Introduction to novel developments in radio-imaging and radiotherapy

Radiation therapy has long been known to be a very effective form of therapy in relieving symptoms and prolonging the life of patients with brain metastases. Novel developments in this field have allowed oncologists to improve on older forms of radiation therapy; these recent advances in radiotherapeutic techniques (stereotactic radiosurgery and hippocampal-avoidant whole brain radiation therapy) allow sparing of the healthy brain from receiving unnecessary radiation while delivering effective treatment to the metastases, thus improving the quality of life for surviving patients. Furthermore, multiple clinical trials have documented the increased loco-regional control in the brain when radiosurgery is interdigitated with immune check point inhibitors for treatment of melanoma brain metastases. Mild hyperthermia has been used for decades as an adjuvant to radiotherapy in the treatment of radiation resistant cancers; lately, however, thermal therapies, such as hyperthermia, cryoablation, radiofrequency ablation and high intensity focused ultrasound are being investigated to provide a new ablative approach to cancer while thermoacoustic imaging and thermometry have recently been proposed as new techniques for monitoring tissue temperature in the breast during ablation treatment. In addition, other hybrid techniques have emerged that combine ultrasounds with other forms of energy such as light to provide a more accurate diagnosis and enhance the efficacy of therapy for early and late stage cancers.

     

Cost-effectiveness of Linac-based single-isocenter non-coplanar technique (HyperArcTM) for brain metastases radiosurgery

In the last few years, the major change has occurred in the expansion of indications for radiosurgery (SRS) to include patients with more than four brain metastases (BM). To address the expanding indications for SRS in the treatment of multiple BMs, HyperArcTM (Varian Medical System, Palo Alto, CA, U.S.) was recently introduced in order to automate and simplify sophisticated treatments such as SRS/FSRT for multiple lesions (up to 20 BM). In this editorial some consideration about HyperArc cost-effectiveness were discussed in terms of reduction of treatment delivery time (multiple intracranial targets can be treated in a few minutes), the reduction of overall treatment time (treatment course of SRS of multiple BMs in a single session, rather than having to irradiate lesion per lesion during separate sessions on different days); reduction of costs for health systems. In summary HyperArc? system is a promising, safe and accurate solution for SRS/SFRT to treat multiple BMs in a single or few sessions. This has the potential to impact direct and indirect costs of SRS/SFRT delivery.     

Radiobiology and radiotherapy of brain metastases

Brain metastases are the most common intracranial tumors in adults, accounting for more than 50% of all such cases. The approach to and management of brain metastases have evolved significantly in recent years due to several reasons. These include advances in neurosurgical and radiotherapeutic techniques, improved systemic therapy options offering better systemic and intracranial disease control and prolongation of survival as a result of these improvements, making side-effects of proposed therapies (e.g. neurocognitive decline from whole brain radiotherapy) an important consideration. In this article, we review the the primary therapeutic approaches to the management of brain metastases, namely, surgery, stereotactic radiosurgery, and whole brain radiation therapy and the primary factors dictating choice.     

RapidArc与Novalis Knife在多发脑转移瘤SRS中的剂量学比较

目的:比较基于多叶准直器的RapidArc与基于圆形限光筒的Novalis Knife在多发脑转移瘤立体定向放射外科（SRS）中的剂量学差异。方法:选取10例已进行Novalis Knife治疗的多发脑转移瘤患者（转移瘤3~5个/人）,共37个转移瘤。重新设计单中心、非共面4弧的RapidArc SRS计划,靶区处方剂量统一为16 Gy。比较Novalis Knife计划和RapidArc SRS计划中靶区的剂量适形度指数和均匀性指数、靶区周围剂量梯度指数、正常脑组织等剂量线体积（V16、V12、V9、V6、V3）以及治疗所需的机器跳数。结果:RapidArc SRS计划相较于Novalis Knife计划,适形度指数更接近于1（0.79[±]0.10 vs 0.50[±]0.22, P=0.000）,均匀性指数更接近于0（0.07[±]0.01 vs 0.15[±]0.07, P=0.000）,但靶区周围剂量梯度指数较大（15.92[±]12.43 vs 5.05[±]3.53, P=0.000）。对于正常脑组织等剂量线体积,RapidArc SRS计划中V16明显小于Novalis Knife计划（P=0.005）;两计划的V12、V9无明显差异（P=0.445, 0.059）;而RapidArc SRS计划中V6、V3明显大于Novalis Knife计划（P=0.005, 0.005）。RapidArc SRS计划的机器跳数明显少于Novalis Knife计划（P=0.005）。结论:RapidArc SRS计划通过设置单一治疗等中心可实现颅内多个转移瘤的同步放射外科治疗,具有更高的靶区剂量适形度及均匀性;但靶区周边剂量跌落陡度不及Novalis Knife计划,正常脑组织低剂量受照范围较大。治疗依从性较差的多发脑转移患者可考虑选择治疗效率更高的RapidArc技术,并根据临床实际情况调整剂量分割模式,以减少放射损伤风险。     

Brain metastases in patients under 50?years of age: retrospective analysis

Several previous publications suggested that younger patients with brain metastases have longer survival than older patients. However, detailed studies of younger patient groups are scarce. Therefore, a multi-institutional analysis of younger patients with brain metastases was performed (defined as adults with age <50?years). Prognostic factors for survival were examined by uni- and multivariate analyses and compared to those obtained in patients with age ??50?years. Multivariate analysis of 106 patients (median age 44?years, range 23?C49?years) revealed three independent prognostic factors for survival: performance status, extracranial metastases and primary tumor control. Survival was significantly better in patients treated after the year 2000 (median 9.4?months) as compared to those treated before the year 2000 (median 5.1?months, p?=?0.04). This improvement appeared to be related to an increased use of surgery or radiosurgery (SRS) and decreasing numbers of patients with uncontrolled primary tumor. Irrespective of management approach, survival beyond 5?years was uncommon (actuarial rate 6?%; 17?% in patients treated with upfront surgery or SRS). In conclusion, more intense multidisciplinary approaches aiming at control both in the brain, extracranial metastatic sites, and primary tumor site might have contributed to gradual survival improvements in recent years. Nevertheless, further efforts are necessary to improve long-term survival.     

Prognosis of non-small cell lung cancer with synchronous brain metastases treated with gamma knife radiosurgery

The clinical outcome and prognostic factors of patients with synchronous brain metastases from non-small cell lung cancer (NSCLC) who were treated with gamma knife radiosurgery (GKS) were analyzed. A total of 35 patients with NSCLC underwent GKS as an initial treatment for metastatic brain lesions of synchronous onset. The period of survival and various prognostic factors such as age, gender, performance status, multiplicity of the brain lesions, intracranial tumor volume, and extent of the primary tumor were analyzed. The overall median survival time for this series was 12 months (range 0.75 to 43 months) from the diagnosis. Of the 21 patients who were no longer alive at the conclusion of this study, only 7 (33.3%) died of neurological causes. Multivariate analysis of these data revealed that N stage, whole-brain radiotherapy (WBRT), and chemotherapy were significant predictors for survival (p<0.05). Survival of patients with NSCLC and synchronous brain metastases is mainly dependent upon the progression of the systemic disease, provided that the cerebral lesions are treated adequately with local treatment modalities including radiosurgery. Application of radiosurgery as an initial treatment option and aggressive local and systemic modalities to control extracranial disease may improve survival.     

Treatment of multiple brain metastases with a divide-and-conquer spatial fractionation radiosurgery approach

Brain metastases are a common problem, managed with surgery, stereotactic radiosurgery (SRS), whole brain irradiation (WBI), or a combination. SRS targets individual tumors with large dosages of radiation. There is a trend toward using more SRS and less WBI, due to a reduction in cognitive damage, shorter treatment course, and improved tumor control. In conventional radiation a total dose of radiation is frequently divided over time into several smaller “fractions”, which helps spare normal tissues such as the brain. Two doses of 10 Gy each given on separate days will result in 45% less damage to normal brain tissue than a single dose of 20 Gy, according to the linear quadratic model for biologically effective dose (BED). Unfortunately, standard fractionation also reduces the effective dose to the tumor. It would therefore be highly beneficial to be able to fractionate the dose to the normal brain, but not fractionate the tumor dose. When a tumor is irradiated, there are dozens of beams that pass through the skull and converge on the tumor, also irradiating healthy brain tissue in the beam paths. If multiple tumors are irradiated, there are areas of brain that are overlapped by beams that are targeting separate tumors. If these tumors were treated on separate days, then on any given day portions of normal brain may only see the radiation beams for one tumor instead of 2 or more. That is how spatial fractionation of multiple metastases works. By treating groups of tumors on separate days the beams are spread out over time, reducing areas of beam overlap, and effectively fractionating the dose to healthy brain. Yet, each tumor still receives a single treatment. The hypothesis is that an array of metastases may be divided into 2–5 different groups that are treated on different days such that the BED to normal brain tissue is minimized. This should benefit patients by reducing side effects, allowing greater numbers of tumors to be treated, and making retreatment safer. An algorithm is discussed, which places the largest tumors and tumors situated close together into different groups. Modifications for axial beam delivery systems such as helical tomotherapy are discussed.     

Treatment of brain oligometastases with hypofractionated stereotactic radiotherapy utilising volumetric modulated arc therapy

Stereotactic radiosurgery (SRS) is commonly used to treat brain metastases, particularly in the oligometastatic setting. This study analyses our initial experience in treating oligometastatic brain disease using Volumetric Modulated Arc Therapy (VMAT) to deliver hypofractionated stereotactic radiotherapy (HFSRT). Sixty-one patients were treated with HFSRT with a median dose of 24 Gy (range 22–40 Gy) in a median of three fractions (range 2–10 fractions). With a median follow-up of 23 months, the local control rate was 74 % for the entire cohort. Local control was 87 % for patients who had surgery with no radiological evidence of residual disease followed by HFSRT compared with 69 % in patients treated with HFSRT alone. The overall median time post radiotherapy to local failure was 8.6 months and to extracranial failure was 7.9 months. The mean time to distant brain failure was 9.9 months. Twenty-two patients (36 %) died during the study with median time to death of 4.4 months. Median overall survival (OS) from treatment was 21 months and 12 month OS was 60 %. Our experience with HFSRT using VMAT for oligometastatic brain metastases in the post-operative setting demonstrates comparable local control and survival rates compared with international published data. In the intact brain metastasis setting, local control using the dose levels and delivery in this cohort may be inferior to radio-surgical series. Local control is independent of histology. Careful selection of patients remains critical.     

Single‐fraction versus hypofractionated gamma knife radiosurgery for small metastatic brain tumors

Clinical & Experimental Metastasis - Stereotactic radiosurgery (SRS) has become a standard of care for the treatment of metastatic brain tumors (METs). Although a better balance of tumor...     

Anniversary Paper: the role of medical physicists in developing stereotactic radiosurgery

This article is a tribute to the pioneering medical physicists over the last 50 years who have participated in the research, development, and commercialization of stereotactic radiosurgery (SRS) and stereotactic radiotherapy utilizing a wide range of technology. The authors have described the evolution of SRS through the eyes of physicists from its beginnings with the Gamma Knife in 1951 to proton and charged particle therapy; modification of commercial linacs to accommodate high precision SRS setups; the multitude of accessories that have enabled fine tuning patients for relocalization, immobilization, and repositioning with submillimeter accuracy; and finally the emerging technology of SBRT. A major theme of the article is the expanding role of the medical physicist from that of advisor to the neurosurgeon to the current role as a primary driver of new technology that has already led to an adaptation of cranial SRS to other sites in the body, including, spine, liver, and lung. SRS continues to be at the forefront of the impetus to provide technological precision for radiation therapy and has demonstrated a host of downstream benefits in improving delivery strategies for conventional therapy as well. While this is not intended to be a comprehensive history, and the authors could not delineate every contribution by all of those working in the pursuit of SRS development, including physicians, engineers, radiobiologists, and the rest of the therapy and dosimetry staff in this important and dynamic radiation therapy modality, it is clear that physicists have had a substantial role in the development of SRS and theyincreasingly play a leading role in furthering SRS technology.     

Spine radiosurgery for the local treatment of spine metastases: Intensity-modulated radiotherapy,image guidance,clinical aspects and future directions

Many cancer patients will develop spinal metastases. Local control is important for preventing neurologic compromise and to relieve pain. Stereotactic body radiotherapy or spinal radiosurgery is a new radiation therapy technique for spinal metastasis that can deliver a high dose of radiation to a tumor while minimizing the radiation delivered to healthy, neighboring tissues. This treatment is based on intensity-modulated radiotherapy, image guidance and rigid immobilization. Spinal radiosurgery is an increasingly utilized treatment method that improves local control and pain relief after delivering ablative doses of radiation. Here, we present a review highlighting the use of spinal radiosurgery for the treatment of metastatic tumors of the spine. The data used in the review were collected from both published studies and ongoing trials. We found that spinal radiosurgery is safe and provides excellent tumor control (up to 94% local control) and pain relief (up to 96%), independent of histology. Extensive data regarding clinical outcomes are available; however, this information has primarily been generated from retrospective and nonrandomized prospective series. Currently, two randomized trials are enrolling patients to study clinical applications of fractionation schedules spinal Radiosurgery. Additionally, a phase I clinical trial is being conducted to assess the safety of concurrent stereotactic body radiotherapy and ipilimumab for spinal metastases. Clinical trials to refine clinical indications and dose fractionation are ongoing. The concomitant use of targeted agents may produce better outcomes in the future.     

D2SRS两种照射技术与CyberKnife在脑转移瘤立体定向放疗中的剂量学研究

目的:分析基于常规加速器的微光刀（D2SRS）系统两种照射技术在脑转移瘤放疗中的剂量学特性,并与射波刀（CyberKnife, CK）进行比较,探讨D2SRS在脑转移瘤立体定向放疗的可行性。方法:选取30例已行CK治疗的脑转移瘤病例,分别设计动态调强（DMLC-IMRT）和动态适形拉弧（DCA）两种D2SRS计划,分析其剂量学特性并与CK计划进行比较。结果:3种计划均能实现处方剂量要求,CK计划具有较好的靶区适形度指数（CI, CI=0.82±0.04）,但剂量均匀性指数（HI, HI=0.42±0.11）最差。DMLC-IMRT计划具有与CK计划相当的靶区CI（0.80±0.07, P=0.24）,且具有更好的HI（0.28±0.13, P=0.00）;DCA计划CI（0.69±0.09）最低,但其HI（0.33±0.11）优于CK计划。靶区外剂量跌落方面CK计划更具优势,但相较于DCA计划无统计学意义（P=0.06）;在实施时间上,DMLC-IMRT计划［（16.94±1.50） min］与DCA计划［（12.67±0.52） min］相较于CK计划［（38.76±5.60） min］具有明显优势。结论:3种技术均能实现处方剂量要求且CK计划具有更好的靶区适形度,靶区外剂量跌落方面DCA计划优于DMLC-IMRT计划且接近CK计划水平,但在实施效率上两种D2SRS计划具有明显优势,能够在脑转移瘤放疗中更为高效地实现对肿瘤靶区的均匀照射,具有一定的临床应用价值。     

The treatment of primary and metastatic renal cell carcinoma (RCC) with image-guided stereotactic body radiation therapy (SBRT)

Purpose:

Brain metastases from renal cell carcinoma (RCC) have been successfully treated with stereotactic radiosurgery (SRS). Metastases to extra-cranial sites may be treated with similar success using stereotactic body radiation therapy (SBRT), where image-guidance allows for the delivery of precise high-dose radiation in a few fractions. This paper reports the authors’ initial experience with image-guided SBRT in treating primary and metastatic RCC.

Materials and methods:

The image-guided Brainlab Novalis stereotactic system was used. Fourteen patients with 23 extra-cranial metastatic RCC lesions (orbits, head and neck, lung, mediastinum, sternum, clavicle, scapula, humerus, rib, spine and abdominal wall) and two patients with biopsy-proven primary RCC (not surgical candidates) were treated with SBRT (24-40 Gy in 3-6 fractions over 1-2 weeks). All patients were immobilised in body cast or head and neck mask. Image-guidance was used for all fractions. PET/CT images were fused with simulation CT images to assist in target delineation and dose determination. SMART (simultaneous modulated accelerated radiation therapy) boost approach was adopted. 4D-CT was utilised to assess tumour/organ motion and assist in determining planning target volume margins.

Results:

Median follow-up was nine months. Thirteen patients (93%) who received SBRT to extra-cranial metastases achieved symptomatic relief. Two patients had local progression, yielding a local control rate of 87%. In the two patients with primary RCC, tumour size remained unchanged but their pain improved, and their renal function was unchanged post SBRT. There were no significant treatment-related side effects.

Conclusion:

Image-guided SBRT provides excellent symptom palliation and local control without any significant toxicity. SBRT may represent a novel, non-invasive, nephron-sparing option for the treatment of primary RCC as well as extra-cranial metastatic RCC.     

Efficacy of Surgical Treatment for Brain Metastasis in Patients with Non-Small Cell Lung Cancer

Purpose

Patients with non-small cell lung cancer (NSCLC) and simultaneously having brain metastases at the initial diagnosis, presenting symptoms related brain metastasis, survived shorter duration and showed poor quality of life. We analyzed our experiences on surgical treatment of brain metastasis in patients with NSCLC.

Materials and Methods

We performed a single-center, retrospective review of 36 patients with NSCLC and synchronous brain metastases between April 2006 and December 2011. Patients were categorized according to the presence of neurological symptoms and having a brain surgery. As a result, 14 patients did not show neurological symptoms and 22 patients presented neurological symptoms. Symptomatic 22 patients were divided into two groups according to undergoing brain surgery (neurosurgery group; n=11, non-neurosurgery group; n=11). We analyzed overall surgery (OS), intracranial progression-free survival (PFS), and quality of life.

Results

Survival analysis showed there was no difference between patients with neurosurgery (OS, 12.1 months) and non-neurosurgery (OS, 10.2 months; p=0.550). Likewise for intracranial PFS, there was no significant difference between patients with neurosurgery (PFS, 6.3 months) and non-neurosurgery (PFS, 5.3 months; p=0.666). Reliable neurological one month follow up by the Medical Research Council neurological function evaluation scale were performed in symptomatic 22 patients. The scale improved in eight (73%) patients in the neurosurgery group, but only in three (27%) patients in the non-neurosurgery group (p=0.0495).

Conclusion

Patients with NSCLC and synchronous brain metastases, presenting neurological symptoms showed no survival benefit from neurosurgical resection, although quality of life was improved due to early control of neurological symptoms.     

A helium-ion beam for stereotactic radiosurgery of central nervous system disorders

A new radiation beamline configuration for stereotactic heavy-ion Bragg peak radiosurgery of patients with intracranial deep arteriovenous malformations, including carotid-cavernous fistulas, has been developed using the 230 MeV/u helium ion beam at the 184-in. Synchrocyclotron at the University of California, Berkeley. The modified beam has five characteristics: uniform field between 10 and 40 mm in diameter; variable depth of penetration between 40 and 140 mm; stopping region for primary ions that can be broadened up to 40 mm; sharply defined lateral and distal borders; and dose rate greater than 2 Gy/min. It is adapted to the ISAH (irradiation stereotactic apparatus for humans) at the 184-in. Synchrocyclotron, with effective stereotactic localization of defined volumes within the brain, and is designed to reach all intracranial targets. It has proven suitable for all patients with intracranial vascular disorders treated with stereotactic radiosurgery at our laboratory.     

PD-L1 blockade exhibits anti-tumor effect on brain metastasis by activating CD8+ T cells in hematogenous metastasis model with lymphocyte infusion

Brain metastases are common complication in cancer patients. Immune checkpoint inhibitors show therapeutic benefits also in patients with central nervous system (CNS) metastases. However, their antitumor effects on metastatic tumors and their underlying mechanisms are still poorly understood. In this study we investigated the antitumor effect of anti-programmed death-ligand 1 (PD-L1) antibody on metastatic brain tumors and evaluated immune responses during treatment. We employed a hematogenous brain metastasis xenograft model using immunodeficient mice with murine lymphocyte infusions. A human non-small-cell lung cancer (NSCLC) cell line stably expressing NanoLuc^® reporter (Nluc-H1915) was inoculated from the internal carotid artery of SCID mice. After metastases were established (24 days after inoculation), splenocytes prepared from H1915-immunized BALB/c mice were injected intravenously and mouse IgG or anti-PD-L1 antibody treatment was started (day 1). Evaluated by Nluc activity, tumor volume in the brain on day 14 was significantly lower in anti-PD-L1-treated mice than in mouse IgG-treated mice. Furthermore CD8⁺ cells were primarily infiltrated intratumorally and peritumorally and anti-PD-L1 treatment induced a significantly higher proportion of Granzyme B (GzmB)⁺ cells among CD8⁺ T cells. The antitumor effect of anti-PD-L1 antibody on brain metastasis is thought to be achieved by the enhanced activation of infiltrated CD8⁺ T cells into metastatic brain tumor. These results suggest that anti-PD-L1 antibody-containing regimens may be promising treatment options for cancer patients with brain metastases.

     

Is maternal duplication of 11p15 associated with Silver-Russell syndrome?

Background: Silver-Russell syndrome (SRS) is a heterogeneous malformation syndrome characterised by intrauterine and postnatal growth retardation (IUGR, PGR) and dysmorphisms. The basic causes are unknown, however in approximately 10% of patients a maternal uniparental disomy (UPD) of chromosome 7 or chromosomal aberrations can be detected. Four growth retarded children, two with SRS-like features, associated with maternal duplications of 11p15 have been described. Considering the involvement of this genomic region in Beckwith-Wiedemann overgrowth syndrome (BWS), we postulated that some cases of SRS—with an opposite phenotype to BWS—might also be caused by genomic disturbances in 11p15.

Methods: A total of 46 SRS patients were screened for genomic rearrangements in 11p15 by STR typing and FISH analysis.

Results: Two SRS patients with duplications of maternal 11p material in our study population (n = 46) were detected. In patient SR46, the duplicated region covered at least 9 Mb; FISH analysis revealed a translocation of 11p15 onto 10q. In patient SR90, additional 11p15 material (approximately 5 Mb) was translocated to the short arm of chromosome 15.

Conclusions: We suggest that diagnostic testing for duplication in 11p15 should be offered to patients with severe IUGR and PGR with clinical signs reminiscent of SRS. SRS is a genetically heterogeneous condition and patients with a maternal duplication of 11p15.5 may form an important subgroup.

     

BSREM for Brain Metastasis Detection with 18F-FDG-PET/CT in Lung Cancer Patients

The aim of the study was to analyze the use of block sequential regularized expectation maximization (BSREM) with different β-values for the detection of brain metastases in digital fluorine-18 labeled 2-deoxy-2-fluoro-D-glucose (18F-FDG) PET/CT in lung cancer patients. We retrospectively analyzed staging/restaging 18F-FDG PET/CT scans of 40 consecutive lung cancer patients with new brain metastases, confirmed by MRI. PET images were reconstructed using BSREM (β-values of 100, 200, 300, 400, 500, 600, 700) and OSEM. Two independent blinded readers (R1 and R2) evaluated each reconstruction using a 4-point scale for general image quality, noise, and lesion detectability. SUVmax of metastases, brain background, target-to-background ratio (TBR), and contrast recovery (CR) ratio were recorded for each reconstruction. Among all reconstruction techniques, differences in qualitative parameters were analyzed using non-parametric Friedman test, while differences in quantitative parameters were compared using analysis of variances for repeated measures. Cohen’s kappa (k) was used to measure inter-reader agreement. The overall detectability of brain metastases was highest for BSREM200 (R1: 2.83 ± 1.17; R2: 2.68 ± 1.32) and BSREM300 (R1: 2.78 ± 1.23; R2: 2.68 ± 1.36), followed by BSREM100, which had lower accuracy owing to noise. The highest median TBR was found for BSREM100 (R1: 2.19 ± 1.05; R2: 2.42 ± 1.08), followed by BSREM200 and BSREM300. Image quality ratings were significantly different among reconstructions (p < 0.001). The median quality score was higher for BSREM100-300, and both noise and metastases’ SUVmax decreased with increasing β-value. Inter-reader agreement was particularly high for the detectability of photopenic metastases and blurring (all k > 0.65). BSREM200 and BSREM300 yielded the best results for the detection of brain metastases, surpassing both BSREM400 and OSEM, typically used in clinical practice.

     

Electrical activity and feeding correlates of intracranial hypothalamic injection of GABA, muscimol and picrotoxin in the rats

Assemblies of electrodes and a cannula were stereotaxically implanted in the ventromedial (VMH), lateral (LHA) and paraventricular (PVH) hypothalamic areas in male albino rats. Electrical activity of these regions was recorded electrographically before and following intracranial injection (ICI) of GABA, muscimol and picrotoxin. In another set of animals, food intake and water intake were also measured. The activity of the ventromedial hypothalamus changed from slow to fast after ICI of GABA and picrotoxin and fast to slow after muscimol. The activity of the lateral hypothalamus changed from slow to fast with ICI of muscimol and picrotoxin and from fast to slow with GABA, while that of the paraventricular hypothalamic nucleus changed from slow to fast with ICI GABA and fast to slow with muscimol and picrotoxin. ICI of GABA into VMH and LHA and muscimol in VMH, LHA and PVH caused a decrease in food intake. Water intake was also decreased after ICI of GABA in PVH and muscimol in LHA and PVH. On the opposite picrotoxin increased food intake in VMA and LHA and water intake in PVH. The possible interaction of GABAergic drugs with the areas of the brain controlling feeding and drinking is being discussed.     

Brain metastases as site of first and isolated recurrence of breast cancer: the role of systemic therapy after local treatment

The role of systemic treatment was assessed after local therapy for breast cancer patients who developed central nervous system (CNS) metastases as a first and isolated recurrence. Subjects were 128 breast cancer patients with brain metastases as the first and isolated site of recurrence that were selected from 673 consecutive breast cancer patients with brain metastases treated at the same institution. Median survival from brain metastases in patients with and without systemic treatment after local therapy was respectively 15 and 4 months (p < 0.001). In patients with a Karnofsky Performance Status ≥70 and those <70, survival was respectively 16 and 5.5 months (p < 0.001). The median survival from brain metastasis in patients with solitary brain metastasis, with and without systemic treatment after local therapy, was respectively 22 and 7 months (p = 0.003). Cox multivariate analysis demonstrated that good performance status, solitary brain metastasis and systemic therapy undertaken after local treatment were factors which prolonged survival. However patient survival was adversely affected by those having leptomeningeal metastasis associated with brain parenchymal lesions. Systemic therapy, undertaken after local treatment improved survival in those patients with breast cancer and brain metastases as the site of first and isolated recurrence. Further study is required in order to fully establish the role of systemic treatment for this patient group.