Impact of breast cancer subtype on clinical outcomes after Gamma Knife radiosurgery for brain metastases from breast cancer: a multi-institutional retrospective study (JLGK1702).

INTRODUCTION: Brain metastasis (BM) is one of the most important issues in the management of breast cancer (BC), since BMs are associated with neurological deficits. However, the importance of BC subtypes remains unclear for BM treated with Gamma Knife radiosurgery (GKS). Thus, we conducted a multicenter retrospective study to compare clinical outcomes based on BC subtypes, with the aim of developing an optimal treatment strategy. METHODS: We studied 439 patients with breast cancer and 1-10 BM from 16 GKS facilities in Japan. Overall survival (OS) was analyzed by the Kaplan-Meier method, and cumulative incidences of systemic death (SD), neurologic death (ND), and tumor progression were estimated by competing risk analysis. RESULTS: OS differed among subtypes. The median OS time (months) after GKS was 10.4 in triple-negative (TN), 13.7 in Luminal, 31.4 in HER2, and 35.8 in Luminal-HER2 subtype BC (p < 0.0001). On multivariate analysis, poor control of the primary disease (hazard ratio [HR] = 1.84, p < 0.0001), active extracranial disease (HR = 2.76, p < 0.0001), neurological symptoms (HR 1.44, p = 0.01), and HER2 negativity (HR = 2.66, p < 0.0001) were significantly associated with worse OS. HER2 positivity was an independent risk factor for local recurrence (p = 0.03) but associated with lower rates of ND (p = 0.03). TN histology was associated with higher rates of distant brain failure (p = 0.03). CONCLUSIONS: HER2 positivity is related to the longer OS after SRS; however, we should pay attention to preventing recurrence in Luminal-HER2 patients. Also, TN patients require meticulous follow-up observation to detect distant metastases and/or LMD.

Salvage gamma knife radiosurgery for active brain metastases from small-cell lung cancer after whole-brain radiation therapy: a retrospective multi-institutional study (JLGK1701).

PURPOSE: To evaluate the efficacy of gamma knife radiosurgery (GKS) for brain metastases (BMs) from small-cell lung cancer after whole-brain radiotherapy (WBRT). METHODS: We retrospectively analyzed the usefulness and safety of GKS in 163 patients from 15 institutions with 1-10 active BMs after WBRT. The usefulness and safety of GKS were evaluated using statistical methods. RESULTS: The median age was 66 years, and 79.1% of patients were men. The median number and largest diameter of BM were 2.0 and 1.4 cm, respectively. WBRT was administered prophylactically in 46.6% of patients. The median overall survival (OS) was 9.3 months, and the neurologic mortality was 20.0%. Crude incidences of local control failure and new lesion appearance were 36.6% and 64.9%, respectively. A BM diameter ≥ 1.0 cm was a significant risk factor for local progression (hazard ratio [HR] 2.556, P = 0.039) and neurologic death (HR 4.940, P = 0.031). Leukoencephalopathy at the final follow-up was more prevalent in the therapeutic WBRT group than in the prophylactic group (P = 0.019). The symptom improvement rate was 61.3%, and neurological function was preserved for a median of 7.6 months. Therapeutic WBRT was not a significant risk factor for OS, neurological death, local control, or functional deterioration (P = 0.273, 0.490, 0.779, and 0.560, respectively). Symptomatic radiation-related adverse effects occurred in 7.4% of patients. CONCLUSIONS: GKS can safely preserve neurological function and prevent neurologic death in patients with 1-10 small, active BMs after prophylactic and therapeutic WBRT.

[Contribution of increasing age to carotid plaque morphology and symptoms].

OBJECTIVE: Aging is considered to cause atherosclerotic changes in the carotid artery, but few studies have evaluated this relationship. In this study, we used carotid plaques removed from patients with carotid artery stenosis and investigated how aging contributes to carotid plaque morphology and symptoms. MATERIALS AND METHODS: A total of 60 patients(55 men, 5 women; mean age, 70.5 years; range, 53-85 years) treated at our hospital between January 2009 and April 2012 were enrolled in this study. All patients underwent carotid endarterectomy; their carotid plaques were stained with hematoxylin-eosin and/or Elastica-Masson stain and examined by a pathologist. Using these data, the carotid systolic velocity and plaque morphology were analyzed considering the age by decade as well as the symptomatology. RESULTS: Of the 60 patients, 29 were symptomatic(transient ischemic attack (TIA) in 8 patients; infarction in 20;and amaurosis in 1). Symptoms were less common as patient age increased. The incidence of TIA also tended to decrease with an increase in age, although the opposite trend was seen with infarction. In plaque morphology, the presence of active plaque, macrophage, inflammatory infiltration, and capillary angiogenesis decreased as age increased, while the presence of degenerative plaques, decrease in smooth muscle cell number, and calcification inversely increased. Active, degenerative, and combined (active/degenerative) lesions are statistically unrelated to symptoms as well as systolic velocity (cm/sec) at the carotid stenosis. The rates of hemorrhagic lesions were similar among decades, but the lesion statistically contributed to increasing symptoms (p=0.0045) and increasing systolic velocity (p=0.031). CONCLUSION: Increasing age contributes to morphological changes in carotid plaques and symptoms. When hemorrhagic lesions are suspected in carotid plaques, patients will be symptomatic and may require surgery.

[CSF leakage and anosmia in aneurysm clipping of anterior communicating artery by basal interhemispheric approach].

We studied the incidence of postoperative infection related to CSF leakage and anosmia in basal interhemispheric approach (BIH). Between April, 1990 to March, 2009, 142 cases of anterior communicating (Acom) aneurysm including both unruptured and ruptured have been treated by clipping surgery using BIH. We retrospectively obtained clinical informations from medical records and video records about infectious complications, CSF leakage of cerebrospinal fluid (CSF), olfactory dysfunction and intraoperative findings of damage to the olfactory nerve. In most cases (139 patients, 97%), frontal sinus were opened at craniotomy. Of all, CSF rinorrhea occurred in 4 cases (2.8%), and meningitis in 6 cases. There was only one patient who sufferd from meningitis due to CSF rinorrhea. All that patients recovered completely without deficit. Anosmia occurred in 6 cases (4.2%), and intraoperative injuries in 4 cases (2.8%). There was only one patient in whom anosmia was consistent with nerve injury. In conclusion, BIH is an appropriate procedure for infection risk control in Acom aneurysm surgery. It is difficult to avoid olfactory dysfunction completely, even if olfactory nerves are preserved in form.

[Is hyperdynamic therapy possible for elderly patients with vasospasm following subarachnoid hemorrhage?].

BACKGROUND: Recently we have an increased number of elderly patients with subarachnoid hemorrhage (SAH) to be treated. Elderly patients are expected to have a worse cardiac function than that of younger patients. A question arises whether management for elderly patients in the vasospasm period can be performed as safely as it is for younger patients. The aim of this study is to examine the cardiac function of the elderly patients (> or =75 y.o.) with SAH correlated with various complications in the vasospasm period. MATERIALS: We retrospectively analyzed consecutive 356 patients with SAH encountered in our institute since 2000 to 2006. Seventy-three patients (20.5% of all) are 75 or more than 75-year-old. Their mean age is 80.4 +/- 4.43 (16 male, 57 female). Cardiac function was examined by trans-thoracic echocardiography (CTE) in 40 patients (54.8%). RESULT: Average value of their ejection fraction (EF) and rates of perioperative complications were not so different from those of the younger patients. But among patients of > or =75 y.o., certain patients in whom EF was under 0.6 significantly have experienced cardiopulmonary complications and longer hospitalization. In a multiple logistic analyses, only EF is significantly related with cardiopulmonary complications (P = 0.013). CONCLUSIONS: Among elderly SAH patients > or =75 year of age, some have experienced more cardiopulmonary complications than younger patients and have needed longer hospitalization. For such patients hyperdynamic therapy must be carefully carried out. TTE is effective to predispose and help eliminate their cardiopulmonary complications in the pre- and postoperative period.

[Elderly patient with cerebellar malignant astrocytoma].

Malignant cerebellar astrocytoma is very rare and the prognosis is extremely poor. We report herein the case of an elderly patient with malignant cerebellar astrocytoma. This 80-year-old man initially presented with dizziness and ataxia of the right hand. Metastatic cerebellar tumor was diagnosed on first admission, based on a past history of colon cancer treated by surgery and magnetic resonance imaging (MRI) findings supporting the diagnosis of metastasis. The patient underwent gamma knife surgery (20 Gy) and was discharged. Follow-up after discharge was insufficient. Two years after gamma knife surgery, he returned to our hospital complaining of dizziness, headache, and right limb ataxia. MRI revealed a cystic mass in the right cerebellar hemisphere, and the lesion was removed by right suboccipital craniotomy. The tumor represented malignant astrocytoma. Optimal management of patients harboring sush difficult. to-treat tumors, including the role of gamma-knife radiosurgery, is discussed.

Comparison of treatment results between 3- and 2-stage Gamma Knife radiosurgery for large brain metastases: a retrospective multi-institutional study.

OBJECTIVE: In order to obtain better local tumor control for large (i.e., > 3 cm in diameter or > 10 cm3 in volume) brain metastases (BMs), 3-stage and 2-stage Gamma Knife surgery (GKS) procedures, rather than a palliative dose of stereotactic radiosurgery, have been proposed. Here, authors conducted a retrospective multi-institutional study to compare treatment results between 3-stage and 2-stage GKS for large BMs. METHODS: This retrospective multi-institutional study involved 335 patients from 19 Gamma Knife facilities in Japan. Major inclusion criteria were 1) newly diagnosed BMs, 2) largest tumor volume of 10.0-33.5 cm3, 3) cumulative intracranial tumor volume ≤ 50 cm3, 4) no leptomeningeal dissemination, 5) no more than 10 tumors, and 6) Karnofsky Performance Status 70% or better. Prescription doses were restricted to between 9.0 and 11.0 Gy in 3-stage GKS and between 11.8 and 14.2 Gy in 2-stage GKS. The total treatment interval had to be within 6 weeks, with at least 12 days between procedures. There were 114 cases in the 3-stage group and 221 in the 2-stage group. Because of the disproportion in patient numbers and the pre-GKS clinical factors between these two GKS groups, a case-matched study was performed using the propensity score matching method. Ultimately, 212 patients (106 from each group) were selected for the case-matched study. Overall survival, tumor progression, neurological death, and radiation-related adverse events were analyzed. RESULTS: In the case-matched cohort, post-GKS median survival time tended to be longer in the 3-stage group (15.9 months) than in the 2-stage group (11.7 months), but the difference was not statistically significant (p = 0.65). The cumulative incidences of tumor progression (21.6% vs 16.7% at 1 year, p = 0.31), neurological death (5.1% vs 6.0% at 1 year, p = 0.58), or serious radiation-related adverse events (3.0% vs 4.0% at 1 year, p = 0.49) did not differ significantly. CONCLUSIONS: This retrospective multi-institutional study showed no differences between 3-stage and 2-stage GKS in terms of overall survival, tumor progression, neurological death, and radiation-related adverse events. Both 3-stage and 2-stage GKS performed according to the aforementioned protocols are good treatment options in selected patients with large BMs.

Acquisition of resistance to antitumor alkylating agent ACNU: a possible target of positron emission tomography monitoring.

Early detection of tumor response to chemotherapy is of great importance for appropriate treatment of tumors. In this study, characteristics of two positron emission tomography (PET) tracers, [(18)F]2-fluoro-2-deoxy-D-glucose (FDG) and[(18)F]3'-fluoro-3'-deoxy-thymidine (FLT), in the early detection of tumor cell response as well as tolerance development to chemotherapy was compared using rat C6 glioma cells and 1-(4-amino-2-methyl-5-pyrimidinyl)-methyl-3-(2-chloroethyl)-3-nitrosoureahydrochloride (ACNU). ACNU is an alkylating agent known to induce drug resistance through expression of O(6)-methylguanine-deoxyribonucleic acid methyl transferase (O(6)-MGMT). We established an ACNU-resistant C6 glioma cell line (C6/ACNU) and investigated the effect of ACNU on the uptake of FLT and FDG. In C6 cells, DNA synthesis presented as [(3)H]thymidine ([(3)H]Thd) incorporation into DNA was quickly suppressed by ACNU. In C6/ACNU cells, the suppression was recovered promptly, indicating that DNA alkylation occurs initially but highly expressed O(6)-MGMT repairs DNA, leading to the recovery of DNA synthesis. The patterns of FLT uptake in C6 and C6/ACNU were difficult to distinguish in the very early stage of the treatment, though it was reported that FLT uptake well correlated with proliferation in certain conditions. FDG uptake showed different patterns between the resistant and control cells, with significantly decreased uptake in C6 cells and unchanged uptake in C6/ACNU cells at 18-24 h after the treatment. Though difficult to be directly translated into clinical situation, the present study will provide a base to develop an appropriate protocol to assess tumor response to treatment by PET and to design effective treatment plans.

Gamma Knife radiosurgery for brain metastases from pulmonary large cell neuroendocrine carcinoma: a Japanese multi-institutional cooperative study (JLGK1401).

OBJECTIVE In 1999, the World Health Organization categorized large cell neuroendocrine carcinoma (LCNEC) of the lung as a variant of large cell carcinoma, and LCNEC now accounts for 3% of all lung cancers. Although LCNEC is categorized among the non-small cell lung cancers, its biological behavior has recently been suggested to be very similar to that of a small cell pulmonary malignancy. The clinical outcome for patients with LCNEC is generally poor, and the optimal treatment for this malignancy has not yet been established. Little information is available regarding management of LCNEC patients with brain metastases (METs). This study aimed to evaluate the efficacy of Gamma Knife radiosurgery (GKRS) for patients with brain METs from LCNEC. METHODS The Japanese Leksell Gamma Knife Society planned this retrospective study in which 21 Gamma Knife centers in Japan participated. Data from 101 patients were reviewed for this study. Most of the patients with LCNEC were men (80%), and the mean age was 67 years (range 39-84 years). Primary lung tumors were reported as well controlled in one-third of the patients. More than half of the patients had extracranial METs. Brain metastasis and lung cancer had been detected simultaneously in 25% of the patients. Before GKRS, brain METs had manifested with neurological symptoms in 37 patients. Additionally, prior to GKRS, resection was performed in 17 patients and radiation therapy in 10. A small cell lung carcinoma-based chemotherapy regimen was chosen for 48 patients. The median lesion number was 3 (range 1-33). The median cumulative tumor volume was 3.5 cm3, and the median radiation dose was 20.0 Gy. For statistical analysis, the standard Kaplan-Meier method was used to determine post-GKRS survival. Competing risk analysis was applied to estimate GKRS cumulative incidences of maintenance of neurological function and death, local recurrence, appearance of new lesions, and complications. RESULTS The overall median survival time (MST) was 9.6 months. MSTs for patients classified according to the modified recursive partitioning analysis (RPA) system were 25.7, 11.0, and 5.9 months for Class 1+2a (20 patients), Class 2b (28), and Class 3 (46), respectively. At 12 months after GKRS, neurological death-free and deterioration-free survival rates were 93% and 87%, respectively. Follow-up imaging studies were available in 78 patients. The tumor control rate was 86% at 12 months after GKRS. CONCLUSIONS The present study suggests that GKRS is an effective treatment for LCNEC patients with brain METs, particularly in terms of maintaining neurological status.

Concept of ideal closure line for clipping of middle cerebral artery aneurysms--technical note.

The concept of optimum closure line was applied to a series of 51 consecutive middle cerebral artery aneurysms (14 ruptured, 37 unruptured) in 41 patients, 16 men and 25 women aged 29-79 years (mean 59.1 years). Visual inspection through the operating microscope revealed 3 types of aneurysm based on the origin of the aneurysm: bifurcation type (n = 39), trunk type (n = 9), and combined type (n = 3). Clipping along the optimum closure line should restore the vascular structure to the original configuration. Combination clip techniques were useful to form a curved closure line. This technique requires adequate operative fields with dissection of the aneurysm and related arteries from the neighboring structures as far as possible. The closure line concept is helpful to decide how to apply clips for particular aneurysms to avoid risks of ischemic complication and future recurrence. Combination clip techniques are often necessary to match a curved closure line.