biologically and clinically heterogeneous tumors of the central nervous system that have variable clinical outcomes. The status of the tumor immune microenvironment in ependymoma remains unclear. Immune cell subsets and programmed death ligand 1 (PD-L1) expression were measured in 178 classical ependymoma cases by immunohistochemistry using monoclonal antibodies that recognized tumor-infiltrating lymphocyte subsets (TILs; CD3, CD4, CD8, FOXP3, and CD20), tumor-associated macrophages (TAMs; CD68, CD163, AIF1), indoleamine 2,3-dioxygenase (IDO)+ cells and PD-L1-expressing tumor cells. Increases in CD3+ and CD8+ cell numbers were associated with a prolonged PFS. In contrast, increased numbers of FOXP3+ and CD68+ cells and a ratio of CD163/AIF1+ cells were significantly associated with a shorter PFS. An increase in the IDO+ cell number was associated with a significantly longer PFS. To consider the quantities of TILs, TAMs, and IDO+ cells together, the cases were clustered into 2 immune cell subgroups using a k-means clustering analysis. Immune cell subgroup A, which was defined by high CD3+, low CD68+ and high IDO+ cell counts, predicted a favorable PFS compared to subgroup B by univariate and multivariate analyses. We found six ependymoma cases expressing PD-L1. All these cases were supratentorial ependymoma, RELA fusion-positive (ST-RELA). PD-L1 expression showed no prognostic significance. This study showed that the analysis of tumor-infiltrating immune cells could aid in predicting the prognosis of ependymoma patients and in determining therapeutic strategies to target the tumor microenvironment. PD-L1 expression in the ST-RELA subgroup suggests that this marker has a potential added value for future immunotherapy treatments.

Single-fraction versus hypofractionated stereotactic radiosurgery for medium-sized brain metastases of 2.5 to 3 cm.

PURPOSE: Given recently suggested utility of hypofractionated stereotactic radiosurgery (SRS) in treating large brain metastases (BMs) > 3 cm, we sought to prospectively control tumor size variable to investigate the efficacy and safety of hypofractionated SRS for medium-sized BMs (2.5 to 3 cm) compared with single-fraction SRS. METHODS: Between 2011 and 2015, a total of 100 patients with newly diagnosed BMs (n = 105) of 2.5 to 3 cm had been treated with either single-fraction (n = 67; median dose 20 Gy) or hypofractionated SRS (n = 38; median cumulative dose 35 Gy in 5 daily fractions). No patients received any prior or upfront whole brain radiotherapy. In each patient, treatment outcome was measured by local tumor control (LTC), overall and progression-free survival (OS and PFS), and the occurrence of radiation necrosis (RN). RESULTS: With a median follow-up of 14 months, significant differences were observed between the single-fraction versus hypofractionated SRS groups in the incidence of RN (29.9% vs. 5.3%, P < 0.001) and LTC (1-year LTC rates 66.6% vs. 92.4%, P = 0.028). There were no differences in PFS (median 6 months vs. 6 months, P = 0.381) and OS (median 13 months vs. 18 months, P = 0.239). Treatment-related adverse events ( ≥ grade 2 toxicity by CTCAE ver. 4.0) occurred more frequently in single-fraction group, although the difference did not reach statistical significance (56.3% vs. 36.1%, P = 0.084). CONCLUSIONS: Our results suggest a better safety and efficacy profile of hypofractionated SRS for medium-sized BMs compared with single-fraction SRS. Further prospective studies are needed to confirm these results.

Growth rate and fate of untreated hemangioblastomas: clinical assessment of the experience of a single institution.

BACKGROUND: The growth rate and natural history of untreated hemangioblastomas remain unclear. This study investigated the natural history of untreated intracranial hemangioblastomas and predictors of tumor growth using volumetric assessment. METHOD: This study retrospectively enrolled 31 patients with untreated hemangioblastomas between 2004 and 2017 who were followed up for at least 12 months. The 31 patients had a total of 52 hemangioblastomas. RESULTS: The 31 patients included 11 (35.5%) men and 20 (64.5%) women, of mean age 42.5 years. Seventeen (54.8%) patients were genetically diagnosed with Von Hippel-Lindau (VHL) disease. Of the 52 lesions, 33 (63.5%) grew during the follow-up period, whereas 19 (36.5%) remained stable. Overall mean actual growth rate (AGR) was 1.94 cm3/year, 2.38 cm3/year in the VHL and 1.79 cm3/year in the non-VHL group (p = 0.31). Overall mean relative growth rate (RGR) was 21%/year, 26%/year in the VHL and 19%/year in the non-VHL group. Time to 50% treatment probability was 34 months. The 1, 3, 5, and 7-year treatment probabilities were 11.5%, 50.1%, 52.7%, and 73%, respectively. The presence of only symptomatic lesions was significantly predictive of the growth of intracranial hemangioblastoma (odds ratio: 5.0, p = 0.02). CONCLUSION: The overall growth rate of intracranial hemangioblastoma was faster than that of other benign intracranial tumors, with symptomatic lesions being the only meaningful predictor of tumor growth. Because of their rapid growth rate and high probability of treatment, a wait and scan management strategy should be carefully applied to intracranial hemangioblastomas.

Prognosis and treatment outcomes of central neurocytomas: clinical interrogation based on a single center experience.

INTRODUCTION: Central neurocytoma (CN) is a very rare neuronal neoplasm. The clinical implications of the potential prognostic factors for these lesions, including tumor atypia, have therefore not been clarified. METHODS: Forty CN patients were enrolled and reclassified as typical or atypical in accordance with an MIB-1 labeling index (LI) of above and below 2%. RESULTS: We classified our retrospective study cohort as 21 (52.5%) typical and 19 (47.5%) atypical CN cases. No significant differences were found in terms of sex, mean age, mean tumor size or tumor location between these groups. Recurrences occurred in 2 (9.5%) typical and 6 (33.3%) atypical cases. The typical CN 2-,3- and 5-year PFS rates were 100%, 100%, 92.3%, and those for the atypical group were 93.8%, 78.1%, 65.1%, respectively (p = 0.02). The PFS rates did not statistically differ by treatment modality (gross total resection alone, subtotal resection (STR) alone and STR plus radiation therapy (RT) or radiosurgery (RS)) either in the whole cohort (p = 0.75) or in the typical CN and atypical CN subgroups (p = 0.45 and 0.98, respectively). An atypical histology was the only prognostic indicator of recurrence by univariate analysis (hazard ratio: 5.40, p = 0.04). CONCLUSIONS: An atypical lesion (MIB-LI > 2%) is an important prognostic indicator in CN. The clinical implications of the extent of resection for CN patients are still debatable. The use of STR plus RT or RS may be a viable treatment strategy for CN but different therapeutic and follow-up approaches for atypical CN will be needed.

Radiosurgical decompression for benign perioptic tumors causing compressive cranial neuropathies: a feasible alternative to microsurgery?

Several studies have reported the efficacy and safety of hypofractionated stereotactic radiosurgery (hSRS) in the treatment of benign perioptic tumors. This study went further and evaluated the feasibility of hSRS in the treatment of those causing compressive cranial neuropathies (CCNs) among perioptic tumors with special consideration of functional improvement. Twenty-six patients with CCNs (CN II = 19; CN III/IV/VI = 9; CN V = 3) caused by perioptic tumors underwent hSRS between 2011 and 2015. hSRS was delivered in five fractions with a median marginal dose of 27.8 Gy (≈14 Gy in a single fraction, assuming an α/ß of three) to a tumor volume of 8.2 ± 8.3 cm3. All tumors except one shrank after treatment, with a mean volume decrease of 35 % (range 4-84 %) during the mean follow-up period of 20 months. In 19 patients (38 eyes) with compressive optic neuropathy, vision improved in 55.3 % of eyes (n = 21), was unchanged in 36.8 % (n = 14), and worsened in 7.9 % (n = 3) (2.6 % after excluding two eyes deteriorated due to transient tumor swelling). A higher conformity index (p = 0.034) and volume of the optic apparatus receiving >23.0 Gy (p = 0.019) were associated with greater tumor shrinkage. A greater decrease in tumor volume (p = 0.035) was associated with a better improvement in vision. Ophthalmoplegia and facial hypesthesia improved in six of nine (66.7 %) and three of three (100 %) patients, respectively. There was no newly developed neurological deficit. Decompressive SRS for benign perioptic tumors causing CCN is feasible using hypofractionation, representing a useful alternative to microsurgical resection.

Hypofractionated stereotactic radiosurgery for pituitary metastases.

Pituitary metastases (PMs) are uncommon, representing only 1% of pituitary lesions. The diagnosis of PMs can be challenging and an optimal management remains to be determined. Here, we present a pilot clinical study on the efficacy and safety of hypofractionated stereotactic radiosurgery (SRS) with an optimized dosimetric plan in treating PMs. Between June 2013 and December 2014, seven consecutive patients (4 men and 3 women; median age 62 years) had been diagnosed with PMs based on their characteristic clinical and radiological features and subsequently treated using hypofractionated SRS. Primary cancers originated from the lung (n = 5) or the breast (n = 2). All patients presented with diabetes insipidus (DI). Anterior pituitary and visual dysfunction were combined in 4 and 3 patients, respectively. On magnetic resonance imaging (MRI), PMs involved the pituitary stalk and/or the posterior lobe in all patients. SRS of a cumulative marginal dose 31 Gy with dose-volume constraints for the optic apparatus was delivered in 5 daily fractions. As results, tumor was locally controlled in all patients with substantial responses on MRI (including complete remission in 4 patients). The median survival time was 14 months (range, 6-24 months) after SRS. DI and visual dysfunction improved in all patients, although anterior pituitary dysfunction did not recover. No patients experienced any deterioration in visual, pituitary, or other cranial nerve functions. These results suggest a promising role of hypofractionated SRS in treating PMs in terms of both tumor control and functional outcomes.

The impact of postoperative radiation therapy on patterns of failure and survival improvement in patients with intracranial hemangiopericytoma.

Because of the rarity of intracranial hemangiopericytomas (HPCs), the role of postoperative radiation therapy (PORT) in the management of HPC remains unclear. This study therefore analyzed the effects of PORT on patterns of failure and survival improvement in patients with HPC. Fifty-two patients surgically treated for intracranial HPC at our institution between 1992 and 2013 were retrospectively analyzed. Patterns of failure were subdivided into local recurrence, regional metastasis, and distant metastasis. Multivariate Cox proportional hazards models were used to assess factors prognostic of treatment failure and survival, and a time-dependent Cox proportional hazards models were used to investigate the correlations between patterns of failure and death. Of the 52 patients, 45 (87 %) underwent gross total resection, and 39 (75 %) received PORT. PORT significantly lengthened local control (LC) and overall survival (OS), by 14 and 13 months, respectively, independent of the extent of resection. Patients who did and did not receive PORT had 5 year LC rates of 97 and 44 %, respectively (HR .05, P = .002); and 10 year OS rates of 83 and 25 %, respectively (hazard ratio (HR) .20, P = .008). PORT, however, did not show preventive effects on regional and distant metastases. The main patterns of failure were local recurrence in patients who did not receive PORT and distant metastasis in those who received PORT. Regional metastasis was a main immediate cause of death (P < .001), and tended to occur more frequently and earlier in patients not receiving PORT.

Transzygomatic approach with anteriorly limited inferior temporal gyrectomy for large medial tentorial meningiomas.

BACKGROUND: Tentorial meningiomas near the middle third of the medial tentorial edge with supratentorial extension are usually removed via the subtemporal approach. This approach, however, may not be practical, especially for huge tumors extending to the posterior subtemporal space. This study describes the use of the transzygomatic approach with anteriorly limited inferior temporal gyrectomy (TZ-AITG) to remove these large tumors. METHODS: Between 2008 and 2012, five patients with symptomatic tentorial meningiomas (median diameter, 5.2 cm; range, 4.0-5.7 cm) near the middle third of the medial tentorial edge with supratentorial extension underwent TZ-AITG, consisting of zygomatic osteotomy, low-positioned craniotomy, and resection of the inferior temporal gyrus around 4 cm from the tip. RESULTS: Tumors were completely resected in all patients. Postoperatively, none had a newly developed neurological morbidity, and none died. Of three patients with preoperative hemianopia, two showed improvement and one remained stationary. One patient with preoperative hemiparesis recovered completely. All patients returned to their normal activities during the follow-up period. Surgical morbidities included epidural hematoma and chronic subdural hematoma in one patient each, with both requiring evacuation. CONCLUSIONS: TZ-AITG may be a good alternative to the subtemporal approach for large tentorial meningiomas near the middle third of the medial tentorial edge. TZ-AITG provides access to the lesions and visualization of the middle fossa, facilitating early feeder control while minimizing brain retraction, thus reducing potential injury to the vein of Labbé. TZ-AITG is also safe and feasible in minimizing neurological compromise.

Experiences on two different stereotactic radiosurgery modalities of Gamma Knife and Cyberknife in treating brain metastases.

BACKGROUND: In this study, we compared the dosimetric properties between Gamma Knife (GK) and Cyberknife (CK), and investigated the clinical implications in treating brain metastases (BMs). METHODS: Between 2011 and 2013, 77 patients treated with either single-fraction GK for small BMs (n = 40) or fractionated CK for large BMs >3 cm (n = 37) were analyzed. Among a total of 160 lesions, 81 were treated with GK (median, 22 Gy) and 38 (large lesions) with three- or five-fraction CK (median, 35 Gy). The median tumor volume was 1.0 cc (IQR, 0.12-4.4 cc) for GK and 17.6 cc (IQR, 12.8-23.7 cc) for fractionated CK. A lesion-to-lesion dosimetric comparison was performed using the identical contour set in both systems. RESULTS: The mean dose to tumor was significantly higher in GK by 1.25-fold (P < 0.001), whereas normal tissue volume receiving 90-10 % of prescription dose was significantly larger in CK by 1.26-fold (P < 0.001). Nevertheless, no differences were observed in local tumor control (rates at 1 year, 89.7 % vs 87.0 %; P = 0.594) and overall survival (median, 14 vs 16 months; P = 0.493) between GK and fractionated CK groups. The incidences of radiation necrosis were also not different (12.3 % vs 15.8 %; P = 0.443). CONCLUSIONS: Despite slightly inferior dosimetric properties of CK, fractionated CK for large BMs appears to be as effective and safe as single-fraction GK for small BMs, representing fractionation as an effective strategy for enhancing efficacy and moderating toxicity in stereotactic radiosurgery for BMs.

BLH1 and KNAT3 modulate ABA responses during germination and early seedling development in Arabidopsis.

The signal transduction pathway governed by the phytohormone abscisic acid (ABA) regulates not only abiotic stress responses but also early developmental programs such as seed dormancy, germination and seedling growth in response to environmental signals. Optimal plant growth and development depend on the integration of environmental stimuli and intrinsic developmental programs. Here, we show that the homeodomain transcription factors BLH1 and KNAT3, previously implicated in embryo sac development, have additional functions in ABA-mediated seed dormancy and early seedling development. The ABA-dependent induction of BLH1 and KNAT3 expression required the presence of functional PYR/PYL/RCAR receptors. The blh1 and knat3 mutants were less sensitive than the wild-type to ABA or salinity exposure during seed germination and early seedling development. In contrast, BLH1 over-expressing lines were hypersensitive to ABA and salinity, and exhibited increased expression of ABA-responsive genes, such as ABI3 and ABI5. BLH1 interacted with KNAT3 and enhanced the retention of KNAT3 in the nucleus. BLH1 and KNAT3 synergistically increased the ABA responses by binding to and subsequently activating the ABI3 promoter. Taken together, we propose that BLH1 and KNAT3 together modulate seed germination and early seedling development by directly regulating ABI3 expression.

BAT1, a putative acyltransferase, modulates brassinosteroid levels in Arabidopsis.

Brassinosteroids (BRs) are essential for various aspects of plant development. Cellular BR homeostasis is critical for proper growth and development of plants; however, its regulatory mechanism remains largely unknown. BAT1 (BR-related acyltransferase 1), a gene encoding a putative acyltransferase, was found to be involved in vascular bundle development in a full-length cDNA over-expressor (FOX) screen. Over-expression of BAT1 resulted in typical BR-deficient phenotypes, which were rescued by exogenously applied castasterone and brassinolide. Analyses of BR profiles demonstrated that BAT1 alters levels of several brassinolide biosynthetic intermediates, including 6-deoxotyphasterol, typhasterol and 6-deoxocastasterone. BAT1 is mainly localized in the endoplasmic reticulum. BAT1 is highly expressed in young tissues and vascular bundles, and its expression is induced by auxin. These data suggest that BAT1 is involved in BR homeostasis, probably by conversion of brassinolide intermediates into acylated BR conjugates.

Changes in graft thickness after skull defect reconstruction with autogenous split calvarial bone graft.

The ideal material for primary reconstruction of skull defect would be the autogenous bone. However, the long-term evaluation regarding the change in bone graft thickness has not been reported. In this article, we analyzed the thickness changes of the graft according to the time period. Between March 2005 and February 2011, a total of 29 patients underwent skull reconstruction with autogenous split calvarial bone grafts. After applying exclusion criteria, computed tomographic (CT) images of 15 patients were analyzed. The donor bone was harvested in full thickness as 1 piece and then as split. One half of the bone plate was transferred to the defect site; the other half, to the donor site. Both halves were fixed with titanium plates. To compare graft thickness changes, immediate postoperative and follow-up CT scans were analyzed by a single researcher. An anatomic reference was appointed for each patient, and the thickness of the graft on the same level was measured on time-series CT images. Collected data were analyzed with a polynomial random coefficient model. The main causes of the skull defects were trauma and tumor excision. In all cases, the graft thickness was not decreased but even increased in both the donor and recipient sites. The mean graft thicknesses between 6 months and 1 year after the surgery as well as those between 2 and 3 years after the surgery were 1.24-times and 1.56-times thicker than the immediate postoperative thickness, respectively. Graft thickness turned out to be either maintained or increased over time.

Local Ablative Therapy Combined With Pembrolizumab in Patients With Synchronous Oligometastatic Non-Small Cell Lung Cancer: A Recursive Partitioning Analysis.

PURPOSE: This study aimed to evaluate the efficacy of local ablative therapy (LAT) combined with pembrolizumab in patients with synchronous oligometastatic non-small cell lung cancer (NSCLC) and to identify patients who would most benefit from LAT. METHODS AND MATERIALS: We retrospectively identified patients who received diagnosis of synchronous oligometastatic NSCLC (≤5 metastatic lesions and ≤3 organs involved) and were treated with first-line pembrolizumab between January 2017 and December 2022. Patients who underwent LAT, including surgery or radiation therapy at all disease sites, were compared with those who did not undergo LAT. A recursive partitioning analysis (RPA) model was developed using prognostic factors for progression-free survival (PFS). RESULTS: Among the 258 patients included, 78 received LAT with pembrolizumab, and 180 received pembrolizumab alone. The median follow-up duration was 15.5 months (range, 3.0-71.2 months). In the entire cohort, LAT was independently associated with significantly improved PFS (hazard ratio [HR], 0.64; P = .015) and overall survival (OS) (HR, 0.61; P = .020). In the propensity score-matched cohort (N = 74 in each group), the median PFS was 19.9 months and 9.6 months, respectively (P = .003), and the median OS was 42.2 months and 20.5 months, respectively (P = .045), for the LAT and non-LAT groups. Based on the RPA model, incorporating the number of metastatic lesions, performance status, and programmed cell death-ligand 1 expression level, patients were stratified into 3 risk groups with distinct PFS. LAT significantly improved PFS and OS in the low- and intermediate-risk groups; however, no difference was observed in the high-risk group. LAT was more effective as a consolidative treatment after pembrolizumab initiation than as an upfront therapy. CONCLUSIONS: LAT combined with pembrolizumab was associated with higher PFS and OS compared with pembrolizumab alone in selected patients with synchronous oligometastatic NSCLC. The RPA model could serve as a valuable clinical tool for identifying appropriate patients for LAT.